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  • 1.
    Alexander, Helen K.
    et al.
    Cancer Care Manitoba, Manitoba Institute of Cell Biology, University of Manitoba.
    Booy, Evan P.
    Cancer Care Manitoba, Manitoba Institute of Cell Biology, University of Manitoba; Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Canada .
    Xiao, Wenyan
    Cancer Care Manitoba, Manitoba Institute of Cell Biology, University of Manitoba.
    Ezzati, Peyman
    Cancer Care Manitoba, Manitoba Institute of Cell Biology, University of Manitoba.
    Baust, Heinrich
    Department of Radiooncology, University of Erlangen, Erlangen, Germany .
    Los, Marek Jan
    Manitoba Institute of Cell Biology, Cancer Care Manitoba; Manitoba Institute of Child Health; Department of Biochemistry and Medical Genetics; Department of Human Anatomy and Cell Science, University Manitoba, Winnipeg, Canada, .
    Selected technologies to control genes and their products for experimental and clinical purposes2007In: Archivum Immunologiae et Therapiae Experimentalis, ISSN 0004-069X, E-ISSN 1661-4917, Vol. 55, no 3, 139-149 p.Article in journal (Refereed)
    Abstract [en]

    "On-demand" regulation of gene expression is a powerful tool to elucidate the functions of proteins and biologically-active RNAs. We describe here three different approaches to the regulation of expression or activity of genes or proteins. Promoter-based regulation of gene expression was among the most rapidly developing techniques in the 1980s and 1990s. Here we provide basic information and also some characteristics of the metallothionein-promoter-based system, the tet-off system, Muristerone-A-regulated expression through the ecdysone response element, RheoSwitch (R), coumermycin/novobiocin-regulated gene expression, chemical dimerizer-based promoter activation systems, the "Dual Drug Control" system, "constitutive androstane receptor"-based regulation of gene expression, and RU486/mifepristone-driven regulation of promoter activity. A large part of the review concentrates on the principles and usage of various RNA interference techniques (RNAi: siRNA, shRNA, and miRNA-based methods). Finally, the last part of the review deals with historically the oldest, but still widely used, methods of temperature-dependent regulation of enzymatic activity or protein stability (temperature-sensitive mutants). Due to space limitations we do not describe in detail but just mention the tet-regulated systems and also fusion-protein-based regulation of protein activity, such as estrogen-receptor fusion proteins. The information provided below is aimed to assist researchers in choosing the most appropriate method for the planned development of experimental systems with regulated expression or activity of studied proteins.

  • 2.
    Auffray, Charles
    et al.
    European Institute Syst Biol and Med, France; University of Lyon, France.
    Balling, Rudi
    University of Luxembourg, Luxembourg.
    Barroso, Ines
    Wellcome Trust Sanger Institute, England.
    Bencze, Laszlo
    Semmelweis University, Hungary.
    Benson, Mikael
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Allergy Center.
    Bergeron, Jay
    Pfizer Inc, MA 02139 USA.
    Bernal-Delgado, Enrique
    IACS IIS Aragon, Spain.
    Blomberg, Niklas
    EL IXIR, England.
    Bock, Christoph
    Austrian Academic Science, Austria; Medical University of Vienna, Austria; Max Planck Institute Informat, Germany.
    Conesa, Ana
    Principe Felipe Research Centre, Spain; University of Florida, FL 32610 USA.
    Del Signore, Susanna
    Bluecompan Ltd, England.
    Delogne, Christophe
    KPMG Luxembourg, Luxembourg.
    Devilee, Peter
    Leiden University, Netherlands.
    Di Meglio, Alberto
    European Org Nucl Research CERN, Switzerland.
    Eijkemans, Marinus
    University of Utrecht, Netherlands.
    Flicek, Paul
    European Bioinformat Institute EMBL EBI, England.
    Graf, Norbert
    University of Saarland, Germany.
    Grimm, Vera
    Forschungszentrum Julich, Germany.
    Guchelaar, Henk-Jan
    Leiden University, Netherlands.
    Guo, Yi-Ke
    University of London Imperial Coll Science Technology and Med, England.
    Glynne Gut, Ivo
    BIST, Spain.
    Hanbury, Allan
    TU Wien, Austria.
    Hanif, Shahid
    Assoc British Pharmaceut Ind, England.
    Hilgers, Ralf-Dieter
    University of Klinikum Aachen, Germany.
    Honrado, Angel
    SYNAPSE Research Management Partners, Spain.
    Rod Hose, D.
    University of Sheffield, England.
    Houwing-Duistermaat, Jeanine
    University of Leeds, England.
    Hubbard, Tim
    Kings Coll London, England; Genom England, England.
    Helen Janacek, Sophie
    European Bioinformat Institute EMBL EBI, England.
    Karanikas, Haralampos
    University of Athens, Greece.
    Kievits, Tim
    Vitr Healthcare Holding BV, Netherlands.
    Kohler, Manfred
    Fraunhofer Institute Molecular Biol and Appl Ecol ScreeningPor, Germany.
    Kremer, Andreas
    ITTM SA, Luxembourg.
    Lanfear, Jerry
    Pfizer Ltd, England.
    Lengauer, Thomas
    Max Planck Institute for Informatics, Saarbrucken, Germany.
    Maes, Edith
    Health Econ and Outcomes Research, Belgium.
    Meert, Theo
    Janssen Pharmaceut NV, Belgium.
    Mueller, Werner
    University of Manchester, England.
    Nickel, Dorthe
    Institute Curie, France.
    Oledzki, Peter
    Linguamat Ltd, England.
    Pedersen, Bertrand
    PwC Luxembourg, Luxembourg.
    Petkovic, Milan
    Philips, Netherlands.
    Pliakos, Konstantinos
    KU Leuven Kulak, Belgium.
    Rattray, Magnus
    University of Manchester, England.
    Redon i Mas, Josep
    University of Valencia, Spain.
    Schneider, Reinhard
    University of Luxembourg, Luxembourg.
    Sengstag, Thierry
    SIB, Switzerland; University of Basel, Switzerland.
    Serra-Picamal, Xavier
    Agency Health Qual and Assessment Catalonia AQuAS, Spain.
    Spek, Wouter
    EuroBioForum Fdn, Netherlands.
    Vaas, Lea A. I.
    Fraunhofer Institute Molecular Biol and Appl Ecol ScreeningPor, Germany.
    van Batenburg, Okker
    EuroBioForum Fdn, Netherlands.
    Vandelaer, Marc
    Integrated BioBank Luxembourg, Luxembourg.
    Varnai, Peter
    Technopolis Grp, England.
    Villoslada, Pablo
    Hospital Clin Barcelona, Spain.
    Antonio Vizcaino, Juan
    European Bioinformat Institute EMBL EBI, England.
    Peter Mary Wubbe, John
    European Platform Patients Org Science and Ind Epposi, Belgium.
    Zanetti, Gianluigi
    CRS4, Italy; BBMRI ERIC, Austria.
    Making sense of big data in health research: Towards an EU action plan2016In: Genome Medicine, ISSN 1756-994X, E-ISSN 1756-994X, Vol. 8, no 71Article in journal (Refereed)
    Abstract [en]

    Medicine and healthcare are undergoing profound changes. Whole-genome sequencing and high-resolution imaging technologies are key drivers of this rapid and crucial transformation. Technological innovation combined with automation and miniaturization has triggered an explosion in data production that will soon reach exabyte proportions. How are we going to deal with this exponential increase in data production? The potential of "big data" for improving health is enormous but, at the same time, we face a wide range of challenges to overcome urgently. Europe is very proud of its cultural diversity; however, exploitation of the data made available through advances in genomic medicine, imaging, and a wide range of mobile health applications or connected devices is hampered by numerous historical, technical, legal, and political barriers. European health systems and databases are diverse and fragmented. There is a lack of harmonization of data formats, processing, analysis, and data transfer, which leads to incompatibilities and lost opportunities. Legal frameworks for data sharing are evolving. Clinicians, researchers, and citizens need improved methods, tools, and training to generate, analyze, and query data effectively. Addressing these barriers will contribute to creating the European Single Market for health, which will improve health arid healthcare for all Europearis.

  • 3.
    Barrenäs, Fredrik
    et al.
    The Unit for Clinical Systems Biology, University of Gothenburg, Gothenburg, Sweden.
    Chavali, Sreenivas
    The Unit for Clinical Systems Biology, University of Gothenburg, Gothenburg, Sweden.
    Holme, Petter
    Department of Physics, Umeå University, Umeå, Sweden; Department of Energy Science, Sungkyunkwan University, Suwon, Korea.
    Mobini, Reza
    The Unit for Clinical Systems Biology, University of Gothenburg, Gothenburg, Sweden.
    Benson, Mikael
    The Unit for Clinical Systems Biology, University of Gothenburg, Gothenburg, Sweden.
    Network properties of complex human disease genes identified through genome-wide association studies2009In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 4, no 11, e8090- p.Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Previous studies of network properties of human disease genes have mainly focused on monogenic diseases or cancers and have suffered from discovery bias. Here we investigated the network properties of complex disease genes identified by genome-wide association studies (GWAs), thereby eliminating discovery bias.

    PRINCIPAL FINDINGS: We derived a network of complex diseases (n = 54) and complex disease genes (n = 349) to explore the shared genetic architecture of complex diseases. We evaluated the centrality measures of complex disease genes in comparison with essential and monogenic disease genes in the human interactome. The complex disease network showed that diseases belonging to the same disease class do not always share common disease genes. A possible explanation could be that the variants with higher minor allele frequency and larger effect size identified using GWAs constitute disjoint parts of the allelic spectra of similar complex diseases. The complex disease gene network showed high modularity with the size of the largest component being smaller than expected from a randomized null-model. This is consistent with limited sharing of genes between diseases. Complex disease genes are less central than the essential and monogenic disease genes in the human interactome. Genes associated with the same disease, compared to genes associated with different diseases, more often tend to share a protein-protein interaction and a Gene Ontology Biological Process.

    CONCLUSIONS: This indicates that network neighbors of known disease genes form an important class of candidates for identifying novel genes for the same disease.

  • 4.
    Bausch, Birke
    et al.
    Albert Ludwigs University, Germany.
    Schiavi, Francesca
    Ist Ricovero and Cura Carattere Science, Italy.
    Ni, Ying
    Cleveland Clin, OH 44106 USA.
    Welander, Jenny
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Patocs, Attila
    Semmelweis University, Hungary; Semmelweis University, Hungary.
    Ngeow, Joanne
    National Cancer Centre Singapore, Singapore; Nanyang Technology University, Singapore.
    Wellner, Ulrich
    University of Lubeck, Germany.
    Malinoc, Angelica
    Albert Ludwigs University, Germany.
    Taschin, Elisa
    Ist Ricovero and Cura Carattere Science, Italy.
    Barbon, Giovanni
    Ist Ricovero and Cura Carattere Science, Italy.
    Lanza, Virginia
    Ist Ricovero and Cura Carattere Science, Italy.
    Söderkvist, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Stenman, Adam
    Karolinska Institute, Sweden.
    Larsson, Catharina
    Karolinska Institute, Sweden.
    Svahn, Fredrika
    Karolinska Institute, Sweden.
    Chen, Jin-Lian
    Cleveland Clin, OH 44106 USA.
    Marquard, Jessica
    Cleveland Clin, OH 44106 USA.
    Fraenkel, Merav
    Hadassah Hebrew University, Israel.
    Walter, Martin A.
    University Hospital, Switzerland.
    Peczkowska, Mariola
    Institute Cardiol, Poland.
    Prejbisz, Aleksander
    Institute Cardiol, Poland.
    Jarzab, Barbara
    Maria Sklodowska Curie Mem Cancer Centre and Institute Oncol, Poland.
    Hasse-Lazar, Kornelia
    Maria Sklodowska Curie Mem Cancer Centre and Institute Oncol, Poland.
    Petersenn, Stephan
    Centre Endocrine Tumors, Germany.
    Moeller, Lars C.
    University of Duisburg Essen, Germany.
    Meyer, Almuth
    HELIOS Klin, Germany.
    Reisch, Nicole
    Ludwigs Maximilians University of Munich, Germany.
    Trupka, Arnold
    City Hospital, Germany.
    Brase, Christoph
    University of Erlangen Nurnberg, Germany.
    Galiano, Matthias
    University Hospital Erlangen, Germany.
    Preuss, Simon F.
    University of Cologne, Germany.
    Kwok, Pingling
    University of Regensburg, Germany.
    Lendvai, Nikoletta
    Semmelweis University, Hungary.
    Berisha, Gani
    Albert Ludwigs University, Germany.
    Makay, Ozer
    Ege University, Turkey.
    Boedeker, Carsten C.
    HELIOS Hanseklinikum Stralsund, Germany.
    Weryha, Georges
    University of Nancy, France.
    Racz, Karoly
    Semmelweis University, Hungary.
    Januszewicz, Andrzej
    Institute Cardiol, Poland.
    Walz, Martin K.
    Kliniken Essen Mitte, Germany; Kliniken Essen Mitte, Germany.
    Gimm, Oliver
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Linköping.
    Opocher, Giuseppe
    Ist Ricovero and Cura Carattere Science, Italy.
    Eng, Charis
    Cleveland Clin, OH 44106 USA; Cleveland Clin, OH 44106 USA.
    Neumann, Hartmut P. H.
    Albert Ludwigs University, Germany.
    Clinical Characterization of the Pheochromocytoma and Paraganglioma Susceptibility Genes SDHA, TMEM127, MAX, and SDHAF2 for Gene-Informed Prevention2017In: JAMA Oncology, ISSN 2374-2437, E-ISSN 2374-2445, Vol. 3, no 9, 1204-1212 p.Article in journal (Refereed)
    Abstract [en]

    IMPORTANCE Effective cancer prevention is based on accurate molecular diagnosis and results of genetic family screening, genotype-informed risk assessment, and tailored strategies for early diagnosis. The expanding etiology for hereditary pheochromocytomas and paragangliomas has recently included SDHA, TMEM127, MAX, and SDHAF2 as susceptibility genes. Clinical management guidelines for patients with germline mutations in these 4 newly included genes are lacking. OBJECTIVE To study the clinical spectra and age-related penetrance of individuals with mutations in the SDHA, TMEM127, MAX, and SDHAF2 genes. DESIGN, SETTING, AND PATIENTS This study analyzed the prospective, longitudinally followed up European-American-Asian Pheochromocytoma-Paraganglioma Registry for prevalence of SDHA, TMEM127, MAX, and SDHAF2 germline mutation carriers from 1993 to 2016. Genetic predictive testing and clinical investigation by imaging from neck to pelvis was offered to mutation-positive registrants and their relatives to clinically characterize the pheochromocytoma/paraganglioma diseases associated with mutations of the 4 new genes. MAIN OUTCOMES AND MEASURES Prevalence and spectra of germline mutations in the SDHA, TMEM127, MAX, and SDHAF2 genes were assessed. The clinical features of SDHA, TMEM127, MAX, and SDHAF2 disease were characterized. RESULTS Of 972 unrelated registrants without mutations in the classic pheochromocytoma- and paraganglioma-associated genes (632 female [65.0%] and 340 male [35.0%]; age range, 8-80; mean [SD] age, 41.0 [13.3] years), 58 (6.0%) carried germline mutations of interest, including 29 SDHA, 20 TMEM127, 8 MAX, and 1 SDHAF2. Fifty-three of 58 patients (91%) had familial, multiple, extra-adrenal, and/or malignant tumors and/or were younger than 40 years. Newly uncovered are 7 of 63 (11%) malignant pheochromocytomas and paragangliomas in SDHA and TMEM127 disease. SDHA disease occurred as early as 8 years of age. Extra-adrenal tumors occurred in 28 mutation carriers (48%) and in 23 of 29 SDHA mutation carriers (79%), particularly with head and neck paraganglioma. MAX disease occurred almost exclusively in the adrenal glands with frequently bilateral tumors. Penetrance in the largest subset, SDHA carriers, was 39% at 40 years of age and is statistically different in index patients (45%) vs mutation-carrying relatives (13%; P amp;lt; .001). CONCLUSIONS AND RELEVANCE The SDHA, TMEM127, MAX, and SDHAF2 genes may contribute to hereditary pheochromocytoma and paraganglioma. Genetic testing is recommended in patients at clinically high risk if the classic genes are mutation negative. Gene-specific prevention and/or early detection requires regular, systematic whole-body investigation.

  • 5.
    Beck, Dominik
    et al.
    Bioengineering and Bioinformatics Program, The Methodist Hospital Research Institute, Weill Cornell Medical College, USA//The University of New South Wales, Canberra, ACT, 2600, Australia..
    Ayers, Steve
    Department of Pathology, The Methodist Hospital and The Methodist.
    Wen, Jianguo
    The Methodist Hospital and The Methodist Hospital Research Institute, Weill Cornell Medical College, Houston, TX, USA.
    Brandl, Miriam B
    Bioengineering and Bioinformatics Program, The Methodist Hospital Research Institute, Weill Cornell Medical College, USA//The University of New South Wales, Canberra, ACT, 2600, Australia..
    Pham, Tuan D
    Bioengineering and Bioinformatics Program, The Methodist Hospital Research Institute, Weill Cornell Medical College.
    Webb, Paul
    The Methodist Hospital Research Institute and Department of Radiology, Weill Cornell Medical College, Houston, TX, 77030, USA..
    Chang, Chung-Che
    The Methodist Hospital and The Methodist Hospital Research Institute, Weill Cornell Medical College, Houston, TX, USA.
    Zhou, Xiaobo
    Bioengineering and Bioinformatics Program, The Methodist Hospital Research Institute, Weill Cornell Medical College, USA.
    Integrative analysis of next generation sequencing for small non-coding RNAs and transcriptional regulation in Myelodysplastic Syndromes2011In: BMC Medical Genomics, ISSN 1755-8794, E-ISSN 1755-8794, Vol. 4, no 19, 1-16 p.Article in journal (Refereed)
    Abstract [en]

    Background

    Myelodysplastic Syndromes (MDSS) are pre-leukemic disorders with increasing incident rates worldwide, but very limited treatment options. Little is known about small regulatory RNAs and how they contribute to pathogenesis, progression and transcriptome changes in MDS.

    Methods

    Patients' primary marrow cells were screened for short RNAs (RNA-seq) using next generation sequencing. Exon arrays from the same cells were used to profile gene expression and additional measures on 98 patients obtained. Integrative bioinformatics algorithms were proposed, and pathway and ontology analysis performed.

    Results

    In low-grade MDS, observations implied extensive post-transcriptional regulation via microRNAs (miRNA) and the recently discovered Piwi interacting RNAs (piRNA). Large expression differences were found for MDS-associated and novel miRNAs, including 48 sequences matching to miRNA star (miRNA*) motifs. The detected species were predicted to regulate disease stage specific molecular functions and pathways, including apoptosis and response to DNA damage. In high-grade MDS, results suggested extensive post-translation editing via transfer RNAs (tRNAs), providing a potential link for reduced apoptosis, a hallmark for this disease stage. Bioinformatics analysis confirmed important regulatory roles for MDS linked miRNAs and TFs, and strengthened the biological significance of miRNA*. The "RNA polymerase II promoters" were identified as the tightest controlled biological function. We suggest their control by a miRNA dominated feedback loop, which might be linked to the dramatically different miRNA amounts seen between low and high-grade MDS.

    Discussion

    The presented results provide novel findings that build a basis of further investigations of diagnostic biomarkers, targeted therapies and studies on MDS pathogenesis.

  • 6.
    Bivik, Caroline
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Developmental Biology. Linköping University, Faculty of Health Sciences.
    Ulvklo, Carina
    Linköping University, Department of Clinical and Experimental Medicine, Developmental Biology. Linköping University, Faculty of Health Sciences.
    Lundin, Erika
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Nilsson, Patrik
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Angel, Anna
    Linköping University, Department of Clinical and Experimental Medicine, Developmental Biology. Linköping University, Faculty of Health Sciences.
    Thor, Stefan
    Linköping University, Department of Clinical and Experimental Medicine, Developmental Biology. Linköping University, Faculty of Health Sciences.
    A genetic screen for genes controlling Apterous neuron identity and FMRFamide expression2010In: Journal of neurogenetics, ISSN 0167-7063, Vol. 24, no Suppl. 1, 70-71 p.Article in journal (Other academic)
    Abstract [en]

    n/a

  • 7.
    Borga, Magnus
    et al.
    Linköping University, Center for Medical Image Science and Visualization (CMIV). Linköping University, Department of Biomedical Engineering, Medical Informatics. Linköping University, The Institute of Technology.
    Virtanen, Kirsi A.
    Turku PET Centre, University of Turku, Finland.
    Romu, Thobias
    Linköping University, Center for Medical Image Science and Visualization (CMIV). Linköping University, Department of Biomedical Engineering, Medical Informatics. Linköping University, The Institute of Technology.
    Dahlqvist Leinhard, Olof
    Linköping University, Center for Medical Image Science and Visualization (CMIV). Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Radiation Physics.
    Persson, Anders
    Linköping University, Center for Medical Image Science and Visualization (CMIV). Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Radiology in Linköping.
    Nuutila, Pirjo
    Turku PET Centre, University of Turku, Finland.
    Enerbäck, Sven
    Department of Biomedicine, University of Gothenburg, Sweden.
    Brown adipose tissue in humans: detection and functional analysis using PET (Positron Emission Tomography), MRI (Magnetic Resonance Imaging), and DECT (Dual Energy Computed Tomography)2014In: Methods in Enzymology: Methods of Adipose Tissue Biology / [ed] Ormond MacDougald, Elsevier, 2014, 1, 141-159 p.Chapter in book (Other academic)
    Abstract [en]

    Research with the aim to translate findings of the beneficial effects induced by brown adipose tissue (BAT) on metabolism, as seen in various non-human experimental systems to also include human metabolism requires tools that accurately measure how BAT influences human metabolism. This review sets out to discuss such techniques, how they can be used, what they can measure and also some of their limitations. The focus is on detection and functional analysis of human BAT and how this can be facilitated by applying advanced imaging technology such as:  PET (Positron Emission Tomography), MRI (Magnetic Resonance Imaging), and DECT (Dual Energy Computed Tomography).

  • 8.
    Borgström, Annelie
    Linköping University, Department of Physics, Chemistry and Biology.
    Analysis of tumour infiltrating leukocytes in colon cancer carcinoma in a syngeneic rat model2010Independent thesis Advanced level (degree of Master (One Year)), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    Tumour immunity is a balance between immune mediators that promote tumor progression versus mediators that promote tumor rejection. Infiltrating lymphocytes in human colorectal cancer tissues are independent prognostic factors for a better survival and a high number of cytotoxic CD8+ T-cells have been associated with a better prognosis in terms of a longer and disease free survival for the patient. In our syngeneic rat model we induce colon carcinoma subperitoneally by injecting a colon cancer cell line BN7005, a cell line expressing the epitope (Lewis Y) for the BR96 antibody. Tumours are dissected out and treated with different fixatives and then either frozen, snap-frozen or embedded in paraffin followed by sectioning. Immunohistochemistry using monoclonal antibodies against the tumour infiltrating leukocytes was performed on the tissue.

    The results were seen as an infiltration of different leukocytes in the tumours.

     

  • 9.
    Bélteky, Johan
    Linköping University, Department of Physics, Chemistry and Biology, Biology. Linköping University, Faculty of Science & Engineering.
    Chicken domestication: Effects of tameness on brain gene expression and DNA methylation2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Domestication greatly increases phenotypic variation in a short time span, with selection for a single phenotype and a plethora of associated phenotypic changes as an outcome of the process. The domestication process influences the underlying genomic architecture of a species, and the success and speed of the process is likely influenced by it. The main aims of my thesis was to study how domestication affects the brain of chickens: specifically changes in morphology, gene expression, and DNA methylation. Differences in gene expression and DNA methylation between White Leghorn and Red Junglefowl chickens were mapped, and inheritance of these patterns were quantified, indicating a faithful transmission of breed-specific epigenetic markers. Selection on the behavioral trait fearfulness, generated high and low fearful lines of Red Junglefowl. Both the parental population and the fifth selected generation were used for the analyses in this thesis. One experiment studied morphological changes in the brain and other vital organs, and found that relative total brain size increased in high fearful birds, as a consequence of an increase in cerebral hemisphere size in high fearful birds and not in low fearful birds. Also, the relative heart, liver, spleen and testis size increased in high fearful birds, indicating correlated morphological changes with selection for fearfulness. Two additional experiments examined differential gene expression in the hypothalamus and the anterior cerebral hemisphere. The hypothalamus differed in expression of genes with reproductive and immunological functions, whilst the cerebral hemisphere differed in expression of genes related to social behaviors and neurological functions especially those upregulated in low fearful birds.  These results indicate the occurrence of tissue- and species-specific changes in gene expression as overlap with other domestication events were nearly nonexistent. A fourth experiment sought to associate the change in fear levels and gene expression differences with DNA methylation. Chromosomal regions with differential DNA methylation between high and low fearful birds were identified, and genes in these regions had annotated functions relevant to phenotypic differences between the selection lines. This thesis is the first to study the genetic alterations of domestication using the wild ancestor of an already domesticated species to repeat the domestication process selecting against fear of humans. The findings corroborate results from previous comparisons of wild and domestic animals, and further support the theory that rigorous selection for a behavioral trait can cause a cascade of genetic and epigenetic changes facilitating the domestication of a population.

    List of papers
    1. Heritable genome-wide variation of gene expression and promoter methylation between wild and domesticated chickens
    Open this publication in new window or tab >>Heritable genome-wide variation of gene expression and promoter methylation between wild and domesticated chickens
    Show others...
    2012 (English)In: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 13, no 59Article in journal (Refereed) Published
    Abstract [en]

    Variations in gene expression, mediated by epigenetic mechanisms, may cause broad phenotypic effects in animals. However, it has been debated to what extent expression variation and epigenetic modifications, such as patterns of DNA methylation, are transferred across generations, and therefore it is uncertain what role epigenetic variation may play in adaptation. Here, we show that in Red Junglefowl, ancestor of domestic chickens, gene expression and methylation profiles in thalamus/hypothalamus differ substantially from that of a domesticated egg laying breed. Expression as well as methylation differences are largely maintained in the offspring, demonstrating reliable inheritance of epigenetic variation. Some of the inherited methylation differences are tissue-specific, and the differential methylation at specific loci are little changed after eight generations of intercrossing between Red Junglefowl and domesticated laying hens. There was an over-representation of differentially expressed and methylated genes in selective sweep regions associated with chicken domestication. Hence, our results show that epigenetic variation is inherited in chickens, and we suggest that selection of favourable epigenomes, either by selection of genotypes affecting epigenetic states, or by selection of methylation states which are inherited independently of sequence differences, may have been an important aspect of chicken domestication.

    Place, publisher, year, edition, pages
    BioMed Central, 2012
    Keyword
    Domestication, gene expression, tiling array, behaviour, methylation
    National Category
    Biological Sciences
    Identifiers
    urn:nbn:se:liu:diva-70159 (URN)10.1186/1471-2164-13-59 (DOI)000301440800001 ()
    Note

    funding agencies|Swedish Research Council| 2008-14496-59340-36 |Swedish Research Council for Environment, Agricultural Sciences and Spatial Planning| 221 2007 838 |

    Available from: 2011-08-22 Created: 2011-08-22 Last updated: 2016-11-30Bibliographically approved
    2. Domestication and tameness: brain geneexpression in red junglefowl selected for less fear of humans suggests effects on reproduction and immunology
    Open this publication in new window or tab >>Domestication and tameness: brain geneexpression in red junglefowl selected for less fear of humans suggests effects on reproduction and immunology
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    2016 (English)In: Royal Society Open Science, ISSN 2052-3068, E-ISSN 2046-2069, no 3, 160033Article in journal (Refereed) Published
    Abstract [en]

    The domestication of animals has generated a set of phenotypicmodifications, affecting behaviour, appearance, physiologyand reproduction, which are consistent across a range ofspecies. We hypothesized that some of these phenotypes couldhave evolved because of genetic correlation to tameness,an essential trait for successful domestication. Starting froman outbred population of red junglefowl, ancestor of alldomestic chickens, we selected birds for either high or lowfear of humans for five generations. Birds from the fifthselected generation (S5) showed a divergent pattern of growthand reproduction, where low fear chickens grew larger andproduced larger offspring. To examine underlying geneticmechanisms, we used microarrays to study gene expressionin thalamus/hypothalamus, a brain region involved in fearand stress, in both the parental generation and the S5. Whileparents of the selection lines did not show any differentiallyexpressed genes, there were a total of 33 genes with adjustedp-values below 0.1 in S5. These were mainly related to spermfunction,immunological functions, with only a few known tobe relevant to behaviour. Hence, five generations of divergentselection for fear of humans produced changes in hypothalamicgene expression profiles related to pathways associated withmale reproduction and to immunology. This may be linked to the effects seen on growth and size of offspring. These results support the hypothesis thatdomesticated phenotypes may evolve because of correlated effects related to reduced fear of humans.

    Place, publisher, year, edition, pages
    Royal Society Publishing, 2016
    Keyword
    artificial selection, gene expression, microarray, chicken, fearfulness
    National Category
    Ecology
    Identifiers
    urn:nbn:se:liu:diva-130501 (URN)10.1098/rsos.160033 (DOI)000384411000002 ()
    Note

    Funding agencies:  Research council Formas; Vetenskapsradet; ERC [322206]

    Available from: 2016-08-11 Created: 2016-08-11 Last updated: 2016-11-30
  • 10.
    Callander, Margarita
    Linköping University, Department of Clinical and Experimental Medicine, Neurology. Linköping University, Faculty of Health Sciences.
    Epidemiological and genetic studies of muliple sclerosis with focus on the Swedish county of Värmland2006Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The aim of this study was to perform detailed investigations of a presumed high-risk area, namely the county of Värmland, to see if previous results from our group indicating a high frequency of multiple sclerosis (MS) could be confirmed. We soon identified an aggregation of MS cases in the parish of Lysvik located in the north of Värmland and initiated epidemiological and genetical analyses of the population. We also extended our genetic research to include studies of a possible association between MS immunopathic trait and the MS susceptibility gene HLA-DR(2)15 type, but in another geographic area.

    The onset-adjusted prevalence of MS in Värmland was 170/105 (95% CI: 154-185) in December 2002, which is higher than prevalence previously reported from other Swedish areas. There was a great variation in MS frequency between communities in Värmland. We found a persistently high occurrence of MS in Torsby and Sunne communities. In the community of Årjäng MS frequency had increased substantially since the previous study performed by our group.

    Epidemiological analysis of a cluster of MS cases in Lysvik revealed 27 MS patients, of whom 23 were the descendants of a Finnish family originated from a common ancestor born in Savolaks in Finland in the 16th century and 18 had relatives with MS. Since this cluster was most likely to have a genetic basis (located in an area with a high inbreeding rate) the mode of MS inheritance was investigated. The linkage study using the genome-wide transmission disequilibrium test (TDT) provided several regions of interest, especially on chromosome 14q (14q24-31). The linkage peak on chromosome 17q was also confirmed by this study.

    The frequency of the HLA-DR(2)15 allele was higher in healthy siblings of MS patients without MS immunopathic trait (MSIT) than in siblings with the trait, which provides further support for the hypothesis that MSIT and MS are two independent, albeit, synergistic conditions.

    The prevalence study supports that Värmland County is a high-risk area. Furthermore, the aggregation of MS cases in Lysvik indicates a concentrated risk zone, possibly due to a combination of genetic, environmental and social risk factors. A widely and evenly spread environmental (i.e., infectious) agent together with cultural changes and industrialisation could possibly induce disease in subgroups of genetically more susceptible individuals. The evidence of linkage to chromosome 14 found in this study indicates that further genetic research is required.

    List of papers
    1. A cluster of multiple sclerosis cases in Lysvik in the Swedish county of Värmland
    Open this publication in new window or tab >>A cluster of multiple sclerosis cases in Lysvik in the Swedish county of Värmland
    2004 (English)In: Acta Neurologica Scandinavica, ISSN 0001-6314, E-ISSN 1600-0404, Vol. 110, no 1, 14-22 p.Article in journal (Refereed) Published
    Abstract [en]

    Objectives – When surveying the county of Värmland in Sweden in order to determine the prevalence of multiple sclerosis (MS), we observed an aggregation of MS cases originating from the parish of Lysvik in the local region called Fryksdalen. Our intention was to analyse this cluster thoroughly, confirming the MS diagnosis and seeing if a hereditary or environmental background was plausible.

    Methods – The medical files were studied and the cases were classified by a neurologist according to Poser's criteria. Hereditary factors were analysed.

    Results – Sixteen living cases of MS were found, either living in the parish (n = 6) or born or raised there and had later moved to another place (n = 10). All patients had clinically definite MS. Eleven patients had relatives with MS, all of these being descendants of the Suhoinen family. Another two cases were Suhoinen descendants who did not have relatives with MS. Other common ancestors were also identified. Two cases were adopted. Eleven deceased MS patients from Lysvik were found, 10 of them had Suhoinen ancestry.

    Conclusion – We report a cluster of MS cases with a common ancestry indicating heredity for MS in 85% of the cases. Lysvik is a parish where Finnish immigration was pronounced in the 17th century and there has been inbreeding to a certain extent through marriage between cousins. Thus, we interpret this aggregation as possibly being genetically based, and neurogenetic studies are now being performed. However, as two of the cases were adopted environmental factors must also be considered.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-28710 (URN)10.1111/j.1600-0404.2004.00266.x (DOI)13879 (Local ID)13879 (Archive number)13879 (OAI)
    Available from: 2009-10-09 Created: 2009-10-09 Last updated: 2012-10-23Bibliographically approved
    2. Genome-wide TDT analysis in a localized population with a high prevalence of multiple sclerosis indicates the importance of a region on chromosome 14q
    Open this publication in new window or tab >>Genome-wide TDT analysis in a localized population with a high prevalence of multiple sclerosis indicates the importance of a region on chromosome 14q
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    2003 (English)In: Genes and Immunity, ISSN 1466-4879, E-ISSN 1476-5470, Vol. 4, no 8, 559-563 p.Article in journal (Refereed) Published
    Abstract [en]

    Epidemiological studies show that susceptibility to multiple sclerosis (MS) has a strong genetic component, but apart from the HLA gene complex, additional genetic factors have proven difficult to map in the general population. Thus, localized populations, where MS patients are assumed to be more closely related, may offer a better opportunity to identify shared chromosomal regions. We have performed a genome-wide scan with 834 microsatellite markers in a data set consisting of 54 MS patients and 114 healthy family members. A group of families from a small village were possible to track back to common ancestors living in the 17th century. We used single marker- and haplotype-based transmission disequilibrium test (TDT) analysis and nonparametric linkage analysis to analyze genotyping data. Regions on chromosomes 2q23–31, 6p24–21, 6q25–27, 14q24–32, 16p13–12 and 17q12–24 were found to be in transmission disequilibrium with MS. Strong transmission disequilibrium was detected in 14q24–32, where several dimarker haplotypes were in transmission disequilibrium in affected individuals. Several regions showed modest evidence for linkage, but linkage and TDT were both clearly positive only for 17q12–24. All patients and controls were also typed for HLA class II genes; however, no evidence for a gene–gene interaction was observed.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-27719 (URN)10.1038/sj.gene.6364024 (DOI)12457 (Local ID)12457 (Archive number)12457 (OAI)
    Available from: 2009-10-08 Created: 2009-10-08 Last updated: 2012-10-23Bibliographically approved
    3. Multiple sclerosis immunopathic trait and HLA-DR(2)15 as independent risk factors in multiple sclerosis
    Open this publication in new window or tab >>Multiple sclerosis immunopathic trait and HLA-DR(2)15 as independent risk factors in multiple sclerosis
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    2007 (English)In: Multiple Sclerosis, ISSN 1352-4585, E-ISSN 1477-0970, Vol. 13, no 4, 441-445 p.Article in journal (Refereed) Published
    Abstract [en]

    We analysed HLA haplotypes in pairs of 78 sporadic multiple sclerosis (MS) patients and 78 healthy siblings. The presence of 2 oligoclonal IgG bands, detected by immunoblotting of the cerebrospinal fluid in healthy siblings, has previously been defined as MS immunopathic trait (MSIT), based on a cut-off derived from healthy unrelated volunteers. The frequency of MSIT was 17.9% (n=14/78 siblings). The HLA-DR(15)2 allelle was present in 21.4% (n=3/14) of the siblings with MSIT, in 40.6% (n =26/64) of the siblings without MSIT, and in 59% (n =46/78) of the patients with clinically-definite (CD) MS. The distribution of zero, one or two HLA-DR(2)15 alleles was significantly skewed towards a lower allelle count in the siblings with MSIT compared with the group of unrelated siblings with MS (P=0.002), and also lower than their related siblings with MS (P=0.1). These results suggest that the MS susceptibility gene, HLA-DR(2)15 type, does not induce MSIT, and conceivably these are two separate risk factors in the development of MS. The effect of HLA-DR(2)15 and MSIT in sporadic MS appears to be synergistic.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-40847 (URN)10.1177/1352458506070264 (DOI)54299 (Local ID)54299 (Archive number)54299 (OAI)
    Available from: 2009-10-10 Created: 2009-10-10 Last updated: 2012-10-23Bibliographically approved
    4. High prevalence of multiple sclerosis in the Swedish county of Värmland
    Open this publication in new window or tab >>High prevalence of multiple sclerosis in the Swedish county of Värmland
    2009 (English)In: Multiple Sclerosis, ISSN 1352-4585, E-ISSN 1477-0970, Vol. 15, no 11, 1253-1262 p.Article in journal (Refereed) Published
    Abstract [en]

    Previous epidemiological studies have indicated that the county of Värmland in western Sweden may be a high-risk zone for multiple sclerosis (MS). The objective of this study was to determine the prevalence in the area. Hospital and general practice medical files were scrutinized. The diagnostic criteria of Poser were used, with 31 December 2002 as prevalence day. The prevalence was 170.07 per 100,000 inhabitants. The average annual incidence was 6.39 to 6.46 per 100,000 (1991—1995, 1996—2000). Multiple sclerosis was 2.3 times more common among women than men. There was a variation in prevalence among the 16 municipalities, however it was not statistically significant. The rates seemed highest in the southwestern part of the county, roughly similar in location to findings some 70 years earlier. When the prevalence ratios by geographical units for the county in 1933 were applied to the current prevalence, the distribution from these estimated cases differed from homogeneity with very high significance (p < 0.00001 ). In conclusion, this study supports previous reports indicating that Värmland continues to be a high-risk zone for MS and shares in the diffusion of the disease at the county level which we had presented for the country as a whole.

    Keyword
    epidemiological, risk, aetiological, genetics, environment
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-51888 (URN)10.1177/1352458509345909 (DOI)
    Available from: 2009-11-23 Created: 2009-11-23 Last updated: 2012-10-23Bibliographically approved
  • 11.
    Campbell, James R.
    et al.
    University of Nebraska Medical Center, Omaha NE USA.
    Talmon, Geoffrey
    University of Nebraska Medical Center, Omaha NE USA.
    Cushman-Vokoun, Allison
    University of Nebraska Medical Center, Omaha NE USA.
    Karlsson, Daniel
    Linköping University, Department of Biomedical Engineering. Linköping University, Faculty of Science & Engineering.
    Campbell, Scott W.
    University of Nebraska Medical Center, Omaha NE USA.
    An Extended SNOMED CT Concept Model for Observations in Molecular Genetics2016In: AMIA Annual Symposium Proceedings, 2016, 352-360 p.Conference paper (Refereed)
    Abstract [en]

    Molecular genetics laboratory reports are multiplying and increasingly of clinical importance in diagnosis and treatment of cancer, infectious disease and managing of public health. Little of this data is structured or maintained in the EHR in format useful for decision support or research. Structured, computable reporting is limited by non-availability of a domain ontology for these data. The IHTSDO and Regenstrief Institute(RI) have been collaborating since 2008 to develop a unified concept model and ontology of observable entities - concepts which represent the results of laboratory and clinical observations. In this paper we report the progress we have made to apply that unified concept model to the structured recording of observations in clinical molecular genetic pathology including immunohistochemistry and sequence variant findings. The primary use case for deployment is the structured and coded reporting of Cancer checklist

  • 12.
    Caren, Helena
    et al.
    University of Gothenburg, Sweden.
    Erichsen, Jennie
    University of Gothenburg, Sweden.
    Olsson, Linda
    University of Gothenburg, Sweden.
    Enerbäck, Charlotta
    University of Gothenburg, Sweden.
    Sjoberg, Rose-Marie
    University of Gothenburg, Sweden.
    Abrahamsson, Jonas
    University of Gothenburg, Sweden.
    Kogner, Per
    Childhood Canc Res Unit, SE-17176 Stockholm, Sweden .
    Martinsson, Tommy
    University of Gothenburg, Sweden.
    High-resolution array copy number analyses for detection of deletion, gain, amplification and copy-neutral LOH in primary neuroblastoma tumors: Four cases of homozygous deletions of the CDKN2A gene2008In: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 9, no 353Article in journal (Refereed)
    Abstract [en]

    Background: Neuroblastoma is a very heterogeneous pediatric tumor of the sympathetic nervous system showing clinically significant patterns of genetic alterations. Favorable tumors usually have near-triploid karyotypes with few structural rearrangements. Aggressive stage 4 tumors often have near-diploid or near-tetraploid karyotypes and structural rearrangements. Whole genome approaches for analysis of genome-wide copy number have been used to analyze chromosomal abnormalities in tumor samples. We have used array-based copy number analysis using oligonucleotide single nucleotide polymorphisms (SNP) arrays to analyze the chromosomal structure of a large number of neuroblastoma tumors of different clinical and biological subsets. Results: Ninety-two neuroblastoma tumors were analyzed with 50 K and/or 250 K SNP arrays from Affymetrix, using CNAG3.0 software. Thirty percent of the tumors harbored 1p deletion, 22% deletion of 11q, 26% had MYCN amplification and 45% 17q gain. Most of the tumors with 1p deletion were found among those with MYCN amplification. Loss of 11q was most commonly seen in tumors without MYCN amplification. In the case of MYCN amplification, two types were identified. One type displayed simple continuous amplicons; the other type harbored more complex rearrangements. MYCN was the only common gene in all cases with amplification. Complex amplification on chromosome 12 was detected in two tumors and three different overlapping regions of amplification were identified. Two regions with homozygous deletions, four cases with CDKN2A deletions in 9p and one case with deletion on 3p (the gene RBMS3) were also detected in the tumors. Conclusion: SNP arrays provide useful tools for high-resolution characterization of significant chromosomal rearrangements in neuroblastoma tumors. The mapping arrays from Affymetrix provide both copy number and allele-specific information at a resolution of 10-12 kb. Chromosome 9p, especially the gene CDKN2A, is subject to homozygous (four cases) and heterozygous deletions (five cases) in neuroblastoma tumors.

  • 13.
    Carlsson Almlöf, Jonas
    et al.
    Uppsala University, Sweden.
    Alexsson, Andrei
    Uppsala University, Sweden.
    Imgenberg-Kreuz, Juliana
    Uppsala University, Sweden.
    Sylwan, Lina
    Uppsala University, Sweden; Karolinska Institute, Sweden.
    Backlin, Christofer
    Uppsala University, Sweden.
    Leonard, Dag
    Uppsala University, Sweden.
    Nordmark, Gunnel
    Uppsala University, Sweden.
    Tandre, Karolina
    Uppsala University, Sweden.
    Eloranta, Maija-Leena
    Uppsala University, Sweden.
    Padyukov, Leonid
    Karolinska University Hospital, Sweden.
    Bengtsson, Christine
    Umeå University, Sweden.
    Jonsen, Andreas
    Lund University, Sweden.
    Rantapaa Dahlqvist, Solbritt
    Umeå University, Sweden.
    Sjöwall, Christopher
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Rheumatology.
    Bengtsson, Anders A.
    Lund University, Sweden.
    Gunnarsson, Iva
    Karolinska University Hospital, Sweden.
    Svenungsson, Elisabet
    Karolinska University Hospital, Sweden.
    Ronnblom, Lars
    Uppsala University, Sweden.
    Sandling, Johanna K.
    Uppsala University, Sweden; Uppsala University, Sweden.
    Syvanen, Ann-Christine
    Uppsala University, Sweden.
    Novel risk genes for systemic lupus erythematosus predicted by random forest classification2017In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, 6236Article in journal (Refereed)
    Abstract [en]

    Genome-wide association studies have identified risk loci for SLE, but a large proportion of the genetic contribution to SLE still remains unexplained. To detect novel risk genes, and to predict an individuals SLE risk we designed a random forest classifier using SNP genotype data generated on the "Immunochip" from 1,160 patients with SLE and 2,711 controls. Using gene importance scores defined by the random forest classifier, we identified 15 potential novel risk genes for SLE. Of them 12 are associated with other autoimmune diseases than SLE, whereas three genes (ZNF804A, CDK1, and MANF) have not previously been associated with autoimmunity. Random forest classification also allowed prediction of patients at risk for lupus nephritis with an area under the curve of 0.94. By allele-specific gene expression analysis we detected cis-regulatory SNPs that affect the expression levels of six of the top 40 genes designed by the random forest analysis, indicating a regulatory role for the identified risk variants. The 40 top genes from the prediction were overrepresented for differential expression in B and T cells according to RNA-sequencing of samples from five healthy donors, with more frequent over-expression in B cells compared to T cells.

  • 14.
    Cauvi, David M
    et al.
    Department of Surgery, University of California, San Diego, 9500 Gilman Drive, No. 0739, La Jolla, CA 92093-0739, USA.
    Gabriel, Rodney
    Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA.
    Kono, Dwight H
    Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037, USA.
    Hultman, Per
    Linköping University, Department of Clinical and Experimental Medicine, Division of Inflammation Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Pollard, K Michael
    Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA.
    A tandem repeat in decay accelerating factor 1 is associated with severity of murine mercury-induced autoimmunity2014In: Autoimmune diseases, ISSN 2090-0422, Vol. 2014, no 260613Article in journal (Refereed)
    Abstract [en]

    Decay accelerating factor (DAF), a complement-regulatory protein, protects cells from bystander complement-mediated lysis and negatively regulates T cells. Reduced expression of DAF occurs in several systemic autoimmune diseases including systemic lupus erythematosus, and DAF deficiency exacerbates disease in several autoimmune models, including murine mercury-induced autoimmunity (mHgIA). Daf1, located within Hmr1, a chromosome 1 locus associated in DBA/2 mice with resistance to mHgIA, could be a candidate. Here we show that reduced Daf1 transcription in lupus-prone mice was not associated with a reduction in the Daf1 transcription factor SP1. Studies of NZB mice congenic for the mHgIA-resistant DBA/2 Hmr1 locus suggested that Daf1 expression was controlled by the host genome and not the Hmr1 locus. A unique pentanucleotide repeat variant in the second intron of Daf1 in DBA/2 mice was identified and shown in F2 intercrosses to be associated with less severe disease; however, analysis of Hmr1 congenics indicated that this most likely reflected the presence of autoimmunity-predisposing genetic variants within the Hmr1 locus or that Daf1 expression is mediated by the tandem repeat in epistasis with other genetic variants present in autoimmune-prone mice. These studies argue that the effect of DAF on autoimmunity is complex and may require multiple genetic elements.

  • 15.
    Dand, Nick
    et al.
    Kings Coll London, England.
    Mucha, Soeren
    Christian Albrechts University of Kiel, Germany.
    Tsoi, Lam C.
    University of Michigan, MI 48109 USA.
    Mahil, Satveer K.
    Kings Coll London, England.
    Stuart, Philip E.
    University of Michigan, MI USA.
    Arnold, Andreas
    University of Medical Greifswald, Germany.
    Baurecht, Hansjoerg
    University Hospital Schleswigholstein, Germany.
    David Burden, A.
    University of Glasgow, Scotland.
    Callis Duffin, Kristina
    University of Utah, UT USA.
    Chandran, Vinod
    University of Toronto, Canada; University of Health Network, Canada.
    Curtis, Charles J.
    NIHR, England; Maudsley NHS Fdn Trust, England; Kings Coll London, England; Kings Coll London, England.
    Das, Sayantan
    University of Michigan, MI 48109 USA.
    Ellinghaus, David
    Christian Albrechts University of Kiel, Germany.
    Ellinghaus, Eva
    Christian Albrechts University of Kiel, Germany.
    Enerbäck, Charlotta
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Dermatology and Venerology.
    Esko, Tonu
    University of Tartu, Estonia.
    Gladman, Dafna D.
    University of Toronto, Canada; University of Health Network, Canada.
    Griffiths, Christopher E. M.
    University of Manchester, England.
    Gudjonsson, Johann E.
    University of Michigan, MI USA.
    Hoffman, Per
    University of Basel, Switzerland; University of Bonn, Germany.
    Homuth, Georg
    University of Med, Germany; Ernst Moritz Arndt University of Greifswald, Germany.
    Hueffmeier, Ulrike
    University Hospital Schleswigholstein, Germany; Friedrich Alexander University of Erlangen Nurnberg, Germany.
    Krueger, Gerald G.
    University of Utah, UT USA.
    Laudes, Matthias
    Christian Albrechts University of Kiel, Germany.
    Hyuck Lee, Sang
    NIHR, England; Maudsley NHS Fdn Trust, England; Kings Coll London, England; Kings Coll London, England.
    Lieb, Wolfgang
    Christian Albrechts University of Kiel, Germany.
    Lim, Henry W.
    Henry Ford Hospital, MI 48202 USA.
    Loehr, Sabine
    Friedrich Alexander University of Erlangen Nurnberg, Germany.
    Mrowietz, Ulrich
    Department of Dermatology, Venereology and Allergy, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.
    Mueller-Nurayid, Martina
    Helmholtz Zentrum Munich, Germany.
    Noethen, Markus
    University of Bonn, Germany.
    Peters, Annette
    Helmholtz Zentrum Munich, Germany.
    Rahman, Proton
    Mem University of Newfoundland, Canada.
    Reis, Andre
    Friedrich Alexander University of Erlangen Nurnberg, Germany.
    Reynolds, Nick J.
    Newcastle University, England; Newcastle Hospital NHS Fdn Trust, England.
    Rodriguez, Elke
    University Hospital Schleswigholstein, Germany.
    Schmidt, Carsten O.
    University of Medical Greifswald, Germany.
    Spain, Sarah L.
    Kings Coll London, England.
    Strauch, Konstantin
    Helmholtz Zentrum Munich, Germany.
    Tejasvi, Trilokraj
    University of Michigan, MI USA.
    Voorhees, John J.
    University of Michigan, MI USA.
    Warren, Richard B.
    University of Manchester, England.
    Weichenthal, Michael
    University of Medical Centre Schleswig Holstein, Germany.
    Weidinger, Stephan
    University Hospital Schleswigholstein, Germany.
    Zawistowski, Matthew
    University of Michigan, MI 48109 USA.
    Nair, Rajan P.
    University of Michigan, MI USA.
    Capon, Francesca
    Kings Coll London, England.
    Smith, Catherine H.
    Kings Coll London, England.
    Trembath, Richard C.
    Kings Coll London, England.
    Abecasis, Goncalo R.
    University of Michigan, MI 48109 USA.
    Elder, James T.
    University of Michigan, MI USA; Ann Arbor Vet Hospital, MI USA.
    Franke, Andre
    Christian Albrechts University of Kiel, Germany.
    Simpson, Michael A.
    Kings Coll London, England.
    Barker, Jonathan N.
    Kings Coll London, England.
    Exome-wide association study reveals novel psoriasis susceptibility locus at TNFSF15 and rare protective alleles in genes contributing to type I IFN signalling2017In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 26, no 21, 4301-4313 p.Article in journal (Refereed)
    Abstract [en]

    Psoriasis is a common inflammatory skin disorder for which multiple genetic susceptibility loci have been identified, but few resolved to specific functional variants. In this study, we sought to identify common and rare psoriasis-associated gene-centric variation. Using exome arrays we genotyped four independent cohorts, totalling 11 861 psoriasis cases and 28 610 controls, aggregating the dataset through statistical meta-analysis. Single variant analysis detected a previously unreported risk locus at TNFSF15 (rs6478108; P = 1.50 x 10(-8), OR = 1.10), and association of common protein-altering variants at 11 loci previously implicated in psoriasis susceptibility. We validate previous reports of protective low-frequency protein-altering variants within IFIH1 (encoding an innate antiviral receptor) and TYK2 (encoding a Janus kinase), in each case establishing a further series of protective rare variants (minor allele frequency amp;lt; 0.01) via gene-wide aggregation testing (IFIH1: p(burden) = 2.53 x 10(-7), OR = 0.707; TYK2: p(burden) = 6.17 x 10(-4), OR = 0.744). Both genes play significant roles in type I interferon (IFN) production and signalling. Several of the protective rare and low-frequency variants in IFIH1 and TYK2 disrupt conserved protein domains, highlighting potential mechanisms through which their effect may be exerted.

  • 16.
    Ek, Weronica E
    et al.
    Karolinska Institutet, Stockholm .
    Reznichenko, Anna
    Karolinska Institutet, Stockholm.
    Ripke, Stephan
    Massachusetts General Hospital Boston, Cambridge Massachussetts, USA .
    Niesler, Beate
    University of Heidelberg, Germany .
    Zucchelli, Marco
    Karolinska Institutet, Stockholm.
    Rivera, Natalia V
    Karolinska Institutet, Stockholm.
    Schmidt, Peter T
    University Hospital, Karolinska institutet, Stockholm .
    Pedersen, Nancy L
    Karolinska Institutet, Stockholm.
    Magnusson, Patrik
    Karolinska Institutet, Stockholm.
    Talley, Nicholas J
    University of Newcastle, Australia .
    Holliday, Elizabeth G
    University of Newcastle, Australia .
    Houghton, Lesley
    University of Manchester UK and Mayo Clinic, Jacksonville USA.
    Gazouli, Maria
    University of Athens, Greece .
    Karamanolis, George
    University of Athens, Greece .
    Rappold, Gudrun
    University of Heidelberg, Germany.
    Burwinkel, Barbara
    University Women's Clinic, University of Heidelberg, Germany.
    Surowy, Harald
    University Women's Clinic, University of Heidelberg, Germany.
    Rafter, Joseph
    Karolinska Institutet, Stockholm .
    Assadi, Ghazaleh
    Karolinska Institutet, Stockholm .
    Li, Ling
    Karolinska Institutet, Stockholm .
    Papadaki, Evangelia
    Karolinska Institutet, Stockholm .
    Gambaccini, Dario
    University of Pisa, Pisa Italy .
    Marchi, Santino
    University of Pisa, Pisa Italy .
    Colucci, Rocchina
    Department of Clinical and Experimental Medicine University of Pisa, Italy .
    Blandizzi, Corrado
    Department of Clinical and Experimental Medicine University of Pisa, Italy .
    Barbaro, Raffaella
    University of Bologna, Italy .
    Karling, Pontus
    Umeå University .
    Walter, Susanna
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Gastroentorology.
    Ohlsson, Bodil
    Skånes University Hospital, Malmö .
    Tornblom, Hans
    Sahlgrenska Academy, University of Gothenburg, Göteborg.
    Bresso, Francesca
    Karolinska University Hospital, Stockholm .
    Andreasson, Anna
    Sweden Stress Research Institute, Stockholm University.
    Dlugosz, Aldona
    Karolinska Instituet, Stockholm .
    Simren, Magnus
    Sahlgrenska Academy, University of Gothenburg, Göteborg.
    Agreus, Lars
    Karolinska Institutet Stockholm .
    Lindberg, Greger
    Karolinska University Hospital, Karolinska Institutet, Stockholm.
    Boeckxstaens, Guy
    Leuven University, Leuven, Belgium .
    Bellini, Massimo
    University of Pisa, Italy .
    Stanghellini, Vincenzo
    University of Bologna, Italy .
    Barbara, Giovanni
    University of Bologna, Italy .
    Daly, Mark J
    Massachusetts General Hospital Boston, Cambridge Massachussetts, USA .
    Camilleri, Michael
    Mayo Clinic, Rochester, Minnesota, USA .
    Wouters, Mira M
    Leuven University, Belgium .
    D'Amato, Mauro
    Karolinska Institutet, Stockholm .
    Exploring the genetics of irritable bowel syndrome: a GWA study in the general population and replication in multinational case-control cohorts.2015In: Gut, ISSN 0017-5749, E-ISSN 1468-3288, Vol. 64, 1774-1782 p.Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: IBS shows genetic predisposition, but adequately powered gene-hunting efforts have been scarce so far. We sought to identify true IBS genetic risk factors by means of genome-wide association (GWA) and independent replication studies.

    DESIGN: We conducted a GWA study (GWAS) of IBS in a general population sample of 11 326 Swedish twins. IBS cases (N=534) and asymptomatic controls (N=4932) were identified based on questionnaire data. Suggestive association signals were followed-up in 3511 individuals from six case-control cohorts. We sought genotype-gene expression correlations through single nucleotide polymorphism (SNP)-expression quantitative trait loci interactions testing, and performed in silico prediction of gene function. We compared candidate gene expression by real-time qPCR in rectal mucosal biopsies of patients with IBS and controls.

    RESULTS: One locus at 7p22.1, which includes the genes KDELR2 (KDEL endoplasmic reticulum protein retention receptor 2) and GRID2IP (glutamate receptor, ionotropic, delta 2 (Grid2) interacting protein), showed consistent IBS risk effects in the index GWAS and all replication cohorts and reached p=9.31×10(-6) in a meta-analysis of all datasets. Several SNPs in this region are associated with cis effects on KDELR2 expression, and a trend for increased mucosal KDLER2 mRNA expression was observed in IBS cases compared with controls.

    CONCLUSIONS: Our results demonstrate that general population-based studies combined with analyses of patient cohorts provide good opportunities for gene discovery in IBS. The 7p22.1 and other risk signals detected in this study constitute a good starting platform for hypothesis testing in future functional investigations.

  • 17.
    Green, Henrik
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Division of Gene Technology, Royal Institute of Technology, Solna, Sweden/ Royal Institute Technology, Sweden; National Board Forens Med, Department Forens Genet and Forens Toxicol, Linkoping, Sweden.
    Hasmats, Johanna
    Royal Institute Technology, Sweden.
    Kupershmidt, Ilya
    Royal Institute Technology, Sweden; NextBio, CA USA.
    Edsgard, Daniel
    Royal Institute Technology, Sweden.
    de Petris, Luigi
    Karolinska Institute, Sweden; Karolinska University Hospital, Sweden.
    Lewensohn, Rolf
    Karolinska Institute, Sweden; Karolinska University Hospital, Sweden.
    Blackhall, Fiona
    Christie Hospital, England; University of Manchester, England.
    Vikingsson, Svante
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    Besse, Benjamin
    University of Paris 11, France.
    Lindgren, Andrea
    Linköping University, Department of Medical and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Clinical Physiology in Linköping. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Respiratory Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Branden, Eva
    Karolinska Institute, Sweden; Karolinska University Hospital, Sweden.
    Koyi, Hirsh
    Karolinska Institute, Sweden; Karolinska University Hospital, Sweden.
    Peterson, Curt
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Lundeberg, Joakim
    Royal Institute Technology, Sweden.
    Using Whole-Exome Sequencing to Identify Genetic Markers for Carboplatin and Gemcitabine-Induced Toxicities2016In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 22, no 2, 366-373 p.Article in journal (Refereed)
    Abstract [en]

    Purpose: Chemotherapies are associated with significant interindividual variability in therapeutic effect and adverse drug reactions. In lung cancer, the use of gemcitabine and carboplatin induces grade 3 or 4 myelosuppression in about a quarter of the patients, while an equal fraction of patients is basically unaffected in terms of myelosuppressive side effects. We therefore set out to identify genetic markers for gemcitabine/carboplatin-induced myelosuppression. Experimental Design: We exome sequenced 32 patients that suffered extremely high neutropenia and thrombocytopenia (grade 3 or 4 after first chemotherapy cycle) or were virtually unaffected (grade 0 or 1). The genetic differences/polymorphism between the groups were compared using six different bioinformatics strategies: (i) whole-exome nonsynonymous single-nucleotide variants association analysis, (ii) deviation from Hardy-Weinberg equilibrium, (iii) analysis of genes selected by a priori biologic knowledge, (iv) analysis of genes selected from gene expression meta-analysis of toxicity datasets, (v) Ingenuity Pathway Analysis, and (vi) FunCoup network enrichment analysis. Results: A total of 53 genetic variants that differed among these groups were validated in an additional 291 patients and were correlated to the patients myelosuppression. In the validation, we identified rs1453542 in OR4D6 (P = 0.0008; OR, 5.2; 95% CI, 1.8-18) as a marker for gemcitabine/carboplatin-induced neutropenia and rs5925720 in DDX53 (P = 0.0015; OR, 0.36; 95% CI, 0.17-0.71) as a marker for thrombocytopenia. Patients homozygous for the minor allele of rs1453542 had a higher risk of neutropenia, and for rs5925720 the minor allele was associated with a lower risk for thrombocytopenia. Conclusions: We have identified two new genetic markers with the potential to predict myelosuppression induced by gemcitabine/ carboplatin chemotherapy. (C)2015 AACR.

  • 18.
    Harnevik, Lotta
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Molecular genetic studies on cystinuria2007Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Cystinuria is defined as an inherited disorder characterized by increased urinary excretion of cystine and the dibasic amino acids arginine, lysine and ornithine. The only clinical manifestation of cystinuria is renal cystine stone formation due to the low solubility of cystine in the urine. Cystinuria can be attributed to mutations in the SLC3A1 and SLC7A9 genes in the majority of all cases and it has been a common expectation that molecular genetic studies of cystinuria would aid in understanding of the varying clinical outcome seen in the disease. Besides human, the disease has been most extensively studied in the domestic dog.

    The present study was undertaken to investigate the molecular genetic basis of cystinuria in patients from Sweden and to correlate genetic findings with phenotypes produced regarding cystine and dibasic amino acid excretion. Further, attempts were made to elucidate the molecular genetics of cystinuria in the dog.

    The entire coding sequences of the SLC3A1 and SLC7A9 genes were analysed by means of SSCA and DNA sequencing in 53 cystinuria patients and genetic findings were related to urinary excretion of cystine and dibasic amino acids in a subset of the patient group. We detected a total number of 22 different mutations in the SLC3A1 and SLC7A9 genes, 18 of which were described for the first time. We have found a probable genetic cause of cystinuria in approximately 74 % of our patients and a possible contribution to the disease in another 19 %. Mutations in the SLC3A1 gene is the major cause of cystinuria in our group, with only a minor contribution of SLC7A9 mutations. The group of patients presenting SLC3A1 mutations in a heterozygous state or lacking mutations in both genes had higher values of total urinary cystine and dibasic amino acids compared to patients homozygous for SLC3A1 mutations. The reason for this discrepancy remains unclear, but the possible impact of medical treatment with sulfhydryl compounds on total cystine values was ruled out.

    Sequencing of the full-length canine SLC7A9 cDNA was accomplished using the RACE technology and results from mutation analyses of SLC7A9 and SLC3A1 in cystinuric dogs showed that only two out of 13 dogs have mutations with possible impact on protein function in these genes. DNA sequencing was used for all exons of both genes in the dog, and in human cystinuria patients, all samples lacking mutations or showing heterozygosity after SSCA screening were sequenced in both genes as well. This implies that all point mutations present have been detected, but the possibility of mutations escaping PCR based methods as well as mutations in regulatory parts of the SLC3A1 and SLC7A9 genes remains in cases lacking a full molecular genetic explanation of the disease.

    Finally, clinical and genetic data from our study of cystinuria both in man and dog exemplifies that manifestation and clinical severity of cystinuria is not determined by genetic alterations in the SLC3A1 and SLC7A9 alone. Environmental factors, congenital malformations and modulating genetic factors are all possible contributors to the clinical outcome of cystinuria.

    List of papers
    1. Identification of 12 novel mutations in the SLC3A1 gene in Swedish cystinuria patients
    Open this publication in new window or tab >>Identification of 12 novel mutations in the SLC3A1 gene in Swedish cystinuria patients
    Show others...
    2001 (English)In: Human Mutation, ISSN 1059-7794, E-ISSN 1098-1004, Vol. 18, no 6, 516-525 p.Article in journal (Refereed) Published
    Abstract [en]

    Cystinuria is an autosomal recessive disorder that affects luminal transport of cystine and dibasic amino acids in the kidneys and the small intestine. Three subtypes of cystinuria can be defined biochemically, and the classical form (type I) has been associated with mutations in the amino acid transporter gene SLC3A1. The mutations detected in SLC3A1 tend to be population specific and have not been previously investigated in Sweden. We have screened the entire coding sequence and the intron/exon boundaries of the SLC3A1 gene in 53 cystinuria patients by means of single strand conformation polymorphism (SSCP) and DNA sequencing. We identified 12 novel mutations (a 2 bp deletion, one splice site mutation, and 10 missense mutations) and detected another three mutations that were previously reported. Five polymorphisms were also identified, four of which were formerly described. The most frequent mutation in this study was the previously reported M467T and it was also detected in the normal population with an allelic frequency of 0.5%. Thirty-seven patients were homozygous for mutations in the SLC3A1 gene and another seven were heterozygous which implies that other genes may be involved in cystinuria. Future investigation of the non-type I cystinuria gene SLC7A9 may complement our results but recent studies also suggest the presence of other potential disease genes.

    Keyword
    cystinuria, CSNU, CNSU1, CNSU3, SLC3A1, SLC7A9, transporter, amino acid
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-12855 (URN)10.1002/humu.1228 (DOI)
    Available from: 2008-02-13 Created: 2008-02-13 Last updated: 2012-10-17Bibliographically approved
    2. Mutation analysis of SLC7A9 in cystinuria patients in Sweden
    Open this publication in new window or tab >>Mutation analysis of SLC7A9 in cystinuria patients in Sweden
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    2003 (English)In: Genetic Testing, ISSN 1090-6576, Vol. 7, no 1, 13-20 p.Article in journal (Refereed) Published
    Abstract [en]

    Cystinuria is an autosomal recessive disorder characterized by increased urinary excretion of cystine and dibasic amino acids, which cause recurrent stone formation in affected individuals. Three subtypes of cystinuria have been described (type I, II, and III): type I is caused by mutations in the SLC3A1 gene, whereas non-type I (II and III) has been associated with SLC7A9 mutations. Of the 53 patients reported in our previous work, patients that showed SLC7A9 mutations in single-strand conformation polymorphism (SSCP) screening and/or either lacked or showed heterozygosity for SLC3A1 mutations were included in the present study. The entire coding region and the exon/intron boundaries of the SLC7A9 gene were analyzed by means of both SSCP and DNA sequencing in 16 patients, all but one of which were clinically diagnosed as homozygous cystinurics. Three novel SLC7A9 mutations were identified in the patient group: two missense mutations (P261L and V330M), and one single base-pair deletion (1009 delA). We also detected the previously reported A182T and nine novel polymorphisms in the patients. Mutations V330M and 1009delA occurred on different alleles in one individual, and we suggest that these mutations cause cystinuria in this patient. One patient that was homozygously mutated in the SLC3A1 gene carried the third novel mutation (P261L). We conclude that SLC3A1 is still the major disease gene among Swedish cystinuria patients, with only a minor contribution of SLC7A9 mutations as the genetic basis of cystinuria. The absence of SLC3A1 and SLC7A9 mutations in a substantial proportion of the patients implies that mutations in parts of the genes that were not analyzed may be present, as well as large deletions that escape detection by the methods used. However, our results raise the question of whether other, as yet unknown genes, may also be involved in cystinuria.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-12856 (URN)10.1089/109065703321560886 (DOI)
    Available from: 2008-02-13 Created: 2008-02-13 Last updated: 2012-10-17Bibliographically approved
    3. Urinary excretion of total cystine and the dibasic amino acids arginine, lysine and ornithine in relation to genetic findings in patients with cystinuria treated with sulfhydryl compounds
    Open this publication in new window or tab >>Urinary excretion of total cystine and the dibasic amino acids arginine, lysine and ornithine in relation to genetic findings in patients with cystinuria treated with sulfhydryl compounds
    Show others...
    2003 (English)In: Urological research, ISSN 0300-5623, E-ISSN 1434-0879, Vol. 31, no 6, 417-425 p.Article in journal (Refereed) Published
    Abstract [en]

    Advances in molecular genetics have brought a deeper understanding of cystinuria. This autosomal recessive disease, which is caused by a defective tubular reabsorption of cystine and the three dibasic amino acids arginine, lysine and ornithine, results in a lifelong risk of renal stone formation because of the low solubility of cystine in urine. Mutations detected within the two genes known to be associated with cystinuria, SLC3A1 (related to type I) and SLC7A9 (related to non-type I), cannot, however, in all cases explain the disease. Inasmuch as a high urinary concentration of cystine is the basis of stone formation in these patients, our aim was to measure urinary total cystine, arginine, lysine and ornithine, in patients currently lacking a full genetic explanation for their disease. Thirty-three patients with cystinuria who were on long-term treatment with tiopronin or D-penicillamine were divided into two groups. Group 1 comprised eight patients who carried mutation in one of the SLC3A1 alleles and two patients who completely lacked mutations both in the SLC3A1 and the SLC7A9 genes, that is genetic findings discordant with the increased urinary excretion of cystine and the dibasic amino acids in these patients. Group 2 comprised 23 patients homozygous for mutations within SLC3A1, that is genetic findings in accordance with the excretion pattern of classic type I cystinuria. When the two groups were compared, Group 1 had a significantly higher total urinary excretion of cystine (p<0.01) as well as of arginine, lysine and ornithine (p<0.05) than Group 2. Also, when the two patients without mutations were excluded from the calculations, there still was a significant difference in the urinary excretion of total cystine (p<0.05). This suggests that the two patients without any detected mutations in the two known cystine transport genes also contributed to the difference. These unexpected findings indicate that an additional gene or genes participate in the urinary cystine reabsorption in the cystinuric patients who currently are without a full genetic explanation for their disease.

    Keyword
    Cystinuria, Urinary cystine, Amino acid transport, SLC3A1, SLC7A9, Inherited disease
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-12857 (URN)10.1007/s00240-003-0366-6 (DOI)
    Available from: 2008-02-13 Created: 2008-02-13 Last updated: 2012-10-17Bibliographically approved
    4. SLC7A9 cDNA clonng and mutational analysis of SLC3A1 and SLC7A9 in canine cystinuria
    Open this publication in new window or tab >>SLC7A9 cDNA clonng and mutational analysis of SLC3A1 and SLC7A9 in canine cystinuria
    2006 (English)In: Mammalian Genome, ISSN 0938-8990, Vol. 17, no 7, 769-776 p.Article in journal (Refereed) Published
    Abstract [en]

    Cystinuria is a genetic disorder in the domestic dog that leads to recurrent urolith formation. The genetic basis of the disorder is best characterized in humans and is caused by mutations in one of the amino acid transporter genes SLC3A1 or SLC7A9, which results in hyperexcretion of cystine and the dibasic amino acids in the urine and subsequent precipitation of cystine due to its low solubility in urine. In this study we describe the cloning of the canine SLC7A9 cDNA and present a thorough mutation analysis of the coding SLC3A1 and SLC7A9 regions in cystinuric dogs of different breeds. Mutation analysis of the two cystinuria disease genes revealed one SLC7A9 mutation (A217T) and two SLC3A1 mutations (I192V and S698G) in French and English Bulldogs that affect nonconserved amino acid residues, arguing against functional impact on the proteins. The absence of deleterious mutations linked to cystinuria in the remainder of our panel of cystinuric dogs is surprising because SLC3A1 or SLC7A9 mutations explain approximately 70% of all human cystinuria cases studied. The present study, along with previous investigations of canine and human cystinuria, implies that regulatory parts of the SLC3A1 and SLC7A9 genes as well as other unknown genes may harbor mutations causing cystinuria.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-12858 (URN)10.1007/s00335-005-0146-4 (DOI)
    Available from: 2008-02-13 Created: 2008-02-13
  • 19.
    Hashemi, Mohammad
    et al.
    Zahedan University of Medical Sciences, Iran.
    Fazaeli, Aliakbar
    Department of Clinical Biochemistry, School of Medicine, Zahedan University of Medical Science, Iran.
    Ghavami, Saeid
    University of Manitoba, Winnipeg, Canada .
    Eskandari-Nasab, Ebrahim
    Zahedan University of Medical Science, Iran.
    Arbabi, Farshid
    Department of Internal Medicine, School of Medicine, Zahedan University of Medical Science, Iran.
    Mashhadi, Mohammad A.
    Department of Internal Medicine, School of Medicine, Zahedan University of Medical Science, Iran.
    Taheri, Mohsen
    Genetic of Non Communicable Disease Research Center, Zahedan University of Medical Science, Iran.
    Chaabane, Wiem
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Jain, Mayur Vilas
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Los, Marek Jan
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Functional Polymorphisms of FAS and FASL Gene andRisk of Breast Cancer – Pilot Study of 134 Cases2013In: PLoS ONE, ISSN 1932-6203, Vol. 8, no 1, e53075- p.Article in journal (Refereed)
    Abstract [en]

    Fas/Fas ligand (FasL) system is one of the key apoptotic signaling entities in the extrinsic apoptotic pathway. De-regulation of this pathway, i.e. by mutations may prevent the immune system from the removal of newly-formed tumor cells, and thus lead to tumor formation. The present study investigated the association between −1377 G/A (rs2234767) and −670 A/G (rs1800682) polymorphisms in Fas as well as single nucleotide polymorphisms INV2nt −124 A/G (rs5030772) and −844 C/T (rs763110) in FasL in a sample of Iranian patients with breast cancer. This case-control study was done on 134 breast cancer patients and 152 normal women. Genomic DNA was extracted from whole blood samples. The polymorphisms were determined by using tetra-ARMS-PCR method. There was no significant difference in the genotype distribution of FAS rs2234767 polymorphism between cases and controls. FAS rs1800682, FASL rs5030772, and FASL rs763110 genotypes showed significant associations with an increasing risk of breast cancer (odds ratio OR = 3.18, P = 0.019; OR = 5.08, P = 0.012; OR = 2.40, P = 0.024, respectively). In conclusion, FAS rs2234767 was not associated with breast cancer risk. Though, FAS rs1800682, FASL rs5030772, and FASL rs763110 polymorphisms were associated with the risk of breast cancer in the examined population.

  • 20.
    Hofvander, Jakob
    et al.
    Lund University, Sweden.
    Arbajian, Elsa
    Lund University, Sweden.
    Stenkula, Karin G.
    Lund University, Sweden.
    Lindkvist-Petersson, Karin
    Lund University, Sweden.
    Larsson, Malin
    Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics. Linköping University, Faculty of Science & Engineering.
    Nilsson, Jenny
    Lund University, Sweden.
    Magnusson, Linda
    Lund University, Sweden.
    Vult von Steyern, Fredrik
    Lund University, Sweden; Skåne University Hospital, Sweden.
    Rissler, Pehr
    Department Pathol, Lund, Sweden.
    Hornick, Jason L.
    Harvard Medical Sch, MA 02115 USA.
    Mertens, Fredrik
    Lund University, Sweden; Department Clin Genet, Sweden.
    Frequent low-level mutations of protein kinase D2 in angiolipoma2017In: Journal of Pathology, ISSN 0022-3417, E-ISSN 1096-9896, Vol. 241, no 5, 578-582 p.Article in journal (Refereed)
    Abstract [en]

    Tumours displaying differentiation towards normal fat constitute the most common subgroup of soft tissue neoplasms. A series of such tumours was investigated by whole-exome sequencing followed by targeted ultra-deep sequencing. Eighty per cent of angiolipomas, but not any other tumour type, displayed mutations in the protein kinase D2 (PRKD2) gene, typically in the part encoding the catalytic domain. The absence of other aberrations at the chromosome or RNA level suggests that PRKD2 mutations are critical for angiolipoma development. Consistently, the mutated PRKD2 alleles were present at low (3-15%) frequencies, indicating that only a subset of the tumour cells is affected. Indeed, by sequencing mature fat cells and other cells separately, the former typically showed the highest mutation frequencies. Thus, we hypothesize that altered PRKD2 signalling in the adipocytic cells drives tumourigenesis and, in agreement with its pivotal role in angiogenesis, induces the vessel formation that is characteristic for angiolipoma. Copyright (c) 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley amp; Sons, Ltd.

  • 21.
    Jufvas, Åsa
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Human Adipocytes: Proteomic Approaches2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Type 2 diabetes is characterized by increased levels of glucose in the blood originating from insulin resistance in insulin sensitive tissues and from reduced pancreatic insulin production. Around 400 million people in the world are diagnosed with type 2 diabetes and the correlation with obesity is strong. In addition to life style induction of obesity and type 2 diabetes, there are indications of genetic and epigenetic influences. This thesis has focused on the characterization of primary human adipocytes, who play a crucial role in the development of type 2 diabetes.

    Histones are important proteins in chromatin dynamics and may be one of the factors behind epigenetic inheritance. In paper I, we characterized histone variants and posttranslational modifications in human adipocytes. Several of the specific posttranslational histone modifications we identified have been characterized in other cell types, but the majority was not previously known. Moreover, we identified a variant of histone H4 on protein level for the first time.

    In paper II, we studied specific histone H3 methylations in the adipocytes. We found that overweight is correlated with a reduction of H3K4me2 while type 2 diabetes is associated with an increase of H3K4me3. This shows a genome-wide difference in important chromatin modifications that could help explain the epidemiologically shown association between epigenetics and metabolic health.

    Caveolae is a plasma membrane structure involved in the initial and important steps of insulin signaling. In paper III we characterized the IQGAP1 interactome in human adipocytes and suggest that IQGAP1 is a link between caveolae and the cytoskeleton. Moreover, the amount of IQGAP1 is drastically lower in adipocytes from type 2 diabetic subjects compared with controls implying a potential role for IQGAP1 in insulin resistance.

    In conclusion, this thesis provides new insights into the insulin signaling frameworks and the histone variants and modifications of human adipocytes.

    List of papers
    1. Histone Variants and Their Post-Translational Modifications in Primary Human Fat Cells
    Open this publication in new window or tab >>Histone Variants and Their Post-Translational Modifications in Primary Human Fat Cells
    2011 (English)In: PLOS ONE, ISSN 1932-6203, Vol. 6, no 1Article in journal (Refereed) Published
    Abstract [en]

    Epigenetic changes related to human disease cannot be fully addressed by studies of cells from cultures or from other mammals. We isolated human fat cells from subcutaneous abdominal fat tissue of female subjects and extracted histones from either purified nuclei or intact cells. Direct acid extraction of whole adipocytes was more efficient, yielding about 100 mu g of protein with histone content of 60%-70% from 10 mL of fat cells. Differential proteolysis of the protein extracts by trypsin or ArgC-protease followed by nanoLC/MS/MS with alternating CID/ETD peptide sequencing identified 19 histone variants. Four variants were found at the protein level for the first time; particularly HIST2H4B was identified besides the only H4 isoform earlier known to be expressed in humans. Three of the found H2A potentially organize small nucleosomes in transcriptionally active chromatin, while two H2AFY variants inactivate X chromosome in female cells. HIST1H2BA and three of the identified H1 variants had earlier been described only as oocyte or testis specific histones. H2AFX and H2AFY revealed differential and variable N-terminal processing. Out of 78 histone modifications by acetylation/trimethylation, methylation, dimethylation, phosphorylation and ubiquitination, identified from six subjects, 68 were found for the first time. Only 23 of these modifications were detected in two or more subjects, while all the others were individual specific. The direct acid extraction of adipocytes allows for personal epigenetic analyses of human fat tissue, for profiling of histone modifications related to obesity, diabetes and metabolic syndrome, as well as for selection of individual medical treatments.

    Place, publisher, year, edition, pages
    Public Library of Science (PLoS), 2011
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-65933 (URN)10.1371/journal.pone.0015960 (DOI)000286512900014 ()
    Note

    Original Publication: Asa Jufvas, Peter Strålfors and Alexander Vener, Histone Variants and Their Post-Translational Modifications in Primary Human Fat Cells, 2011, PLOS ONE, (6), 1. http://dx.doi.org/10.1371/journal.pone.0015960 Licensee: Public Library of Science (PLoS) http://www.plos.org/

    Available from: 2011-02-28 Created: 2011-02-28 Last updated: 2016-03-08
    2. Global differences in specific histone H3 methylation are associated with overweight and type 2 diabetes.
    Open this publication in new window or tab >>Global differences in specific histone H3 methylation are associated with overweight and type 2 diabetes.
    Show others...
    2013 (English)In: Clinical Epigenetics, E-ISSN 1868-7083, Vol. 5, no 1, 15Article in journal (Refereed) Published
    Abstract [en]

    BACKGROUND: Epidemiological evidence indicates yet unknown epigenetic mechanisms underlying a propensity for overweight and type 2 diabetes. We analyzed the extent of methylation at lysine 4 and lysine 9 of histone H3 in primary human adipocytes from 43 subjects using modification-specific antibodies.

    RESULTS: The level of lysine 9 dimethylation was stable, while adipocytes from type 2 diabetic and non-diabetic overweight subjects exhibited about 40% lower levels of lysine 4 dimethylation compared with cells from normal-weight subjects. In contrast, trimethylation at lysine 4 was 40% higher in adipocytes from overweight diabetic subjects compared with normal-weight and overweight non-diabetic subjects. There was no association between level of modification and age of subjects.

    CONCLUSIONS: The findings define genome-wide molecular modifications of histones in adipocytes that are directly associated with overweight and diabetes, and thus suggest a molecular basis for existing epidemiological evidence of epigenetic inheritance.

    Place, publisher, year, edition, pages
    BioMed Central, 2013
    National Category
    Endocrinology and Diabetes
    Identifiers
    urn:nbn:se:liu:diva-99450 (URN)10.1186/1868-7083-5-15 (DOI)000329455000001 ()24004477 (PubMedID)
    Available from: 2013-10-18 Created: 2013-10-18 Last updated: 2016-03-08Bibliographically approved
  • 22.
    Knip, Mikael
    et al.
    University of Helsinki, Helsinki, Finland.
    Åkerblom, Hans K
    University of Helsinki, Helsinki, Finland.
    Becker, Dorothy
    University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
    Dosch, Hans-Michael
    University of Toronto, Toronto, Ontario, Canada.
    Dupre, John
    University of Western Ontario, London, Canada.
    Fraser, William
    University of Montréal, Montréal, Québec, Canada.
    Howard, Neville
    Children’s Hospital of Westmead, Sydney, Australia.
    Ilonen, Jorma
    University of Turku, Turku, Finland.
    Krischer, Jeffrey P
    University of South Florida, Tampa, USA.
    Kordonouri, Olga
    Kinder- und Jugendkrankenhaus AUF DER BULT, Hannover, Germany.
    Lawson, Margaret L
    Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada .
    Palmer, Jerry P
    University of Washington, Seattle, USA.
    Savilahti, Erkki
    University of Helsinki, Helsinki, Finland.
    Vaarala, Outi
    National Institute for Health and Welfare, Helsinki, Finland.
    Virtanen, Suvi M
    National Institute for Health and Welfare, Helsinki, Finland.
    Hydrolyzed infant formula and early β-cell autoimmunity: a randomized clinical trial.2014In: Journal of the American Medical Association (JAMA), ISSN 0098-7484, E-ISSN 1538-3598, Vol. 311, no 22, 2279-2287 p.Article in journal (Refereed)
    Abstract [en]

    IMPORTANCE: The disease process leading to clinical type 1 diabetes often starts during the first years of life. Early exposure to complex dietary proteins may increase the risk of β-cell autoimmunity in children at genetic risk for type 1 diabetes. Extensively hydrolyzed formulas do not contain intact proteins.

    OBJECTIVE: To test the hypothesis that weaning to an extensively hydrolyzed formula decreases the cumulative incidence of diabetes-associated autoantibodies in young children.

    DESIGN, SETTING, AND PARTICIPANTS: A double-blind randomized clinical trial of 2159 infants with HLA-conferred disease susceptibility and a first-degree relative with type 1 diabetes recruited from May 2002 to January 2007 in 78 study centers in 15 countries; 1078 were randomized to be weaned to the extensively hydrolyzed casein formula and 1081 were randomized to be weaned to a conventional cows' milk-based formula. The participants were observed to April 16, 2013.

    INTERVENTIONS: The participants received either a casein hydrolysate or a conventional cows' milk formula supplemented with 20% of the casein hydrolysate.

    MAIN OUTCOMES: AND MEASURES: Primary outcome was positivity for at least 2 diabetes-associated autoantibodies out of 4 analyzed. Autoantibodies to insulin, glutamic acid decarboxylase, and the insulinoma-associated-2 (IA-2) molecule were analyzed using radiobinding assays and islet cell antibodies with immunofluorescence during a median observation period of 7.0 years (mean, 6.3 years).

    RESULTS: The absolute risk of positivity for 2 or more islet autoantibodies was 13.4% among those randomized to the casein hydrolysate formula (n = 139) vs 11.4% among those randomized to the conventional formula (n = 117). The unadjusted hazard ratio for positivity for 2 or more autoantibodies among those randomized to be weaned to the casein hydrolysate was 1.21 (95% CI, 0.94-1.54), compared with those randomized to the conventional formula, while the hazard ratio adjusted for HLA risk, duration of breastfeeding, vitamin D use, study formula duration and consumption, and region was 1.23 (95% CI, 0.96-1.58). There were no clinically significant differences in the rate of reported adverse events between the 2 groups.

    CONCLUSIONS AND RELEVANCE: Among infants at risk for type 1 diabetes, the use of a hydrolyzed formula, when compared with a conventional formula, did not reduce the incidence of diabetes-associated autoantibodies after 7 years. These findings do not support a benefit from hydrolyzed formula. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00179777.

  • 23.
    Kottyan, Leah C.
    et al.
    Division of Rheumatology, Center for Autoimmune Genomics and Etiology and US Department of Veterans Affairs Medical Center, Cincinnati, OH, USA .
    Zoller, Erin E.
    Division of Rheumatology, Center for Autoimmune Genomics and Etiology.
    Bene, Jessica
    Division of Rheumatology, Center for Autoimmune Genomics and Etiology.
    Lu, Xiaoming
    Division of Rheumatology, Center for Autoimmune Genomics and Etiology .
    Kelly, Jennifer A.
    Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA..
    Rupert, Andrew M.
    Division of Biomedical Informatics, Cincinnati Childrens Hospital Medical Center, Cincinnati, OH, USA..
    Lessard, Christopher J.
    Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA Department of Pathology .
    Vaughn, Samuel E.
    Division of Rheumatology, Center for Autoimmune Genomics and Etiology.
    Marion, Miranda
    Department of Biostatistical Sciences and Center for Public Health Genomics .
    Weirauch, Matthew T.
    Division of Rheumatology, Center for Autoimmune Genomics and Etiology and US Department of Veterans Affairs Medical Center, Cincinnati, OH, USA Division of Biomedical Informatics, Cincinnati Childrens Hospital Medical Center, Cincinnati, OH, USA..
    Namjou, Bahram
    Division of Rheumatology, Center for Autoimmune Genomics and Etiology .
    Adler, Adam
    Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA..
    Rasmussen, Astrid
    Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA..
    Glenn, Stuart
    Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA..
    Montgomery, Courtney G.
    Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA..
    Hirschfield, Gideon M.
    NIHR Biomedical Research Unit, University of Birmingham, Birmingham, UK..
    Xie, Gang
    Mount Sinai Hospital Samuel Lunenfeld Research Institute, Toronto, ON, Canada..
    Coltescu, Catalina
    Liver Centre, Toronto Western Hospital, Toronto, ON, Canada..
    Amos, Chris
    Department of Community and Family Medicine, Geisel School of Medicine, Dartmouth College, Hanover, NH, USA..
    Li, He
    Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA Department of Pathology and..
    Ice, John A.
    Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA..
    Nath, Swapan K.
    Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA..
    Mariette, Xavier
    Department of Rheumatology, Hôpitaux Universitaires Paris-Sud, INSERM U1012, Le Kremlin Bicêtre, France..
    Bowman, Simon
    Rheumatology Department, University Hospital Birmingham, Birmingham, UK..
    Rischmueller, Maureen
    The Queen Elizabeth Hospital, Adelaide, Australia..
    Lester, Sue
    The Queen Elizabeth Hospital, Adelaide, Australia The University of Adelaide, Adelaide, Australia..
    Brun, Johan G.
    Institute of Internal Medicine, University of Bergen, Bergen, Norway Department of Rheumatology, Haukeland University Hospital, Bergen, Norway..
    Gøransson, Lasse G.
    Clinical Immunology Unit, Department of Internal Medicine, Stavanger University Hospital, Stavanger, Norway..
    Harboe, Erna
    Clinical Immunology Unit, Department of Internal Medicine, Stavanger University Hospital, Stavanger, Norway..
    Omdal, Roald
    Clinical Immunology Unit, Department of Internal Medicine, Stavanger University Hospital, Stavanger, Norway..
    Cunninghame-Graham, Deborah S.
    Department of Medical and Molecular Genetics, Kings College London, London, UK..
    Vyse, Tim
    Department of Medical and Molecular Genetics, Kings College London, London, UK..
    Miceli-Richard, Corinne
    Department of Rheumatology, Hôpitaux Universitaires Paris-Sud, INSERM U1012, Le Kremlin Bicêtre, France..
    Brennan, Michael T.
    Department of Oral Medicine, Carolinas Medical Center, Charlotte, NC, USA..
    Lessard, James A.
    Valley Bone and Joint Clinic, Grand Forks, ND, USA..
    Wahren-Herlenius, Marie
    Department of Medicine, Karolinska Institute, Stockholm, Sweden..
    Kvarnström, Marika
    Department of Medicine, Karolinska Institute, Stockholm, Sweden..
    Illei, Gabor G.
    National Institute of Dental and Craniofacial Research, NIH, Bethesda, MD, USA..
    Witte, Torsten
    Hannover Medical School, Hanover, Germany..
    Jonsson, Roland
    Department of Rheumatology, Haukeland University Hospital, Bergen, Norway Broegelmann Research Laboratory, The Gade Institute, University of Bergen, Bergen, Norway..
    Eriksson, Per
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Rheumatology.
    Nordmark, Gunnel
    Department of Medical Sciences, Rheumatology, Uppsala University, Uppsala, Sweden..
    Ng, Wan-Fai
    Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK..
    Anaya, Juan-Manuel
    Center for Autoimmune Diseases Research (CREA), Universidad del Rosario, Bogotá, Colombia..
    Rhodus, Nelson N.
    Department of Oral Surgery, University of Minnesota School of Dentistry, Minneapolis, MN, USA..
    Segal, Barbara M.
    Division of Rheumatology, University of Minnesota Medical School, Minneapolis, MN, USA..
    Merrill, Joan T.
    Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA..
    James, Judith A.
    Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA..
    Guthridge, Joel M.
    Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA..
    Hal Scofield, R
    Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA Division of Veterans Affairs Medical Center, Oklahoma City, OK, USA Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA..
    Alarcon-Riquelme, Marta
    Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA de Genómica e Investigación Oncológica (GENYO), Pfizer-Universidad de Granada-Junta de Andalucia, Granada, Spain..
    Bae, Sang-Cheol
    Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul, South Korea..
    Boackle, Susan A.
    Division of Rheumatology, University of Colorado School of Medicine, Aurora, CO, USA..
    Criswell, Lindsey A.
    Division of Rheumatology, Rosalind Russell Medical Research Center for Arthritis, University of California San Francisco, San Francisco, CA, USA..
    Gilkeson, Gary
    Division of Rheumatology and Immunology, Medical University of South Carolina, Charleston, SC, USA..
    Kamen, Diane L
    Division of Rheumatology and Immunology, Medical University of South Carolina, Charleston, SC, USA..
    Jacob, Chaim O.
    Divison of Gastrointestinal and Liver Diseases, Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA..
    Kimberly, Robert
    Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA..
    Brown, Elizabeth
    Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA..
    Edberg, Jeffrey
    Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA..
    Alarcón, Graciela S.
    Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA..
    Reveille, John D.
    Division of Rheumatology and Clinical Immunogenetics, The Univeristy of Texas Health Science Center at Houston, Houston, TX, USA..
    Vilá, Luis M.
    University of Puerto Rico Medical Sciences Campus, San Juan, Puerto Rico, USA..
    Petri, Michelle
    Division of Rheumatology, Johns Hopkins, Baltimore, MD, USA..
    Ramsey-Goldman, Rosalind
    Division of Rheumatology, Northwestern University, Chicago, IL, USA..
    Freedman, Barry I.
    Wake Forest School of Medicine, Winston-Salem, NC, USA..
    Niewold, Timothy
    Division of Rheumatology and Immunology, Mayo Clinic, Rochester, MN, USA..
    Stevens, Anne M.
    University of Washington and Seattle Childrens Hospital, Seattle, WA, USA..
    Tsao, Betty P.
    David Geffen School of Medicine, University of California, Los Angeles, CA, USA..
    Ying, Jun
    MD Anderson Cancer Center, University of Texas, Houston, TX, USA..
    Mayes, Maureen D.
    MD Anderson Cancer Center, University of Texas, Houston, TX, USA..
    Gorlova, Olga Y.
    MD Anderson Cancer Center, University of Texas, Houston, TX, USA..
    Wakeland, Ward
    University of Texas Southwestern Medical School, Dallas, TX, USA..
    Radstake, Timothy
    Department of Rheumatology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands..
    Martin, Ezequiel
    Instituto de Parasitología y Biomedicina López Neyra Avda, Granada, Spain and..
    Martin, Javier
    Instituto de Parasitología y Biomedicina López Neyra Avda, Granada, Spain and..
    Siminovitch, Katherine
    Mount Sinai Hospital Samuel Lunenfeld Research Institute, Toronto, ON, Canada Department of Medicine, University of Toronto, Toronto, ON, Canada..
    Moser Sivils, Kathy L.
    Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA..
    Gaffney, Patrick M.
    Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA..
    Langefeld, Carl D.
    Department of Biostatistical Sciences and Center for Public Health Genomics and..
    Harley, John B.
    Division of Rheumatology, Center for Autoimmune Genomics and Etiology and US Department of Veterans Affairs Medical Center, Cincinnati, OH, USA..
    Kaufman, Kenneth M.
    Division of Rheumatology, Center for Autoimmune Genomics and Etiology and US Department of Veterans Affairs Medical Center, Cincinnati, OH, USA..
    The IRF5-TNPO3 association with systemic lupus erythematosus has two components that other autoimmune disorders variably share.2015In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 24, no 2, 582-596 p.Article in journal (Refereed)
    Abstract [en]

    Exploiting genotyping, DNA sequencing, imputation and trans-ancestral mapping, we used Bayesian and frequentist approaches to model the IRF5-TNPO3 locus association, now implicated in two immunotherapies and seven autoimmune diseases. Specifically, in systemic lupus erythematosus (SLE), we resolved separate associations in the IRF5 promoter (all ancestries) and with an extended European haplotype. We captured 3230 IRF5-TNPO3 high-quality, common variants across 5 ethnicities in 8395 SLE cases and 7367 controls. The genetic effect from the IRF5 promoter can be explained by any one of four variants in 5.7 kb (P-valuemeta = 6 × 10(-49); OR = 1.38-1.97). The second genetic effect spanned an 85.5-kb, 24-variant haplotype that included the genes IRF5 and TNPO3 (P-valuesEU = 10(-27)-10(-32), OR = 1.7-1.81). Many variants at the IRF5 locus with previously assigned biological function are not members of either final credible set of potential causal variants identified herein. In addition to the known biologically functional variants, we demonstrated that the risk allele of rs4728142, a variant in the promoter among the lowest frequentist probability and highest Bayesian posterior probability, was correlated with IRF5 expression and differentially binds the transcription factor ZBTB3. Our analytical strategy provides a novel framework for future studies aimed at dissecting etiological genetic effects. Finally, both SLE elements of the statistical model appear to operate in Sjögrens syndrome and systemic sclerosis whereas only the IRF5-TNPO3 gene-spanning haplotype is associated with primary biliary cirrhosis, demonstrating the nuance of similarity and difference in autoimmune disease risk mechanisms at IRF5-TNPO3.

  • 24.
    Kroczak, Tadeusz J.
    et al.
    Manitoba Institute of Cell Biology (MICB), 675 McDermot Avenue, Rm. ON6010, Winnipeg, MB, R3E 0V9, Canada.
    Baran, Jarosław
    Jagiellonian University Medical College, Krakow, Poland.
    Pryjma, Juliusz
    Institute of Molecular Biology, Krakow, Poland.
    Siedlar, Marcin
    , Jagiellonian University Medical College, Krakow, Poland.
    Rashedi, Iran
    Manitoba Institute of Cell Biology, CancerCare Manitoba, University of Manitoba, Winnipeg, Manitoba, Canada; Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Canada .
    Hernandez, Elisabeth
    International Center for Neurological Restoration (CIREN), Havana, Cuba.
    Alberti, Esteban
    International Center for Neurological Restoration (CIREN), Havana, Cuba.
    Maddika, Subbareddy
    Manitoba Institute of Cell Biology, Cancer Care Manitoba; Department of Biochemistry and Medical Genetics,University of Manitoba, Winnipeg, Canada .
    Los, Marek Jan
    Department of Immunology and Cell Biology, University of Münster, Münster, Germany.
    The emerging importance of DNA mapping and other comprehensive screening techniques, as tools to identify new drug targets and as a means of (cancer) therapy personalisation2006In: Expert opinion on therapeutic targets, ISSN 1472-8222, E-ISSN 1744-7631, ISSN 1472-8222, Vol. 10, no 2, 289-302 p.Article, review/survey (Refereed)
    Abstract [en]

    Every human being is genetically unique and this individuality is not only marked by morphologic and physical characteristics but also by an individual's response to a particular drug. Single nucleotide polymorphisms (SNPs) are largely responsible for one's individuality. A drug may be ineffective in one patient, whereas the exact same drug may cure another patient. Recent advances in DNA mapping and other screening technologies have provided researchers and drug developers with crucial information needed to create drugs that are specific for a given individual. In the future, physicians will be able to prescribe individualised drugs adjusted to, for example, activities of specific enzymatic pathways that would either be targeted by these drugs, or would be responsible for drug conversion or inactivation. Furthermore, the mapping of the human genome allows broader development and application of drugs that act on the level of gene transcription rather than as simple biochemical inhibitors or activators of certain enzymes. Such new approaches will maximise desired therapeutic results and may completely eliminate severe side effects. To illustrate the potential of genetic translational research, the authors discuss available analytical methodologies such as; gene arrays, flow cytometry-based screening for SNPs, proteomics, metabolomics, real-time PCR, and other methods capable of detecting both SNPs, as well as more profound changes in cell metabolism. Finally, the authors provide several examples that focus mostly on targeting protein-DNA interactions, but also other processes.

  • 25.
    Langefeld, Carl D.
    et al.
    Wake Forest School Med, NC 27101 USA; Wake Forest School Med, NC 27101 USA.
    Ainsworth, Hannah C.
    Wake Forest School Med, NC 27101 USA; Wake Forest School Med, NC 27101 USA.
    Cunninghame Graham, Deborah S.
    Kings Coll London, England.
    Kelly, Jennifer A.
    Oklahoma Medical Research Fdn, OK 73104 USA.
    Comeau, Mary E.
    Wake Forest School Med, NC 27101 USA.
    Marion, Miranda C.
    Wake Forest School Med, NC 27101 USA.
    Howard, Timothy D.
    Wake Forest School Med, NC 27101 USA.
    Ramos, Paula S.
    Medical University of South Carolina, SC 29425 USA.
    Croker, Jennifer A.
    UAB School Med, AL 35294 USA.
    Morris, David L.
    Kings Coll London, England.
    Sandling, Johanna K.
    Uppsala University, Sweden; University of Nacl Mayor San Marcos, Peru.
    Carlsson Almlof, Jonas
    Uppsala University, Sweden; University of Nacl Mayor San Marcos, Peru.
    Acevedo-Vasquez, Eduardo M.
    University of Nacl Mayor San Marcos, Peru.
    Alarcon, Graciela S.
    UAB School of Medicine, Birmingham, Alabama, USA.
    Babini, Alejandra M.
    Hospital Italiano Cordoba, Argentina.
    Baca, Vicente
    Hospital Pediat Mexico City, Mexico.
    Bengtsson, Anders A.
    Lund University, Sweden.
    Berbotto, Guillermo A.
    Hospital Eva Peron, Argentina.
    Bijl, Marc
    Martini Hospital, Netherlands.
    Brown, Elizabeth E.
    UAB School of Medicine, Birmingham, Alabama, USA..
    Brunner, Hermine I.
    Cincinnati Childrens Hospital Medical Centre, OH 45229 USA; University of Cincinnati, OH 45229 USA.
    Cardiel, Mario H.
    Centre Invest Clin Morelia, Mexico.
    Catoggio, Luis
    Hospital Italiano Buenos Aires, Argentina.
    Cervera, Ricard
    University of Barcelona, Spain.
    Cucho-Venegas, Jorge M.
    University of Nacl Mayor San Marcos, Peru.
    Rantapaa Dahlqvist, Solbritt
    Umeå University, Sweden.
    DAlfonso, Sandra
    University of Piemonte Orientale, Italy.
    Martins Da Silva, Berta
    University of Porto, Portugal.
    de la Rua Figueroa, Inigo
    Hospital University of Gran Canaria Dr Negrin, Spain.
    Doria, Andrea
    University of Padua, Italy.
    Edberg, Jeffrey C.
    UAB School Med, AL 35294 USA.
    Endreffy, Emoke
    University of Szeged, Hungary; University of Szeged, Hungary.
    Esquivel-Valerio, Jorge A.
    Hospital University of Dr Jose Eleuterio Gonzalez University of Autonom, Mexico.
    Fortin, Paul R.
    University of Laval, Canada.
    Freedman, Barry I.
    Wake Forest School Med, NC 27101 USA; Wake Forest School Med, NC 27101 USA; Wake Forest School Med, NC 27101 USA.
    Frostegard, Johan
    Karolinska Institute, Sweden.
    Garcia, Mercedes A.
    Hospital Interzonal Gen Agudos Gen San Martin, Argentina.
    Garcia de la Torre, Ignacio
    University of Guadalajara, Mexico.
    Gilkeson, Gary S.
    Medical University of South Carolina, SC 29425 USA.
    Gladman, Dafna D.
    Toronto Western Hospital, Canada.
    Gunnarsson, Iva
    Karolinska University Hospital, Sweden.
    Guthridge, Joel M.
    Oklahoma Medical Research Fdn, OK 73104 USA.
    Huggins, Jennifer L.
    Cincinnati Childrens Hospital Medical Centre, OH 45229 USA; University of Cincinnati, OH 45229 USA.
    James, Judith A.
    Hospital Eva Peron, Argentina; University of Oklahoma, OK 73104 USA; University of Oklahoma, OK 73104 USA.
    Kallenberg, Cees G. M.
    University of Medical Centre Groningen, Netherlands.
    Kamen, Diane L.
    Medical University of South Carolina, Charleston, USA.
    Karp, David R.
    University of Texas Southwestern Medical Centre Dallas, TX 75235 USA.
    Kaufman, Kenneth M.
    Cincinnati Childrens Hospital Medical Centre, OH 45229 USA.
    Kottyan, Leah C.
    Cincinnati Childrens Hospital Medical Centre, OH 45229 USA.
    Kovacs, Laszlo
    University of Szeged, Hungary.
    Laustrup, Helle
    Odense University Hospital, Denmark.
    Lauwerys, Bernard R.
    Catholic University of Louvain, Belgium; Catholic University of Louvain, Belgium.
    Li, Quan-Zhen
    University of Texas Southwestern Medical Centre Dallas, TX 75235 USA.
    Maradiaga-Cecena, Marco A.
    Hospital Gen Culiacan, Mexico.
    Martin, Javier
    CSIC, Spain.
    McCune, Joseph M.
    University of Michigan, MI 48103 USA.
    McWilliams, David R.
    Wake Forest School Med, NC 27101 USA; Wake Forest School Med, NC 27101 USA.
    Merrill, Joan T.
    Oklahoma Medical Research Fdn, OK 73104 USA.
    Miranda, Pedro
    Centre Estudios Reumatol, Chile.
    Moctezuma, Jose F.
    Hospital Gen Mexico City, Mexico.
    Nath, Swapan K.
    Oklahoma Medical Research Fdn, OK 73104 USA.
    Niewold, Timothy B.
    Mayo Clin, MN 94158 USA.
    Orozco, Lorena
    Institute Nacl Medical Genom INMEGEN, Mexico.
    Ortego-Centeno, Norberto
    Hospital University of San Cecilio, Spain.
    Petri, Michelle
    Johns Hopkins University, MD 21218 USA.
    Pineau, Christian A.
    McGill University, Canada.
    Pons-Estel, Bernardo A.
    Sanatorio Parque, Argentina.
    Pope, Janet
    University of Western Ontario, Canada.
    Raj, Prithvi
    University of Texas Southwestern Medical Centre Dallas, TX 75235 USA.
    Ramsey-Goldman, Rosalind
    Northwestern University, IL 60611 USA.
    Reveille, John D.
    University of Texas Health Science Centre Houston UTHealth, TX 77030 USA.
    Russell, Laurie P.
    Wake Forest School Med, NC 27101 USA.
    Sabio, Jose M.
    Hospital University of Virgen de las Nieves, Spain.
    Aguilar-Salinas, Carlos A.
    Institute Nacl Ciencias Medical and Nutr Salvador Zubiran, Mexico.
    Scherbarth, Hugo R.
    Autoinmunes HIGA Dr Alende Mar Plata, Argentina.
    Scorza, Raffaella
    Fdn IRCCS CaGranda Osped Ma Repiore Policlin, Italy; University of Milan, Italy.
    Seldin, Michael F.
    UC Davis School Med, CA 95616 USA.
    Sjöwall, Christopher
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Rheumatology.
    Svenungsson, Elisabet
    Karolinska University Hospital, Sweden.
    Thompson, Susan D.
    Cincinnati Childrens Hospital Medical Centre, OH 45229 USA.
    Toloza, Sergio M. A.
    Minist Heatlh, Argentina.
    Truedsson, Lennart
    Lund University, Sweden.
    Tusie-Luna, Teresa
    UNAM Institute Nacl Ciencias Medical and Nutr Salvador Zubir, Mexico.
    Vasconcelos, Carlos
    University of Porto, Portugal.
    Vila, Luis M.
    University of Puerto Rico, PR 00936 USA.
    Wallace, Daniel J.
    Cedars Sinai Medical Centre, CA 90048 USA.
    Weisman, Michael H.
    Cedars Sinai Medical Centre, CA 90048 USA.
    Wither, Joan E.
    Toronto Western Hospital, Canada.
    Bhangale, Tushar
    Genentech Inc, CA 94080 USA.
    Oksenberg, Jorge R.
    University of Calif San Francisco, CA 94158 USA; University of Calif San Francisco, CA 94158 USA.
    Rioux, John D.
    University of Montreal, Canada; Montreal Heart Institute, Canada.
    Gregersen, Peter K.
    Feinstein Institute Medical Research, NY 11030 USA.
    Syvanen, Ann-Christine
    Uppsala University, Sweden; University of Nacl Mayor San Marcos, Peru.
    Ronnblom, Lars
    Uppsala University, Sweden.
    Criswell, Lindsey A.
    UCSF School Med, CA 94158 USA.
    Jacob, Chaim O.
    Keck School Medical USC, CA 90033 USA.
    Sivils, Kathy L.
    Oklahoma Medical Research Fdn, OK 73104 USA.
    Tsao, Betty P.
    Medical University of South Carolina, SC 29425 USA.
    Schanberg, Laura E.
    Duke University, NC 27708 USA.
    Behrens, Timothy W.
    Genentech Inc, CA 94080 USA.
    Silverman, Earl D.
    Hospital Sick Children, Canada; Hospital Sick Children, Canada; University of Toronto, Canada.
    Alarcon-Riquelme, Marta E.
    Oklahoma Medical Research Fdn, OK 73104 USA; University of Granada, Spain; Karolinska Institute, Sweden.
    Kimberly, Robert P.
    UAB School Med, AL 35294 USA.
    Harley, John B.
    Cincinnati Childrens Hospital Medical Centre, OH 45229 USA.
    Wakeland, Edward K.
    University of Texas Southwestern Medical Centre Dallas, TX 75235 USA.
    Graham, Robert R.
    Genentech Inc, CA 94080 USA.
    Gaffney, Patrick M.
    Oklahoma Medical Research Fdn, OK 73104 USA.
    Vyse, Timothy J.
    Kings Coll London, England.
    Transancestral mapping and genetic load in systemic lupus erythematosus2017In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 8, 16021Article in journal (Refereed)
    Abstract [en]

    Systemic lupus erythematosus (SLE) is an autoimmune disease with marked gender and ethnic disparities. We report a large transancestral association study of SLE using Immunochip genotype data from 27,574 individuals of European (EA), African (AA) and Hispanic Amerindian (HA) ancestry. We identify 58 distinct non-HLA regions in EA, 9 in AA and 16 in HA (similar to 50% of these regions have multiple independent associations); these include 24 novel SLE regions (P amp;lt; 5 x 10(-8)), refined association signals in established regions, extended associations to additional ancestries, and a disentangled complex HLA multigenic effect. The risk allele count (genetic load) exhibits an accelerating pattern of SLE risk, leading us to posit a cumulative hit hypothesis for autoimmune disease. Comparing results across the three ancestries identifies both ancestry-dependent and ancestry-independent contributions to SLE risk. Our results are consistent with the unique and complex histories of the populations sampled, and collectively help clarify the genetic architecture and ethnic disparities in SLE.

  • 26.
    Lawrenson, Kate
    et al.
    University of Southern Calif, CA 90033 USA; Cedars Sinai Medical Centre, CA 90048 USA.
    Kar, Siddhartha
    University of Cambridge, England.
    McCue, Karen
    QIMR Berghofer Medical Research Institute, Australia.
    Kuchenbaeker, Karoline
    University of Cambridge, England.
    Michailidou, Kyriaki
    University of Cambridge, England.
    Tyrer, Jonathan
    University of Cambridge, England.
    Beesley, Jonathan
    QIMR Berghofer Medical Research Institute, Australia.
    Ramus, Susan J.
    University of Southern Calif, CA 90033 USA.
    Li, Qiyuan
    Xiamen University, Peoples R China; Dana Farber Cancer Institute, MA 02215 USA.
    Delgado, Melissa K.
    University of Southern Calif, CA 90033 USA.
    Lee, Janet M.
    University of Southern Calif, CA 90033 USA.
    Aittomaki, Kristiina
    University of Helsinki, Finland.
    Andrulis, Irene L.
    Mt Sinai Hospital, Canada; University of Toronto, Canada.
    Anton-Culver, Hoda
    University of Calif Irvine, CA 92697 USA.
    Arndt, Volker
    German Cancer Research Centre, Germany.
    Arun, Banu K.
    University of Texas MD Anderson Cancer Centre, TX 77030 USA.
    Arver, Brita
    Karolinska University Hospital, Sweden.
    Bandera, Elisa V.
    Rutgers Cancer Institute New Jersey, NJ 08903 USA.
    Barile, Monica
    Ist Europeo Oncol, Italy.
    Barkardottir, Rosa B.
    University of Iceland, Iceland; University of Iceland, Iceland.
    Barrowdale, Daniel
    University of Cambridge, England.
    Beckmann, Matthias W.
    University of Erlangen Nurnberg, Germany.
    Benitez, Javier
    Spanish National Cancer Research Centre, Spain; Centre Invest Red Enfermedades Raras, Spain.
    Berchuck, Andrew
    Duke University, NC 27710 USA.
    Bisogna, Maria
    Mem Sloan Kettering Cancer Centre, NY 10065 USA.
    Bjorge, Line
    Haukeland Hospital, Norway; University of Bergen, Norway.
    Blomqvist, Carl
    University of Helsinki, Finland.
    Blot, William
    Vanderbilt University, TN 37203 USA; Int Epidemiol Institute, MD 20850 USA.
    Bogdanova, Natalia
    Hannover Medical Sch, Germany.
    Bojesen, Anders
    Vejle Hospital, Denmark; Seoul National University, South Korea; Lunenfeld Tanenbaum Research Institute Mt Sinai Hospital, Canada.
    Bojesen, Stig E.
    University of Copenhagen, Denmark; Copenhagen University Hospital, Denmark; Copenhagen University Hospital, Denmark.
    Bolla, Manjeet K.
    University of Cambridge, England.
    Bonanni, Bernardo
    Ist Europeo Oncol, Italy.
    Borresen-Dale, Anne-Lise
    Oslo University Hospital, Norway; University of Oslo, Norway.
    Brauch, Hiltrud
    Dr Margarete Fischer Bosch Institute Clin Pharmacol, Germany; University of Tubingen, Germany; German Cancer Research Centre, Germany.
    Brennan, Paul
    Int Agency Research Canc, France.
    Brenner, Hermann
    German Cancer Research Centre, Germany; German Cancer Research Centre, Germany; German Cancer Research Centre, Germany.
    Bruinsma, Fiona
    Cancer Council Victoria, Australia.
    Brunet, Joan
    Catalan Institute Oncol, Spain.
    Ahmad Buhari, Shaik
    National University of Health Syst, Singapore.
    Burwinkel, Barbara
    German Cancer Research Centre, Germany; Heidelberg University, Germany.
    Butzow, Ralf
    University of Helsinki, Finland.
    Buys, Saundra S.
    University of Utah, UT 84112 USA.
    Cai, Qiuyin
    Vanderbilt University, TN 37203 USA.
    Caldes, Trinidad
    IdISSC El Institute Invest Sanitaria Hospital Clin San Car, Spain.
    Campbell, Ian
    Peter MacCallum Cancer Centre, Australia.
    Canniotto, Rikki
    Roswell Pk Cancer Institute, NY 14263 USA.
    Chang-Claude, Jenny
    German Cancer Research Centre, Germany; University of Medical Centre Hamburg Eppendorf, Germany.
    Chiquette, Jocelyne
    University of Quebec, Canada.
    Choi, Ji-Yeob
    Seoul National University, South Korea.
    Claes, Kathleen B. M.
    University of Ghent, Belgium.
    Cook, Linda S.
    University of New Mexico, NM 87131 USA.
    Cox, Angela
    University of Sheffield, England.
    Cramer, Daniel W.
    Harvard University, MA 02115 USA; Brigham and Womens Hospital, MA 02115 USA; Harvard University, MA 02115 USA.
    Cross, Simon S.
    University of Sheffield, England.
    Cybulski, Cezary
    Pomeranian Medical University, Poland.
    Czene, Kamila
    Karolinska Institute, Sweden.
    Daly, Mary B.
    Fox Chase Cancer Centre, PA 19111 USA.
    Damiola, Francesca
    University of Lyon, France.
    Dansonka-Mieszkowska, Agnieszka
    Maria Sklodowska Curie Mem Cancer Centre, Poland; Institute Oncol, Poland.
    Darabi, Hatef
    Karolinska Institute, Sweden.
    Dennis, Joe
    University of Cambridge, England.
    Devilee, Peter
    Leiden University, Netherlands.
    Diez, Orland
    University Hospital Vall Hebron, Spain; University of Autonoma Barcelona, Spain.
    Doherty, Jennifer A.
    Geisel School Medical Dartmouth, NH 03755 USA.
    Domchek, Susan M.
    University of Penn, PA 19104 USA.
    Dorfling, Cecilia M.
    University of Pretoria, South Africa.
    Doerk, Thilo
    Hannover Medical Sch, Germany.
    Dumont, Martine
    University of Laval, Canada.
    Ehrencrona, Hans
    Uppsala University, Sweden; University of Lund Hospital, Sweden.
    Ejlertsen, Bent
    Copenhagen University Hospital, Denmark.
    Ellis, Steve
    University of Cambridge, England.
    Engel, Christoph
    University of Leipzig, Germany.
    Lee, Eunjung
    University of Southern Calif, CA 90033 USA.
    Gareth Evans, D.
    University of Manchester, England.
    Fasching, Peter A.
    University of Erlangen Nurnberg, Germany; University of Calif Los Angeles, CA 90095 USA.
    Feliubadalo, Lidia
    Catalan Institute Oncol, Spain.
    Figueroa, Jonine
    NCI, MD 20892 USA.
    Flesch-Janys, Dieter
    University of Medical Centre Hamburg Eppendorf, Germany; University of Medical Centre Hamburg Eppendorf, Germany.
    Fletcher, Olivia
    Institute Cancer Research, England.
    Flyger, Henrik
    Copenhagen University Hospital, Denmark.
    Foretova, Lenka
    Masaryk Mem Cancer Institute, Czech Republic; Medical Fac MU, Czech Republic.
    Fostira, Florentia
    Aghia Paraskevi Attikis, Greece.
    Foulkes, William D.
    McGill University, Canada.
    Fridley, Brooke L.
    University of Kansas, KS 66103 USA.
    Friedman, Eitan
    Chaim Sheba Medical Centre, Israel.
    Frost, Debra
    University of Cambridge, England.
    Gambino, Gaetana
    University of and University Hospital Pisa, Italy.
    Ganz, Patricia A.
    Jonsson Comprehens Cancer Centre, CA 90024 USA.
    Garber, Judy
    Dana Farber Cancer Institute, MA 02215 USA.
    Garcia-Closas, Montserrat
    NCI, MD 20892 USA; Institute Cancer Research, England.
    Gentry-Maharaj, Aleksandra
    UCL EGA Institute Womens Heatlh, England.
    Ghoussaini, Maya
    University of Cambridge, England.
    Giles, Graham G.
    Cancer Council Victoria, Australia; University of Melbourne, Australia.
    Glasspool, Rosalind
    Beatson West Scotland Cancer Centre, Scotland.
    Godwin, Andrew K.
    University of Kansas, KS 66160 USA.
    Goldberg, Mark S.
    McGill University, Canada; McGill University, Canada.
    Goldgar, David E.
    University of Utah, UT 84132 USA.
    Gonzalez-Neira, Anna
    Spanish National Cancer Research Centre, Spain.
    Goode, Ellen L.
    Mayo Clin, MN 55902 USA.
    Goodman, Marc T.
    Cedars Sinai Medical Centre, CA 90048 USA; Cedars Sinai Medical Centre, CA 90048 USA.
    Greene, Mark H.
    NCI, MD 20892 USA.
    Gronwald, Jacek
    Pomeranian Medical University, Poland.
    Guenel, Pascal
    INSERM, France; University of Paris 11, France.
    Haiman, Christopher A.
    University of Southern Calif, CA 90033 USA.
    Hall, Per
    Karolinska Institute, Sweden.
    Hallberg, Emily
    Mayo Clin, MN 55902 USA.
    Hamann, Ute
    German Cancer Research Centre, Germany.
    Hansen, Thomas V. O.
    Copenhagen University Hospital, Denmark.
    Harrington, Patricia A.
    University of Cambridge, England.
    Hartman, Mikael
    National University of Health Syst, Singapore; National University of Singapore, Singapore.
    Hassan, Norhashimah
    University of Malaya, Malaysia; Cancer Research Initiat Fdn, Malaysia.
    Healey, Sue
    QIMR Berghofer Medical Research Institute, Australia.
    Heitz, Florian
    Kliniken Essen Mitte, Germany; Dr Horst Schmidt Kliniken Wiesbaden, Germany.
    Herzog, Josef
    City Hope Clin Cancer Genet Community Research Network, CA 91010 USA.
    Hogdall, Estrid
    University of Copenhagen, Denmark; Danish Cancer Soc Research Centre, Denmark.
    Hogdall, Claus K.
    University of Copenhagen, Denmark.
    Hogervorst, Frans B. L.
    Netherlands Cancer Institute, Netherlands.
    Hollestelle, Antoinette
    Erasmus MC Cancer Institute, Netherlands.
    Hopper, John L.
    University of Melbourne, Australia.
    Hulick, Peter J.
    NorthShore University of Health Syst, IL 60201 USA.
    Huzarski, Tomasz
    Pomeranian Medical University, Poland.
    Imyanitov, Evgeny N.
    NN Petrov Institute Oncol, Russia.
    Isaacs, Claudine
    Georgetown University, DC 20057 USA.
    Ito, Hidemi
    Aichi Cancer Centre, Japan.
    Jakubowska, Anna
    Pomeranian Medical University, Poland.
    Janavicius, Ramunas
    Centre Innovat Med, Lithuania.
    Jensen, Allan
    University of Copenhagen, Denmark.
    John, Esther M.
    Cancer Prevent Institute Calif, CA 94538 USA.
    Johnson, Nichola
    Institute Cancer Research, England.
    Kabisch, Maria
    German Cancer Research Centre, Germany.
    Kang, Daehee
    Seoul National University, South Korea.
    Kapuscinski, Miroslav
    University of Melbourne, Australia.
    Karlan, Beth Y.
    Cedars Sinai Medical Centre, CA 90048 USA.
    Khan, Sofia
    University of Helsinki, Finland.
    Kiemeney, Lambertus A.
    Radboud University of Nijmegen, Netherlands.
    Kruger Kjaer, Susanne
    Danish Cancer Soc Research Centre, Denmark; University of Copenhagen, Denmark.
    Knight, Julia A.
    Lunenfeld Tanenbaum Research Institute Mt Sinai Hospital, Canada; University of Toronto, Canada.
    Konstantopoulou, Irene
    Aghia Paraskevi Attikis, Greece.
    Kosma, Veli-Matti
    Kuopio University Hospital, Finland; University of Eastern Finland, Finland.
    Kristensen, Vessela
    Oslo University Hospital, Norway; University of Oslo, Norway; University of Oslo, Norway.
    Kupryjanczyk, Jolanta
    Maria Sklodowska Curie Mem Cancer Centre, Poland; Institute Oncol, Poland.
    Kwong, Ava
    Hong Kong Sanat and Hospital, Peoples R China; University of Hong Kong, Peoples R China.
    de la Hoya, Miguel
    IdISSC El Institute Invest Sanitaria Hospital Clin San Car, Spain.
    Laitman, Yael
    Chaim Sheba Medical Centre, Israel.
    Lambrechts, Diether
    VIB, Belgium; University of Leuven, Belgium.
    Le, Nhu
    University of Southern Calif, CA 90033 USA.
    De Leeneer, Kim
    University of Ghent, Belgium.
    Lester, Jenny
    Cedars Sinai Medical Centre, CA 90048 USA.
    Levine, Douglas A.
    Mem Sloan Kettering Cancer Centre, NY 10065 USA.
    Li, Jingmei
    Karolinska Institute, Sweden.
    Lindblom, Annika
    Karolinska Institute, Sweden.
    Long, Jirong
    Vanderbilt University, TN 37203 USA.
    Lophatananon, Artitaya
    University of Warwick, England.
    Loud, Jennifer T.
    NCI, MD 20892 USA.
    Lu, Karen
    University of Texas MD Anderson Cancer Centre, TX 77030 USA.
    Lubinski, Jan
    Pomeranian Medical University, Poland.
    Mannermaa, Arto
    Kuopio University Hospital, Finland; Kuopio University Hospital, Finland; University of Eastern Finland, Finland.
    Manoukian, Siranoush
    Ist Nazl Tumori, Italy.
    Le Marchand, Loic
    University of Hawaii, HI 96813 USA.
    Margolin, Sara
    Karolinska Institute, Sweden.
    Marme, Frederik
    Heidelberg University, Germany; Heidelberg University, Germany.
    Massuger, Leon F. A. G.
    Radboud University of Nijmegen, Netherlands.
    Matsuo, Keitaro
    Kyushu University, Japan.
    Mazoyer, Sylvie
    University of Lyon, France.
    McGuffog, Lesley
    University of Cambridge, England.
    McLean, Catriona
    Alfred Hospital, Australia.
    McNeish, Iain
    University of Glasgow, Scotland.
    Meindl, Alfons
    Technical University of Munich, Germany.
    Menon, Usha
    UCL EGA Institute Womens Heatlh, England.
    Mensenkamp, Arjen R.
    Radboud University of Nijmegen, Netherlands.
    Milne, Roger L.
    Cancer Council Victoria, Australia; University of Melbourne, Australia.
    Montagna, Marco
    IRCCS, Italy.
    Moysich, Kirsten B.
    Roswell Pk Cancer Institute, NY 14263 USA.
    Muir, Kenneth
    University of Warwick, England; University of Manchester, England.
    Mulligan, Anna Marie
    University of Health Network, Canada; University of Toronto, Canada.
    Nathanson, Katherine L.
    University of Penn, PA 19104 USA.
    Ness, Roberta B.
    University of Texas Houston, TX 77030 USA.
    Neuhausen, Susan L.
    Beckman Research Institute City Hope, CA 91010 USA.
    Nevanlinna, Heli
    University of Helsinki, Finland; University of Helsinki, Finland.
    Nord, Silje
    University of Oslo, Norway.
    Nussbaum, Robert L.
    University of Calif San Francisco, CA 94143 USA.
    Odunsi, Kunle
    Roswell Pk Cancer Institute, NY 14263 USA.
    Offit, Kenneth
    Mem Sloan Kettering Cancer Centre, NY 10065 USA.
    Olah, Edith
    National Institute Oncol, Hungary.
    Olopade, Olufunmilayo I.
    University of Chicago, IL 60637 USA.
    Olson, Janet E.
    Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, USA.
    Olswold, Curtis
    Mayo Clin, MN 55902 USA.
    OMalley, David
    Ohio State University, OH 43210 USA; James Graham Brown Cancer Centre, OH 43210 USA.
    Orlow, Irene
    Mem Sloan Kettering Cancer Centre, NY 10017 USA.
    Orr, Nick
    Institute Cancer Research, England.
    Osorio, Ana
    University of Copenhagen, Denmark; Spanish National Cancer Centre CNIO, Spain; Biomed Network Rare Disease CIBERER, Spain.
    Kyung Park, Sue
    Seoul National University, South Korea; Seoul National University, South Korea; Seoul National University, South Korea.
    Pearce, Celeste L.
    University of Southern Calif, CA 90033 USA.
    Pejovic, Tanja
    Oregon Health and Science University, OR 97239 USA; Oregon Health and Science University, OR 97239 USA.
    Peterlongo, Paolo
    FIRC Italian Fdn Cancer Research, Italy.
    Pfeiler, Georg
    Medical University of Vienna, Austria.
    Phelan, Catherine M.
    H Lee Moffitt Cancer Centre and Research Institute, FL 33606 USA.
    Poole, Elizabeth M.
    Harvard University, MA 02115 USA; Brigham and Womens Hospital, MA 02115 USA; Harvard University, MA 02115 USA.
    Pylkas, Katri
    Centre NordLab, Finland; University of Oulu, Finland.
    Radice, Paolo
    Ist Nazl Tumori, Italy.
    Rantala, Johanna
    Karolinska University Hospital, Sweden.
    Usman Rashid, Muhammad
    German Cancer Research Centre, Germany; Shaukat Khanum Mem Cancer Hospital and Research Centre SKMCH and RC, Pakistan.
    Rennert, Gad
    Clalit National Israeli Cancer Control Centre, Israel; Carmel Hospital, Israel.
    Rhenius, Valerie
    University of Cambridge, England.
    Rhiem, Kerstin
    University Hospital Cologne, Germany; University Hospital Cologne, Germany.
    Risch, Harvey A.
    Yale University, CT 06510 USA.
    Rodriguez, Gus
    NorthShore University of HealthSyst, IL 60201 USA.
    Anne Rossing, Mary
    Fred Hutchinson Cancer Research Centre, WA 98109 USA; University of Washington, WA 98109 USA.
    Rudolph, Anja
    German Cancer Research Centre, Germany.
    Salvesen, Helga B.
    Haukeland Hospital, Norway; University of Bergen, Norway.
    Sangrajrang, Suleeporn
    National Cancer Institute, Thailand.
    Sawyer, Elinor J.
    Kings Coll London, England.
    Schildkraut, Joellen M.
    Duke University, NC 27710 USA; Duke Cancer Institute, NC 27710 USA.
    Schmidt, Marjanka K.
    Netherlands Cancer Institute, Netherlands.
    Schmutzler, Rita K.
    University Hospital Cologne, Germany; University Hospital Cologne, Germany; University Hospital Cologne, Germany; University Hospital Cologne, Germany.
    Sellers, Thomas A.
    H Lee Moffitt Cancer Centre and Research Institute, FL 33606 USA.
    Seynaeve, Caroline
    Erasmus MC Cancer Institute, Netherlands.
    Shah, Mitul
    University of Cambridge, England.
    Shen, Chen-Yang
    Academic Sinica, Taiwan; China Medical University, Taiwan.
    Shu, Xiao-Ou
    Vanderbilt University, TN 37203 USA.
    Sieh, Weiva
    Stanford University, CA 94305 USA.
    Singer, Christian F.
    Medical University of Vienna, Austria.
    Sinilnikova, Olga M.
    Centre Leon Berard, France; University of Lyon 1, France.
    Slager, Susan
    Mayo Clin, MN 55902 USA.
    Song, Honglin
    University of Cambridge, England.
    Soucy, Penny
    University of Laval, Canada.
    Southey, Melissa C.
    University of Melbourne, Australia.
    Stenmark Askmalm, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics. University of Lund Hospital, Sweden.
    Stoppa-Lyonnet, Dominique
    Institute Curie, France; Institute Curie, France; Sorbonne Paris Cite, France.
    Sutter, Christian
    University of Heidelberg Hospital, Germany.
    Swerdlow, Anthony
    Institute Cancer Research, England; Institute Cancer Research, England.
    Tchatchou, Sandrine
    Mt Sinai Hospital, Canada.
    Teixeira, Manuel R.
    Portuguese Oncology Institute, Portugal; University of Porto, Portugal.
    Teo, Soo H.
    University of Malaya, Malaysia; Cancer Research Initiat Fdn, Malaysia.
    Terry, Kathryn L.
    Harvard University, MA 02115 USA; Brigham and Womens Hospital, MA 02115 USA; Harvard University, MA 02115 USA.
    Beth Terry, Mary
    Columbia University, NY 10027 USA.
    Thomassen, Mads
    Odense University Hospital, Denmark.
    Grazia Tibiletti, Maria
    University of Insubria, Italy.
    Tihomirova, Laima
    Latvian Biomed Research and Study Centre, Latvia.
    Tognazzo, Silvia
    IRCCS, Italy.
    Ewart Toland, Amanda
    Vanderbilt University, TN 37203 USA; IdISSC El Institute Invest Sanitaria Hospital Clin San Car, Spain; Ohio State University, OH 43210 USA.
    Tomlinson, Ian
    University of Oxford, England; University of Oxford, England.
    Torres, Diana
    German Cancer Research Centre, Germany; Pontificia University of Javeriana, Colombia.
    Truong, Therese
    INSERM, France; University of Paris 11, France.
    Tseng, Chiu-chen
    University of Southern Calif, CA 90033 USA.
    Tung, Nadine
    Beth Israel Deaconess Medical Centre, MA 02215 USA.
    Tworoger, Shelley S.
    Harvard University, MA 02115 USA; Brigham and Womens Hospital, MA 02115 USA; Harvard University, MA 02115 USA.
    Vachon, Celine
    Mayo Clin, MN 55902 USA.
    van den Ouweland, Ans M. W.
    Erasmus University, Netherlands.
    van Doorn, Helena C.
    Erasmus MC Cancer Institute, Netherlands.
    van Rensburg, Elizabeth J.
    University of Pretoria, South Africa.
    Vant Veer, Laura J.
    Netherlands Cancer Institute, Netherlands.
    Vanderstichele, Adriaan
    University Hospital Leuven, Belgium.
    Vergote, Ignace
    University Hospital Leuven, Belgium.
    Vijai, Joseph
    Mem Sloan Kettering Cancer Centre, NY 10065 USA.
    Wang, Qin
    University of Cambridge, England.
    Wang-Gohrke, Shan
    University Hospital Ulm, Germany.
    Weitzel, Jeffrey N.
    City Hope Clin Cancer Genet Community Research Network, CA 91010 USA.
    Wentzensen, Nicolas
    NCI, MD 20892 USA.
    Whittemore, Alice S.
    Stanford University, CA 94305 USA.
    Wildiers, Hans
    University Hospital Leuven, Belgium.
    Winqvist, Robert
    Centre NordLab, Finland; University of Oulu, Finland.
    Wu, Anna H.
    University of Southern Calif, CA 90033 USA.
    Yannoukakos, Drakoulis
    National Centre Science Research Demokritos, Greece.
    Yoon, Sook-Yee
    Sime Darby Medical Centre, Malaysia; University of Malaya, Malaysia.
    Yu, Jyh-Cherng
    National Def Medical Centre, Taiwan.
    Zheng, Wei
    Vanderbilt University, TN 37203 USA.
    Zheng, Ying
    Shanghai Centre Disease Control and Prevent, Peoples R China.
    Kum Khanna, Kum
    QIMR Berghofer Medical Research Institute, Australia.
    Simard, Jacques
    University of Laval, Canada.
    Monteiro, Alvaro N.
    H Lee Moffitt Cancer Centre and Research Institute, FL 33612 USA.
    French, Juliet D.
    QIMR Berghofer Medical Research Institute, Australia.
    Couch, Fergus J.
    Mayo Clin, MN 55902 USA; Mayo Clin, MN 55905 USA.
    Freedman, Matthew L.
    Dana Farber Cancer Institute, MA 02215 USA.
    Easton, Douglas F.
    University of Cambridge, England; University of Cambridge, England.
    Dunning, Alison M.
    University of Cambridge, England.
    Pharoah, Paul D.
    University of Cambridge, England.
    Edwards, Stacey L.
    QIMR Berghofer Medical Research Institute, Australia.
    Chenevix-Trench, Georgia
    QIMR Berghofer Medical Research Institute, Australia.
    Antoniou, Antonis C.
    University of Cambridge, England.
    Gayther, Simon A.
    University of Southern Calif, CA 90033 USA; Cedars Sinai Medical Centre, CA 90048 USA.
    Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus2016In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 7, 12675Article in journal (Refereed)
    Abstract [en]

    A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 × 10−20), ER-negative BC (P=1.1 × 10−13), BRCA1-associated BC (P=7.7 × 10−16) and triple negative BC (P-diff=2 × 10−5). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 × 10−3) and ABHD8 (P<2 × 10−3). Chromosome conformation capture identifies interactions between four candidate SNPs and ABHD8, and luciferase assays indicate six risk alleles increased transactivation of the ADHD8 promoter. Targeted deletion of a region containing risk SNP rs56069439 in a putative enhancer induces ANKLE1 downregulation; and mRNA stability assays indicate functional effects for an ANKLE1 3′-UTR SNP. Altogether, these data suggest that multiple SNPs at 19p13 regulate ABHD8 and perhaps ANKLE1 expression, and indicate common mechanisms underlying breast and ovarian cancer risk.

  • 27.
    Leandro-Garcia, Luis J.
    et al.
    Spanish National Cancer Research Centre, Spain .
    Inglada-Perez, Lucia
    Spanish National Cancer Research Centre, Spain .
    Pita, Guillermo
    Spanish National Cancer Research Centre, Spain .
    Hjerpe, Elisabet
    Karolinska University Hospital, Sweden .
    Leskelae, Susanna
    Spanish National Cancer Research Centre, Spain .
    Jara, Carlos
    Fdn Hospital Alcorcon, Spain .
    Mielgo, Xabier
    Fdn Hospital Alcorcon, Spain .
    Gonzalez-Neira, Anna
    Spanish National Cancer Research Centre, Spain .
    Robledo, Mercedes
    Spanish National Cancer Research Centre, Spain .
    Åvall-Lundqvist, Elisabeth
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology. Karolinska University Hospital, Sweden .
    Green, Henrik
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences.
    Rodriguez-Antona, Cristina
    Spanish National Cancer Research Centre, Spain .
    Genome-wide association study identifies ephrin type A receptors implicated in paclitaxel induced peripheral sensory neuropathy2013In: Journal of Medical Genetics, ISSN 0022-2593, E-ISSN 1468-6244, Vol. 50, no 9, 599-605 p.Article in journal (Refereed)
    Abstract [en]

    Background Peripheral neuropathy is the dose limiting toxicity of paclitaxel, a chemotherapeutic drug widely used to treat solid tumours. This toxicity exhibits great inter-individual variability of unknown origin. The present study aimed to identify genetic variants associated with paclitaxel induced neuropathy via a whole genome approach. less thanbrgreater than less thanbrgreater thanMethods A genome-wide association study (GWAS) was performed in 144 white European patients uniformly treated with paclitaxel/carboplatin and for whom detailed data on neuropathy was available. Per allele single nucleotide polymorphism (SNP) associations were assessed by Cox regression, modelling the cumulative dose of paclitaxel up to the development of grade 2 sensory neuropathy. less thanbrgreater than less thanbrgreater thanResults The strongest evidence of association was observed for the ephrin type A receptor 4 (EPHA4) locus (rs17348202, p=1.0x10(-6)), and EPHA6 and EPHA5 were among the top 25 and 50 hits (rs301927, p=3.4x10(-5) and rs1159057, p=6.8x10(-5)), respectively. A meta-analysis of EPHA5-rs7349683, the top marker for paclitaxel induced neuropathy in a previous GWAS (r(2)=0.79 with rs1159057), gave a hazard ratio (HR) estimate of 1.68 (p=1.4x10(-9)). Meta-analysis of the second hit of this GWAS, XKR4-rs4737264, gave a HR of 1.71 (p=3.1x10(-8)). Imputed SNPs at LIMK2 locus were also strongly associated with this toxicity (HR=2.78, p=2.0x10(-7)). less thanbrgreater than less thanbrgreater thanConclusions This study provides independent support of EPHA5-rs7349683 and XKR4-rs4737264 as the first markers of risk of paclitaxel induced neuropathy. In addition, it suggests that other EPHA genes also involved in axonal guidance and repair following neural injury, as well as LIMK2 locus, may play an important role in the development of this toxicity. The identified SNPs could form the basis for individualised paclitaxel chemotherapy.

  • 28.
    Li, He
    et al.
    Oklahoma Medical Research Fdn, OK 73104 USA; University of Oklahoma, OK USA; University of Calif San Diego, CA 92093 USA.
    Ragna Reksten, Tove
    Oklahoma Medical Research Fdn, OK 73104 USA; University of Bergen, Norway.
    Ice, John A.
    Oklahoma Medical Research Fdn, OK 73104 USA.
    Kelly, Jennifer A.
    Oklahoma Medical Research Fdn, OK 73104 USA.
    Adrianto, Indra
    Oklahoma Medical Research Fdn, OK 73104 USA.
    Rasmussen, Astrid
    Oklahoma Medical Research Fdn, OK 73104 USA.
    Wang, Shaofeng
    Oklahoma Medical Research Fdn, OK 73104 USA.
    He, Bo
    Oklahoma Medical Research Fdn, OK 73104 USA; University of Oklahoma, OK USA.
    Grundahl, Kiely M.
    Oklahoma Medical Research Fdn, OK 73104 USA.
    Glenn, Stuart B.
    Oklahoma Medical Research Fdn, OK 73104 USA.
    Miceli-Richard, Corinne
    University of Paris Sud, France.
    Bowman, Simon
    University Hospital Birmingham, England.
    Lester, Sue
    Queen Elizabeth Hospital, Australia.
    Eriksson, Per
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Region Östergötland, Heart and Medicine Center, Department of Rheumatology. Linköping University, Faculty of Medicine and Health Sciences.
    Eloranta, Maija-Leena
    Uppsala University, Sweden.
    Brun, Johan G.
    University of Bergen, Norway; Haukeland Hospital, Norway.
    Goransson, Lasse G.
    Stavanger University Hospital, Norway.
    Harboe, Erna
    Stavanger University Hospital, Norway.
    Guthridge, Joel M.
    Oklahoma Medical Research Fdn, OK 73104 USA.
    Kaufman, Kenneth M.
    Cincinnati Childrens Hospital Medical Centre, OH 45229 USA; US Department Vet Affairs, OH USA.
    Kvarnstrom, Marika
    Karolinska Institute, Sweden.
    Cunninghame Graham, Deborah S.
    Kings Coll London, England.
    Patel, Ketan
    University of Minnesota, MN 55455 USA; North Mem Medical Centre, MN USA.
    Adler, Adam J.
    Oklahoma Medical Research Fdn, OK 73104 USA.
    Darise Farris, A.
    Oklahoma Medical Research Fdn, OK 73104 USA; University of Oklahoma, OK USA.
    Brennan, Michael T.
    Carolinas Medical Centre, NC 28203 USA.
    Chodosh, James
    Harvard Medical Sch, MA USA.
    Gopalakrishnan, Rajaram
    University of Minnesota, MN 55455 USA.
    Weisman, Michael H.
    Cedars Sinai Medical Centre, CA 90048 USA.
    Venuturupalli, Swamy
    Cedars Sinai Medical Centre, CA 90048 USA.
    Wallace, Daniel J.
    Cedars Sinai Medical Centre, CA 90048 USA.
    Hefner, Kimberly S.
    Cedars Sinai Medical Centre, CA 90048 USA; Hefner Eye Care and Opt Centre, OK USA.
    Houston, Glen D.
    University of Oklahoma, OK USA; Heartland Pathol Consultants, OK USA.
    Huang, Andrew J. W.
    Washington University, MO 63130 USA.
    Hughes, Pamela J.
    University of Minnesota, MN 55455 USA.
    Lewis, David M.
    University of Oklahoma, OK USA.
    Radfar, Lida
    University of Oklahoma, OK USA.
    Vista, Evan S.
    Oklahoma Medical Research Fdn, OK 73104 USA; University of Santo Tomas Hospital, Philippines.
    Edgar, Contessa E.
    Oklahoma Baptist University, OK USA.
    Rohrer, Michael D.
    University of Minnesota, MN 55455 USA.
    Stone, Donald U.
    Johns Hopkins University, MD USA.
    Vyse, Timothy J.
    Kings Coll London, England.
    Harley, John B.
    Cincinnati Childrens Hospital Medical Centre, OH 45229 USA; US Department Vet Affairs, OH USA.
    Gaffney, Patrick M.
    Oklahoma Medical Research Fdn, OK 73104 USA.
    James, Judith A.
    Oklahoma Medical Research Fdn, OK 73104 USA; University of Oklahoma, OK USA; University of Oklahoma, OK USA.
    Turner, Sean
    Oklahoma Medical Research Fdn, OK 73104 USA.
    Alevizos, Ilias
    National Institute Dent and Craniofacial Research, MD USA.
    Anaya, Juan-Manuel
    University of Rosario, Colombia.
    Rhodus, Nelson L.
    University of Minnesota, MN 55455 USA.
    Segal, Barbara M.
    University of Minnesota, MN 55455 USA.
    Montgomery, Courtney G.
    Oklahoma Medical Research Fdn, OK 73104 USA.
    Hal Scofield, R.
    Oklahoma Medical Research Fdn, OK 73104 USA; University of Oklahoma, OK USA; US Department Vet Affairs, OK USA.
    Kovats, Susan
    Oklahoma Medical Research Fdn, OK 73104 USA.
    Mariette, Xavier
    University of Paris Sud, France.
    Ronnblom, Lars
    Uppsala University, Sweden.
    Witte, Torsten
    Hannover Medical Sch, Germany.
    Rischmueller, Maureen
    Queen Elizabeth Hospital, Australia; University of Adelaide, Australia.
    Wahren-Herlenius, Marie
    Karolinska Institute, Sweden.
    Omdal, Roald
    Stavanger University Hospital, Norway.
    Jonsson, Roland
    University of Bergen, Norway; Haukeland Hospital, Norway.
    Ng, Wan-Fai
    Newcastle University, England; Newcastle University, England.
    Nordmark, Gunnel
    Uppsala University, Sweden.
    Lessard, Christopher J.
    Oklahoma Medical Research Fdn, OK 73104 USA; University of Oklahoma, OK USA.
    Sivils, Kathy L.
    Oklahoma Medical Research Fdn, OK 73104 USA; University of Oklahoma, OK USA.
    Identification of a Sjögrens syndrome susceptibility locus at OAS1 that influences isoform switching, protein expression, and responsiveness to type I interferons2017In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 13, no 6, e1006820Article in journal (Refereed)
    Abstract [en]

    Sjogrens syndrome (SS) is a common, autoimmune exocrinopathy distinguished by keratoconjunctivitis sicca and xerostomia. Patients frequently develop serious complications including lymphoma, pulmonary dysfunction, neuropathy, vasculitis, and debilitating fatigue. Dysregulation of type I interferon (IFN) pathway is a prominent feature of SS and is correlated with increased autoantibody titers and disease severity. To identify genetic determinants of IFN pathway dysregulation in SS, we performed cis-expression quantitative trait locus (eQTL) analyses focusing on differentially expressed type I IFN-inducible transcripts identified through a transcriptome profiling study. Multiple cis-eQTLs were associated with transcript levels of 2-5-oligoadenylate synthetase 1 (OAS1) peaking at rs10774671 (PeQTL = 6.05 x 10(-14)). Association of rs10774671 with SS susceptibility was identified and confirmed through meta-analysis of two independent cohorts (P-meta = 2.59 x 10(-9); odds ratio = 0.75; 95% confidence interval = 0.66-0.86). The risk allele of rs10774671 shifts splicing of OAS1 from production of the p46 isoform to multiple alternative transcripts, including p42, p48, and p44. We found that the isoforms were differentially expressed within each genotype in controls and patients with and without autoantibodies. Furthermore, our results showed that the three alternatively spliced isoforms lacked translational response to type I IFN stimulation. The p48 and p44 isoforms also had impaired protein expression governed by the 3 end of the transcripts. The SS risk allele of rs10774671 has been shown by others to be associated with reduced OAS1 enzymatic activity and ability to clear viral infections, as well as reduced responsiveness to IFN treatment. Our results establish OAS1 as a risk locus for SS and support a potential role for defective viral clearance due to altered IFN response as a genetic pathophysiological basis of this complex autoimmune disease.

  • 29.
    Lidell, Martin E.
    et al.
    Medicinsk genetik, Göteborgs universitet.
    Betz, Matthias J.
    Medicinsk genetik, Göteborgs universitet.
    Dahlqvist Leinhard, Olof
    Linköping University, Center for Medical Image Science and Visualization (CMIV). Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Radiation Physics.
    Heglind, Mikael
    Medicinsk genetik, Göteborgs universitet.
    Elander, Louise
    Linköping University, Center for Medical Image Science and Visualization (CMIV). Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Slawik, Marc
    Klinikum der Ludwig Maximilians University (LMU), Munich, Germany.
    Mussack, Thomas
    Klinikum der LMU, Munich, Germany.
    Nilsson, Daniel
    Medicinsk genetik, Göteborgs universitet.
    Romu, Thobias
    Linköping University, Center for Medical Image Science and Visualization (CMIV). Linköping University, Department of Biomedical Engineering, Medical Informatics. Linköping University, The Institute of Technology.
    Nuutila, Pirjo
    University of Turku, Turku, Finland.
    Virtanen, Kirsi A.
    University of Turku, Turku, Finland.
    Beuschlein, Felix
    Klinikum der Ludwig Maximilians University (LMU), Munich, Germany.
    Persson, Anders
    Linköping University, Center for Medical Image Science and Visualization (CMIV). Linköping University, Department of Medical and Health Sciences, Radiology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Radiology in Linköping.
    Borga, Magnus
    Linköping University, Center for Medical Image Science and Visualization (CMIV). Linköping University, Department of Biomedical Engineering, Medical Informatics. Linköping University, The Institute of Technology.
    Enerbäck, Sven
    Medicinsk genetik, Göteborgs universitet.
    Evidence for two types of brown adipose tissue in humans2013In: Nature Medicine, ISSN 1078-8956, Vol. 19, no 5, 631-634 p.Article in journal (Refereed)
    Abstract [en]

    The previously observed supraclavicular depot of brown adipose tissue (BAT) in adult humans was commonly believed to be the equivalent of the interscapular thermogenic organ of small mammals. This view was recently disputed on the basis of the demonstration that this depot consists of beige (also called brite) brown adipocytes, a newly identified type of brown adipocyte that is distinct from the classical brown adipocytes that make up the interscapular thermogenic organs of other mammals. A combination of high-resolution imaging techniques and histological and biochemical analyses showed evidence for an anatomically distinguishable interscapular BAT (iBAT) depot in human infants that consists of classical brown adipocytes, a cell type that has so far not been shown to exist in humans. On the basis of these findings, we conclude that infants, similarly to rodents, have the bona fide iBAT thermogenic organ consisting of classical brown adipocytes that is essential for the survival of small mammals in a cold environment.

  • 30.
    Lilljebjorn, Henrik
    et al.
    Lund University, Sweden.
    Henningsson, Rasmus
    Lund University, Sweden.
    Hyrenius-Wittsten, Axel
    Lund University, Sweden.
    Olsson, Linda
    Lund University, Sweden.
    Orsmark-Pietras, Christina
    Lund University, Sweden.
    von Palffy, Sofia
    Lund University, Sweden.
    Askmyr, Maria
    Lund University, Sweden.
    Rissler, Marianne
    Lund University, Sweden.
    Schrappe, Martin
    University Hospital Schleswig Holstein, Germany.
    Cario, Gunnar
    University Hospital Schleswig Holstein, Germany.
    Castor, Anders
    Lund University, Sweden.
    Pronk, Cornelis J. H.
    Lund University, Sweden.
    Behrendtz, Mikael
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, Department of Paediatrics in Linköping. Linköping University, Faculty of Medicine and Health Sciences.
    Mitelman, Felix
    Lund University, Sweden.
    Johansson, Bertil
    Lund University, Sweden; University of and Regional Labs Regional Skåne, Sweden.
    Paulsson, Kajsa
    Lund University, Sweden.
    Andersson, Anna K.
    Lund University, Sweden.
    Fontes, Magnus
    Lund University, Sweden.
    Fioretos, Thoas
    Lund University, Sweden; University of and Regional Labs Regional Skåne, Sweden.
    Identification of ETV6-RUNX1-like and DUX4-rearranged subtypes in paediatric B-cell precursor acute lymphoblastic leukaemia2016In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 7, no 11790Article in journal (Refereed)
    Abstract [en]

    Fusion genes are potent driver mutations in cancer. In this study, we delineate the fusion gene landscape in a consecutive series of 195 paediatric B-cell precursor acute lymphoblastic leukaemia (BCP ALL). Using RNA sequencing, we find in-frame fusion genes in 127 (65%) cases, including 27 novel fusions. We describe a subtype characterized by recurrent IGH-DUX4 or ERG-DUX4 fusions, representing 4% of cases, leading to overexpression of DUX4 and frequently co-occurring with intragenic ERG deletions. Furthermore, we identify a subtype characterized by an ETV6-RUNX1-like gene-expression profile and coexisting ETV6 and IKZF1 alterations. Thus, this study provides a detailed overview of fusion genes in paediatric BCP ALL and adds new pathogenetic insights, which may improve risk stratification and provide therapeutic options for this disease.

  • 31.
    Lindqvist, Maria
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Health and Developmental Care, Department of Infection Control.
    Isaksson, Barbro
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Health and Developmental Care, Department of Infection Control. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Microbiology.
    Nilsson, Lennart
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Wistedt, Annika
    Department of Clinical Microbiology and Infection Control, Kalmar County Hospital, Kalmar, Sweden.
    Swanberg, Jonas
    Clinical Microbiology Laboratory, Ryhov Hospital, Jönköping, Sweden.
    Skov, Robert
    Staphylococcus Laboratory, Department of Microbiology and Infection Control, Statens Serum Institut, Copenhagen, Denmark.
    Rhod Larsen, Anders
    Staphylococcus Laboratory, Department of Microbiology and Infection Control, Statens Serum Institut, Copenhagen, Denmark.
    Larsen, Jesper
    Staphylococcus Laboratory, Department of Microbiology and Infection Control, Statens Serum Institut, Copenhagen, Denmark.
    Petersen, Andreas
    Staphylococcus Laboratory, Department of Microbiology and Infection Control, Statens Serum Institut, Copenhagen, Denmark.
    Hällgren, Anita
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Infectious Diseases.
    Genetic relatedness of multi-resistant methicillin-susceptible Staphylococcus aureus in southeast Sweden2014Manuscript (preprint) (Other academic)
    Abstract [en]

    Background: A high exchange of patients occurs between the hospitals in southeast Sweden, resulting in a possible transmission of nosocomial pathogens. The objective of this study was to investigate the incidence and possible genetic relatedness of multi-resistant methicillinsusceptible Staphylococcus aureus (MSSA) in the region in general, and in particular the possible persistence and transmission of the ECT-R clone (t002) showing resistance to erythromycin, clindamycin and tobramycin previously found in Östergötland County.

    Methods: Three groups of S. aureus isolates with different antibiotic resistance profiles, including the ECT-R profile, were collected from the three County Councils in southeast Sweden and investigated with spa typing, real-time PCR targeting the staphylococcal cassette chromosome (SCC) mec right extremity junction (MREJ), and microarray.

    Results: All isolates with the ECT-R resistance profile (n = 12) from Östergötland County and two additional isolates with another antibiotic resistance profile were designated spa type t002, MREJ type ii, and were clustered in the same clonal cluster (CC) (i.e. CC5) by the microarray result, indicating the persistence of the ECT-R clone. In addition, 60 % of the isolates belonged to CC15 from newborns, with 94 % sharing spa type t084, indicating interhospital transmission.

    Conclusions: The persistence of the ECT-R clone and the possible transmission of the t084 strain indicate that there is still an insufficiency in the maintenance of basic hygiene guidelines. The ECT-R clone probably possesses mechanisms of virulence and transmission that make it so successful.

  • 32.
    Ljunggren, Stefan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Lipoproteomics: Environmental and Genetic Factors Affecting High-Density Lipoprotein (HDL)2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Lipoprotein particles act as lipid transporters in the blood stream, and measuring cholesterol content in specific subclasses of lipoprotein particles has long been, and still is, a frequently used tool to estimate the risk of cardiovascular disease (CVD). High-density lipoprotein (HDL) is a subclass of lipoproteins often regarded as providing protection against CVD via several functions including reverse cholesterol transport and anti-inflammatory capacities. However, the precise relationship between HDL cholesterol levels and health outcome is still unclear. Lately, new approaches to study HDL composition and function have therefore become more important.

    HDL function is to a large extent dependent on its proteome, containing more than 100 proteins. Investigating the proteome in individuals with altered gene expression for HDL-associated proteins or with known exposure to environmental contaminants may reveal new insights into how HDL metabolism is affected by various factors. This is of interest in order to better understand the role of HDL in CVD.

    Papers I and II focus on two different mutations in a structural HDL protein, apolipoprotein A-I (L202P and K131del), and one mutation in the scavenger receptor class B-1 (P297S), which is involved in selective lipid uptake of cholesterol mainly into hepatocytes and adrenal cells. The HDL proteome was analyzed using two-dimensional gel electrophoresis and mass spectrometry. The L202P mutation was identified in HDL of the heterozygote carriers together with a significant decrease of apolipoprotein E and increased zinc-alpha-2-glycoprotein. By contrast, the second apolipoprotein AI mutation (K131del) was associated with significantly elevated alpha-1-antitrypsin and transthyretin levels. Protein analyses of the scavenger receptor class B1 P297S heterozygotes showed a significant increase in HDL apoL-1 along with increased free apoE. The carriers showed no difference in antioxidative capability but a significant increase in apoA-I methionine oxidation.

    Papers III and IV focus on persistent organic pollutants that may influence HDL composition and function. These compounds accumulate in humans, and exposure has been linked to an increased risk of CVD. To provide a better understanding of the HDL system in relation to pollutants, a population living in a contaminated area was studied. Persistent organic pollutants in isolated HDL were quantified using high-resolution gas chromatography mass spectrometry and significantly increased levels were found in individuals with CVD as compared to healthy controls. Furthermore, there was a significant negative association between the pollutants and paraoxonase-1 anti-oxidant activity. Studying the proteome with nano-liquid chromatography tandem mass spectrometry led to the identification of 118 proteins in HDL, of which ten were significantly associated with the persistent organic pollutants.

    In summary, the present studies demonstrate protein pattern alterations in HDL associated with inherited genetic variants or pollutant exposure. The studies also provide a set of methods that are useful tools to further comprehend the complexity of lipoprotein metabolism and function. The results are important in order to improve our understanding of HDL in CVD and to explain an increased risk of CVD associated with exposure to organic pollutants.

    List of papers
    1. ApoA-I mutations, L202P and K131del, in HDL from heterozygotes with low HDL-C
    Open this publication in new window or tab >>ApoA-I mutations, L202P and K131del, in HDL from heterozygotes with low HDL-C
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    2014 (English)In: PROTEOMICS - Clinical Applications, ISSN 1862-8354, E-ISSN 1862-8354, Vol. 8, no 3-4, 241-250 p.Article in journal (Refereed) Published
    Abstract [en]

    PURPOSE: Mutations in apolipoprotein A-I (apoA-I) may affect plasma high-density lipoprotein (HDL) cholesterol levels and the risk for cardiovascular disease but little is known about the presence and effects of circulating apoA-I variants. This study investigates whether the apoA-I mutations, apoA-I(L202P) and apoA-I(K131del) , are present on plasma HDL particles derived from heterozygote carriers and whether this is associated to changes in HDL protein composition.

    EXPERIMENTAL DESIGN: Plasma HDL of heterozygotes for either apoA-I(L202P) or apoA-I(K131del) and family controls was isolated using ultracentrifugation. HDL proteins were separated by 2DE and analyzed by MS.

    RESULTS: ApoA-I peptides containing apoA-I(L202P) or apoA-I(K131del) were identified in HDL from heterozygotes. The apoA-I(L202P) mutant peptide was less abundant than wild-type peptide while the apoA-I(K131del) mutant peptide was more abundant than wild-type peptide in the heterozygotes. Two-dimensional gel electrophoresis analyses indicated that, compared to controls, HDL in apoA-I(L202P) carriers contained less apoE and more zinc-α-2-glycoprotein while HDL from the apoA-I(K131del) heterozygotes contained more alpha-1-antitrypsin and transthyretin.

    CONCLUSIONS AND CLINICAL RELEVANCE: Both apoA-I(L202P) and apoA-I(K131del) were identified in HDL. In heterozygotes, these mutations have markedly differential effects on the concentration of wild-type apoA-I in the circulation, as well as the HDL proteome, both of which might affect the clinical phenotype encountered in the heterozygous carriers.

    Place, publisher, year, edition, pages
    Wiley-Blackwell, 2014
    National Category
    Cell and Molecular Biology Biochemistry and Molecular Biology
    Identifiers
    urn:nbn:se:liu:diva-105992 (URN)10.1002/prca.201300014 (DOI)000334251600013 ()24273187 (PubMedID)
    Available from: 2014-04-16 Created: 2014-04-16 Last updated: 2016-09-30
    2. Lipoprotein profiles in human heterozygote carriers of a functional mutation P297S in scavenger receptor class B1.
    Open this publication in new window or tab >>Lipoprotein profiles in human heterozygote carriers of a functional mutation P297S in scavenger receptor class B1.
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    2015 (English)In: Biochimica et Biophysica Acta, ISSN 0006-3002, E-ISSN 1878-2434, Vol. 1851, no 12, 1587-1595 p.Article in journal (Refereed) Published
    Abstract [en]

    The scavenger receptor class B type 1 (SR-B1) is an important HDL receptor involved in cholesterol uptake and efflux, but its physiological role in human lipoprotein metabolism is not fully understood. Heterozygous carriers of the SR-B1P297S mutation are characterized by increased HDL cholesterol levels, impaired cholesterol efflux from macrophages and attenuated adrenal function. Here, the composition and function of lipoproteins were studied in SR-B1P297S heterozygotes.

    Lipoproteins from six SR-B1P297S carriers and six family controls were investigated. HDL and LDL/VLDL were isolated by ultracentrifugation and proteins were separated by two-dimensional gel electrophoresis and identified by mass spectrometry. HDL antioxidant properties, paraoxonase 1 activities, apoA-I methionine oxidations and HDL cholesterol efflux capacity were assessed.

    Multivariate modeling separated carriers from controls based on lipoprotein composition. Protein analyses showed a significant enrichment of apoE in LDL/VLDL and of apoL-1 in HDL from heterozygotes compared to controls. The relative distribution of plasma apoE was increased in LDL and in lipid-free form. There were no significant differences in paraoxonase 1 activities, HDL antioxidant properties or HDL cholesterol efflux capacity but heterozygotes showed a significant increase of oxidized methionines in apoA-I.

    The SR-B1P297S mutation affects both HDL and LDL/VLDL protein compositions. The increase of apoE in carriers suggests a compensatory mechanism for attenuated SR-B1 mediated cholesterol uptake by HDL. Increased methionine oxidation may affect HDL function by reducing apoA-I binding to its targets. The results illustrate the complexity of lipoprotein metabolism that has to be taken into account in future therapeutic strategies aiming at targeting SR-B1.

    Place, publisher, year, edition, pages
    Elsevier, 2015
    Keyword
    ApoE; ApoL-1; HDL; LDL/VLDL; P297S; SR-B1
    National Category
    Biochemistry and Molecular Biology
    Identifiers
    urn:nbn:se:liu:diva-122723 (URN)10.1016/j.bbalip.2015.09.006 (DOI)000364252800008 ()26454245 (PubMedID)
    Note

    Funding agencies: EUs Sixth Framework Program [037631]; European Union [FP7-603091-2]; CardioVascular Research Initiative [CVON2011-16]; Research Council of South East Sweden [FORSS-3755]; County Council of Ostergotland (C-ALF); Faculty of Health Sciences in Linkoping; Ven

    Available from: 2015-11-18 Created: 2015-11-18 Last updated: 2016-10-19
    3. Persistent organic pollutants distribution in lipoprotein fractions in relation to cardiovascular disease and cancer.
    Open this publication in new window or tab >>Persistent organic pollutants distribution in lipoprotein fractions in relation to cardiovascular disease and cancer.
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    2014 (English)In: Environment International, ISSN 0160-4120, E-ISSN 1873-6750, Vol. 65, 93-9 p.Article in journal (Refereed) Published
    Abstract [en]

    Persistent organic pollutants (POPs) are lipophilic environmental toxins that have been associated with cardiovascular disease (CVD) and cancer. The aim of this study was to investigate the concentrations of POPs in human high and low/very low-density lipoproteins (HDL and LDL/VLDL) and the possible association with CVD and cancer occurrence in individuals living in a contaminated area. Lipoproteins from 28 individuals (7 healthy controls, 8 subjects with cancer, 13 subjects with CVD) were isolated and the fraction-specific concentration of 20 different POPs was analyzed by high resolution gas chromatography/high resolution mass spectrometry. The activity of Paraoxonase 1 (PON1), an anti-oxidant in HDL, was determined in plasma of these 28 subjects and additional 50 subjects from the same area excluding diseases other than cancer or CVD. Fourteen polychlorinated biphenyls (PCBs) and three organochlorine pesticides were detected, and especially highly chlorinated PCBs were enriched in lipoproteins. Significantly higher concentrations of POPs were found among individuals with CVD or cancer compared to controls. Principal component analyses showed that POP concentrations in HDL were more associated with CVD, while POP concentrations in LDL/VLDL were more associated with cancer. PON1 activity was negatively correlated to sumPCB and a co-variation between decreased arylesterase-activity, increased PCB concentrations and CVD was found. This study shows that POPs are present in lipoproteins and were more abundant in individuals with CVD or cancer compared to healthy controls. The results also indicate that PCB exposure is accompanied by reduced PON1 activity that could impair the HDL function to protect against oxidation.

    Place, publisher, year, edition, pages
    Elsevier, 2014
    National Category
    Clinical Medicine Other Basic Medicine
    Identifiers
    urn:nbn:se:liu:diva-104755 (URN)10.1016/j.envint.2013.12.017 (DOI)000334728500010 ()24472825 (PubMedID)
    Available from: 2014-02-25 Created: 2014-02-25 Last updated: 2016-09-30
  • 33.
    Montelius, Kerstin
    et al.
    National Board of Forensic Medicine, Linköping, Sweden.
    Karlsson, Andreas O
    National Board of Forensic Medicine, Linköping, Sweden.
    Holmlund, Gunilla
    National Board of Forensic Medicine, Linköping, Sweden.
    STR data for the AmpFlSTR Identifiler loci from Swedish population in comparison to European, as well as with non-European population2008In: Forensic Science International: Genetics, ISSN 1872-4973, E-ISSN 1878-0326, Vol. 2, no 3, e49-e52 p.Article in journal (Refereed)
    Abstract [en]

    The modern Swedish population is a mixture of people that originate from different parts of the world. This is also the truth for the clients participating in the paternity cases investigated at the department. Calculations based on a Swedish frequency database only, could give us overestimated figures of probability and power of exclusion in cases including clients with a genetic background other than Swedish. Here, we describe allele frequencies regarding the markers in the Identifiler-kit. We have compared three sets of population samples; Swedish, European and non-European to investigate how these three groups of population samples differ. Also, all three population sets were compared to data reported from other European and non-European populations.

    Swedish allele frequencies for the 15 autosomal STRs included in the Identifiler kit were obtained from unrelated blood donors with Swedish names. The European and non-European frequencies were based on DNA-profiles of alleged fathers from our paternity cases in 2005 and 2006.

  • 34.
    Mosrati, Mohamed Ali
    et al.
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Malmström, Annika
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Advanced Home Care in Linköping. Linköping University, Faculty of Medicine and Health Sciences.
    Lysiak, Malgorzata
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Krysztofiak, Adam
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Hallbeck, Martin
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Milos, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Neurosurgery. Linköping University, Faculty of Medicine and Health Sciences.
    Hallbeck, Anna-Lotta
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology. Linköping University, Faculty of Medicine and Health Sciences.
    Bratthall, Charlotte
    Dist Hospital, Sweden.
    Strandeus, Michael
    Ryhov Hospital, Sweden.
    Stenmark Askmalm, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Söderkvist, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    TERT promoter mutations and polymorphisms as prognostic factors in primary glioblastoma2015In: OncoTarget, ISSN 1949-2553, Vol. 6, no 18, 16663-16673 p.Article in journal (Refereed)
    Abstract [en]

    Telomerase reverse transcriptase (TERT) activity is up-regulated in several types of tumors including glioblastoma (GBM). In the present study, 128 primary glioblastoma patients were examined for single nucleotide polymorphisms of TERT in blood and in 92 cases for TERT promoter mutations in tumors. TERT promoter mutations were observed in 86% of the tumors and of these, C228T (-124 bp upstream start codon) was detected in 75% and C250T (-146 bp) in 25% of cases. TERT promoter mutations were associated with shorter overall survival (11 vs. 20 months p = 0.002 and 12 vs. 20, p = 0.04 for C228T and C250T, respectively). The minor alleles of rs2736100 and rs10069690 SNPs, located in intron 2 and the promotor regions, respectively, were associated with an increased risk of developing GBM (p = 0.004 and 0.001). GBM patients having both TERT promoter mutations and being homozygous carriers of the rs2853669 C-allele displayed significantly shorter overall survival than those with the wild type allele. The rs2853669 SNP is located in a putative Ets2 binding site in the promoter (-246 bp upstream start codon) close to the C228T and C250T mutation hot spots. Interleukin-6 (IL-6) expression regulated by TERT promoter status and polymorphism, what leads us to think that TERT and IL-6 plays a significant role in GBM, where specific SNPs increase the risk of developing GBM while the rs2853669 SNP and specific mutations in the TERT promoter of the tumor lead to shorter survival.

  • 35.
    Mukwaya, Anthonny
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Mirabelli, Pierfrancesco
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Ophthalmology in Linköping.
    Lennikov, Anton
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Xeroudaki, Maria
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Ophthalmology in Linköping.
    Schaupper, Mira
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Peebo, Beatrice
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Ophthalmology in Linköping.
    Lagali, Neil
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Ophthalmology in Linköping.
    Genome-wide expression datasets of anti-VEGF and dexamethasone treatment of angiogenesis in the rat cornea2017In: Scientific Data, E-ISSN 2052-4463, Vol. 4, 170111Article in journal (Refereed)
    Abstract [en]

    Therapeutics against pathologic new blood vessel growth, particularly those targeting vascular endothelial growth factor (VEGF) are of enormous clinical interest. In the eye, where anti-VEGF agents are in widespread clinical use for treating retinal and corneal blindness, only partial or transient efficacy and resistance to anti-VEGF agents are among the major drawbacks. Conversely, corticosteroids have long been used in ophthalmology for their potency in suppressing inflammation and angiogenesis, but their broad biological activity can give rise to side effects such as glaucoma and cataract. To aid in the search for more targeted and effective anti-angiogenic therapies in the eye, we present here a dataset comparing gene expression changes in dexamethasone versus anti-Vegfa treatment of inflammation leading to angiogenesis in the rat cornea. Global gene expression analysis with GeneChip Rat 230 2.0 microarrays was conducted and the metadata submitted to Expression Omnibus repository. Here, we present a high-quality validated dataset enabling genome-wide comparison of genes differentially targeted by dexamethasone and anti-Vegf treatments, to identify potential alternative therapeutic targets for evaluation.

  • 36.
    Onengut-Gumuscu, Suna
    et al.
    Center for Public Health Genomics, Univ Department of Medicine, Division of Endocrinology, University of Virginia, Charlottesville, Virginia, USA.
    Chen, Wei-Min
    Center for Public Health Genomics, Department of Public Health Sciences, Division of Biostatistics and Epidemiology, University of Virginia, Charlottesville, Virginia, USA.
    Burren, Oliver
    Juvenile Diabetes Research Foundation (JDRF)/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, Cambridge Institute for Medical Research, National Institute for Health Research (NIHR) Biomedical Research Centre, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK.
    Cooper, Nick J
    Juvenile Diabetes Research Foundation (JDRF)/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, Cambridge Institute for Medical Research, National Institute for Health Research (NIHR) Biomedical Research Centre, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK.
    Quinlan, Aaron R
    Center for Public Health Genomics, Department of Public Health Sciences, Division of Biostatistics and Epidemiology, University of Virginia, Charlottesville, Virginia, USA.
    Mychaleckyj, Josyf C
    Center for Public Health Genomics, Department of Public Health Sciences, Division of Biostatistics and Epidemiology, University of Virginia, Charlottesville, Virginia, USA.
    Farber, Emily
    Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia, USA.
    Bonnie, Jessica K
    Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia, USA.
    Szpak, Michal
    Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia, USA.
    Schofield, Ellen
    Juvenile Diabetes Research Foundation (JDRF)/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, Cambridge Institute for Medical Research, National Institute for Health Research (NIHR) Biomedical Research Centre, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK.
    Achuthan, Premanand
    Juvenile Diabetes Research Foundation (JDRF)/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, Cambridge Institute for Medical Research, National Institute for Health Research (NIHR) Biomedical Research Centre, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK.
    Guo, Hui
    Juvenile Diabetes Research Foundation (JDRF)/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, Cambridge Institute for Medical Research, National Institute for Health Research (NIHR) Biomedical Research Centre, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK.
    Fortune, Mary D
    Juvenile Diabetes Research Foundation (JDRF)/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, Cambridge Institute for Medical Research, National Institute for Health Research (NIHR) Biomedical Research Centre, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK.
    Stevens, Helen
    Juvenile Diabetes Research Foundation (JDRF)/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, Cambridge Institute for Medical Research, National Institute for Health Research (NIHR) Biomedical Research Centre, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK.
    Walker, Neil M
    Juvenile Diabetes Research Foundation (JDRF)/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, Cambridge Institute for Medical Research, National Institute for Health Research (NIHR) Biomedical Research Centre, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK.
    Ward, Lucas D
    Department of Computer Science, Massachusetts Institute of Technology (MIT), Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
    Kundaje, Anshul
    Department of Computer Science, Massachusetts Institute of Technology (MIT), Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA / Department of Genetics, Stanford University, Stanford, California, USA / Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, USA.
    Kellis, Manolis
    Department of Computer Science, Massachusetts Institute of Technology (MIT), Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
    Daly, Mark J
    Broad Institute of MIT and Harvard, Cambridge, Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, USA.
    Barrett, Jeffrey C
    Wellcome Trust Sanger Institute, Hinxton, UK.
    Cooper, Jason D
    Juvenile Diabetes Research Foundation (JDRF)/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, Cambridge Institute for Medical Research, National Institute for Health Research (NIHR) Biomedical Research Centre, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK.
    Deloukas, Panos
    Wellcome Trust Sanger Institute, Hinxton, UK.
    Todd, John A
    Juvenile Diabetes Research Foundation (JDRF)/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, Cambridge Institute for Medical Research, National Institute for Health Research (NIHR) Biomedical Research Centre, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK.
    Wallace, Chris
    Juvenile Diabetes Research Foundation (JDRF)/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, Cambridge Institute for Medical Research, National Institute for Health Research (NIHR) Biomedical Research Centre, University of Cambridge, Addenbrooke's Hospital, Medical Research Council (MRC) Biostatistics Unit, Institute of Public Health, University Forvie Site, Cambridge, UK.
    Concannon, Patrick
    Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia, USA.
    Rich, Stephen S
    Center for Public Health Genomics, University of Virginia, Department of Public Health Sciences, Division of Biostatistics and Epidemiology, Charlottesville, Virginia, USA.
    Fine mapping of type 1 diabetes susceptibility loci and evidence for colocalization of causal variants with lymphoid gene enhancers.2015In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 47, no 4, 381-386 p.Article in journal (Refereed)
    Abstract [en]

    Genetic studies of type 1 diabetes (T1D) have identified 50 susceptibility regions, finding major pathways contributing to risk, with some loci shared across immune disorders. To make genetic comparisons across autoimmune disorders as informative as possible, a dense genotyping array, the Immunochip, was developed, from which we identified four new T1D-associated regions (P < 5 × 10(-8)). A comparative analysis with 15 immune diseases showed that T1D is more similar genetically to other autoantibody-positive diseases, significantly most similar to juvenile idiopathic arthritis and significantly least similar to ulcerative colitis, and provided support for three additional new T1D risk loci. Using a Bayesian approach, we defined credible sets for the T1D-associated SNPs. The associated SNPs localized to enhancer sequences active in thymus, T and B cells, and CD34(+) stem cells. Enhancer-promoter interactions can now be analyzed in these cell types to identify which particular genes and regulatory sequences are causal.

  • 37.
    Parenti, I.
    et al.
    University of Lubeck, Germany; University of Milan, Italy.
    Gervasini, C.
    University of Milan, Italy.
    Pozojevic, J.
    University of Lubeck, Germany.
    Wendt, K. S.
    Erasmus MC, Netherlands.
    Watrin, E.
    UMR6290 CNRS, France.
    Azzollini, J.
    University of Milan, Italy.
    Braunholz, D.
    University of Lubeck, Germany.
    Buiting, K.
    University of Dusseldorf, Germany.
    Cereda, A.
    AOS Gerardo, Italy.
    Engels, H.
    University of Bonn, Germany.
    Garavelli, L.
    IRCCS S Maria Nuova Hospital, Italy.
    Glazar, R.
    Centre Medical Genet GENESIS Poznan, Poland.
    Graffmann, B.
    Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, Department of Paediatrics in Linköping.
    Larizza, L.
    IRCCS Ist Auxol Italiano, Italy.
    Luedecke, H. J.
    University of Dusseldorf, Germany.
    Mariani, M.
    AOS Gerardo, Italy.
    Masciadri, M.
    IRCCS Ist Auxol Italiano, Italy.
    Pie, J.
    University of Zaragoza, Spain; University of Zaragoza, Spain; ISS Aragon, Spain.
    Ramos, F. J.
    University of Zaragoza, Spain; University of Zaragoza, Spain; ISS Aragon, Spain; Hospital Clin University of Lozano Blesa, Spain.
    Russo, S.
    IRCCS Ist Auxol Italiano, Italy.
    Selicorni, A.
    AOS Gerardo, Italy.
    Stefanova, Margarita
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Strom, T. M.
    Technical University of Munich, Germany; German Research Centre Environm Heatlh, Germany.
    Werner, R.
    University of Lubeck, Germany.
    Wierzba, J.
    Medical University of Gdansk, Poland; Medical University of Gdansk, Poland.
    Zampino, G.
    University of Cattolica Sacro Cuore, Italy.
    Gillessen-Kaesbach, G.
    University of Lubeck, Germany.
    Wieczorek, D.
    University of Dusseldorf, Germany.
    Kaiser, F. J.
    University of Lubeck, Germany.
    Expanding the clinical spectrum of the "HDAC8-phenotype - implications for molecular diagnostics, counseling and risk prediction2016In: Clinical Genetics, ISSN 0009-9163, E-ISSN 1399-0004, Vol. 89, no 5, 564-573 p.Article in journal (Refereed)
    Abstract [en]

    Cornelia de Lange syndrome (CdLS) is a clinically heterogeneous disorder characterized by typical facial dysmorphism, cognitive impairment and multiple congenital anomalies. Approximately 75% of patients carry a variant in one of the five cohesin-related genes NIPBL, SMC1A, SMC3, RAD21 and HDAC8. Herein we report on the clinical and molecular characterization of 11 patients carrying 10 distinct variants in HDAC8. Given the high number of variants identified so far, we advise sequencing of HDAC8 as an indispensable part of the routine molecular diagnostic for patients with CdLS or CdLS-overlapping features. The phenotype of our patients is very broad, whereas males tend to be more severely affected than females, who instead often present with less canonical CdLS features. The extensive clinical variability observed in the heterozygous females might be at least partially associated with a completely skewed X-inactivation, observed in seven out of eight female patients. Our cohort also includes two affected siblings whose unaffected mother was found to be mosaic for the causative mutation inherited to both affected children. This further supports the urgent need for an integration of highly sensitive sequencing technology to allow an appropriate molecular diagnostic, genetic counseling and risk prediction.

  • 38.
    Paulsson, Johan O.
    et al.
    Karolinska University Hospital, Sweden.
    Svahn, F.
    Karolinska University Hospital, Sweden.
    Welander, Jenny
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Brunaud, L.
    University of Lorraine, France.
    Söderkvist, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Gimm, Oliver
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Linköping.
    Stenman, A.
    Karolinska University Hospital, Sweden.
    Juhlin, C. C.
    Karolinska University Hospital, Sweden.
    Editorial Material: Absence of the BRAF V600E mutation in pheochromocytoma in JOURNAL OF ENDOCRINOLOGICAL INVESTIGATION, vol 39, issue 6, pp 715-7162016In: Journal of Endocrinological Investigation, ISSN 0391-4097, E-ISSN 1720-8386, Vol. 39, no 6, 715-716 p.Article in journal (Other academic)
    Abstract [en]

    Purpose Pheochromocytomas (PCCs) are rare endocrine tumors originating from the adrenal medulla. These tumors display a highly heterogeneous mutation profile, and a substantial part of the causative genetic events remains to be explained. Recent studies have reported presence of the activating BRAF V600E mutation in PCC, suggesting a role for BRAF activation in tumor development. This study sought to further investigate the occurrence of the BRAF V600E mutation in these tumors. Methods A cohort of 110 PCCs was screened for the BRAF V600E mutation using direct Sanger sequencing. Results All cases investigated displayed wild-type sequences at nucleotide 1799 in the BRAF gene. Conclusions Taken together with all previously screened tumors up to date, only 1 BRAF V600E mutation has been found among 361 PCCs. These findings imply that the BRAF V600E mutation is a rare event in pheochromocytoma.

  • 39.
    Ran, Caroline
    et al.
    Karolinska Institute, Sweden.
    Brodin, Lovisa
    Karolinska University Hospital, Sweden.
    Forsgren, Lars
    Umeå University, Sweden.
    Westerlund, Marie
    Karolinska Institute, Sweden.
    Ramezani, Mehrafarin
    Karolinska Institute, Sweden.
    Gellhaar, Sandra
    Karolinska Institute, Sweden.
    Xiang, Fengqing
    Karolinska University Hospital, Sweden.
    Fardell, Camilla
    University of Gothenburg, Sweden.
    Nissbrandt, Hans
    University of Gothenburg, Sweden.
    Söderkvist, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Puschmann, Andreas
    Skåne University Hospital, Sweden; Lund University, Sweden.
    Ygland, Emil
    Lund University, Sweden.
    Olson, Lars
    Karolinska Institute, Sweden.
    Willows, Thomas
    Karolinska University Hospital, Sweden.
    Johansson, Anders
    Karolinska University Hospital, Sweden.
    Sydow, Olof
    Karolinska University Hospital, Sweden.
    Wirdefeldt, Karin
    Karolinska University Hospital, Sweden; Karolinska Institute, Sweden.
    Galter, Dagmar
    Karolinska Institute, Sweden.
    Svenningsson, Per
    Karolinska University Hospital, Sweden.
    Carmine Belin, Andrea
    Karolinska Institute, Sweden.
    Strong association between glucocerebrosidase mutations and Parkinsons disease in Sweden2016In: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 45, no 212.e5Article in journal (Refereed)
    Abstract [en]

    Several genetic studies have demonstrated an association between mutations in glucocerebrosidase (GBA), originally implicated in Gauchers disease, and an increased risk of Parkinsons disease (PD). We have investigated the possible involvement of genetic GBA variations in PD in the Swedish population. Three GBA variants, E326K, N370S, and L444P were screened in the largest Swedish Parkinson cohort reported to date; 1625 cases and 2025 control individuals. We found a significant association with high effect size of the rare variant L444P with PD (odds ratio 8.17; 95% confidence interval: 2.51-26.23; p-value = 0.0020) and a significant association of the common variant E326K (odds ratio 1.60; 95% confidence interval: 1.16-2.22; p-value = 0.026). The rare variant N370S showed a trend for association. Most L444P carriers (68%) were found to reside in northern Sweden, which is consistent with a higher prevalence of Gauchers disease in this part of the country. Our findings support the role of GBA mutations as risk factors for PD and point to lysosomal dysfunction as a mechanism contributing to PD etiology. (C) 2016 The Author(s). Published by Elsevier Inc.

  • 40.
    Sandin, Linnea
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Bergkvist, Liza
    Linköping University, Faculty of Science & Engineering. Linköping University, Department of Physics, Chemistry and Biology, Chemistry.
    Nath, Sangeeta
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Kielkopf, Claudia
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Janefjord, Camilla
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Helmfors, Linda
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Zetterberg, Henrik
    Clinical Neurochemistry Laboratory, Department of Neuroscience and Physiology, Sahlgrenska University Hospital, Mölndal, Sweden / UCL Institute of Neurology, London, UK.
    Blennow, Kaj
    Clinical Neurochemistry Laboratory, Department of Neuroscience and Physiology, Sahlgrenska University Hospital, Mölndal, Sweden.
    Li, Hongyun
    Illawarra Health and Medical Research Institute, University of Wollongong, Australia.
    Nilsberth, Camilla
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Acute Internal Medicine and Geriatrics.
    Garner, Brett
    Illawarra Health and Medical Research Institute, University of Wollongong, Australia / School of Biological Sciences, University of Wollongong, Australia.
    Brorsson, Ann-Christin
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Kågedal, Katarina
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Beneficial effects of increased lysozyme levels in Alzheimer’s disease modelled in Drosophila melanogaster2016In: The FEBS Journal, ISSN 1742-464X, E-ISSN 1742-4658, Vol. 283, no 19, 3508-3522 p.Article in journal (Refereed)
    Abstract [en]

    Genetic polymorphisms of immune genes that associate with higher risk to develop Alzheimer’s disease (AD) have led to an increased research interest on the involvement of the immune system in AD pathogenesis. A link between amyloid pathology and immune gene expression was suggested in a genome-wide gene expression study of transgenic amyloid mouse models. In this study, the gene expression of lysozyme, a major player in the innate immune system, was found to be increased in a comparable pattern as the amyloid pathology developed in transgenic mouse models of AD. A similar pattern was seen at protein levels of lysozyme in human AD brain and CSF, but this lysozyme pattern was not seen in a tau transgenic mouse model. Lysozyme was demonstrated to be beneficial for different Drosophila melanogaster models of AD. In flies that expressed Aβ1-42 or AβPP together with BACE1 in the eyes, the rough eye phenotype indicative of toxicity was completely rescued by coexpression of lysozyme. In Drosophila flies bearing the Aβ1-42 variant with the Arctic gene mutation, lysozyme increased the fly survival and decreased locomotor dysfunction dose dependently. An interaction between lysozyme and Aβ1-42 in the Drosophila eye was discovered. We propose that the increased levels of lysozyme, seen in mouse models of AD and in human AD cases, were triggered by Aβ1-42 and caused a beneficial effect by binding of lysozyme to toxic species of Aβ1-42, which prevented these from exerting their toxic effects. These results emphasize the possibility of lysozyme as biomarker and therapeutic target for AD.

  • 41.
    Tillmar, Andreas
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. National Board Forens Med, Department Forens Genet and Forens Toxicol, Artillerigatan 12, SE-58758 Linkoping, Sweden.
    Kling, Daniel
    Oslo University Hospital, Norway.
    Butler, John M.
    NIST, MD 20899 USA.
    Parson, Walther
    Medical University of Innsbruck, Austria; Penn State University, PA 16802 USA.
    Prinz, Mechthild
    John Jay Coll Criminal Justice, NY USA.
    Schneider, Peter M.
    University of Cologne, Germany.
    Egeland, Thore
    Norwegian University of Life Science, Norway.
    Gusmao, Leonor
    State University of Rio de Janeiro UERJ, Brazil.
    DNA Commission of the International Society for Forensic Genetics ( ISFG): Guidelines on the use of X-STRs in kinship analysis2017In: Forensic Science International: Genetics, ISSN 1872-4973, E-ISSN 1878-0326, Vol. 29, 269-275 p.Article in journal (Refereed)
    Abstract [en]

    Forensic genetic laboratories perform an increasing amount of genetic analyses of the X chromosome, in particular to solve complex cases of kinship analysis. For some biological relationships X-chromosomal markers can be more informative than autosomal markers, and there are a large number of markers, methods and databases that have been described for forensic use. Due to their particular mode of inheritance, and their physical location on a single chromosome, some specific considerations are required when estimating the weight of evidence for X-chromosomal marker DNA data. The DNA Commission of the International Society for Forensic Genetics (ISFG) hereby presents guidelines and recommendations for the use of X-chromosomal markers in kinship analysis with a special focus on the biostatistical evaluation. Linkage and linkage disequilibrium (association of alleles) are of special importance for such evaluations and these concepts and the implications for likelihood calculations are described in more detail. Furthermore it is important to use appropriate computer software that accounts for linkage and linkage disequilibrium among loci, as well as for mutations. Even though some software exist, there is still a need for further improvement of dedicated software. (C) 2017 Elsevier B.V. All rights reserved.

  • 42.
    Tsoi, Lam C.
    et al.
    University of Michigan, MI 48109 USA; University of Michigan, MI 48109 USA; University of Michigan, MI 48109 USA.
    Stuart, Philip E.
    University of Michigan, MI 48109 USA.
    Tian, Chao
    23andMe Inc, CA 94041 USA.
    Gudjonsson, Johann E.
    University of Michigan, MI 48109 USA.
    Das, Sayantan
    University of Michigan, MI 48109 USA.
    Zawistowski, Matthew
    University of Michigan, MI 48109 USA.
    Ellinghaus, Eva
    Christian Albrechts University of Kiel, Germany.
    Barker, Jonathan N.
    Kings Coll London, England.
    Chandran, Vinod
    University of Toronto, Canada; University of Toronto, Canada.
    Dand, Nick
    Kings Coll London, England.
    Callis Duffin, Kristina
    University of Utah, UT 84132 USA.
    Enerbäck, Charlotta
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Dermatology and Venerology.
    Esko, Tonu
    University of Tartu, Estonia; Broad Institute MIT and Harvard, MA 02142 USA.
    Franke, Andre
    Christian Albrechts University of Kiel, Germany.
    Gladman, Dafna D.
    University of Toronto, Canada; University of Toronto, Canada.
    Hoffmann, Per
    University of Bonn, Germany; University of Basel, Switzerland.
    Kingo, Kulli
    University of Tartu, Estonia.
    Koks, Sulev
    University of Tartu, Estonia; University of Tartu, Estonia; Estonian University of Life Science, Estonia.
    Krueger, Gerald G.
    University of Utah, UT 84132 USA.
    Lim, Henry W.
    Henry Ford Hospital, MI 48202 USA.
    Metspalu, Andres
    University of Tartu, Estonia.
    Mrowietz, Ulrich
    University of Medical Centre Schleswig Holstein, Germany.
    Mucha, Soren
    Christian Albrechts University of Kiel, Germany.
    Rahman, Proton
    Mem University, Canada.
    Reis, Andre
    FAU Erlangen Nurnberg, Germany.
    Tejasvi, Trilokraj
    University of Michigan, MI 48109 USA; Ann Arbor Vet Affairs Hospital, MI 48105 USA.
    Trembath, Richard
    Kings Coll London, England.
    Voorhees, John J.
    University of Michigan, MI 48109 USA.
    Weidinger, Stephan
    University of Medical Centre Schleswig Holstein, Germany.
    Weichenthal, Michael
    University of Medical Centre Schleswig Holstein, Germany.
    Wen, Xiaoquan
    University of Michigan, MI 48109 USA.
    Eriksson, Nicholas
    23andMe Inc, CA 94041 USA.
    Kang, Hyun M.
    University of Michigan, MI 48109 USA.
    Hinds, David A.
    23andMe Inc, CA 94041 USA.
    Nair, Rajan P.
    University of Michigan, MI 48109 USA.
    Abecasis, Goncalo R.
    University of Michigan, MI 48109 USA.
    Elder, James T.
    University of Michigan, MI 48109 USA; Ann Arbor Vet Affairs Hospital, MI 48105 USA.
    Large scale meta-analysis characterizes genetic architecture for common psoriasis associated variants2017In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 8, 15382Article in journal (Refereed)
    Abstract [en]

    Psoriasis is a complex disease of skin with a prevalence of about 2%. We conducted the largest meta-analysis of genome-wide association studies (GWAS) for psoriasis to date, including data from eight different Caucasian cohorts, with a combined effective sample size amp;gt;39,000 individuals. We identified 16 additional psoriasis susceptibility loci achieving genome-wide significance, increasing the number of identified loci to 63 for European-origin individuals. Functional analysis highlighted the roles of interferon signalling and the NFkB cascade, and we showed that the psoriasis signals are enriched in regulatory elements from different T cells (CD8(+) T-cells and CD4(+) T-cells including T(H)0, T(H)1 and T(H)17). The identified loci explain similar to 28% of the genetic heritability and generate a discriminatory genetic risk score (AUC = 0.76 in our sample) that is significantly correlated with age at onset (p = 2 x 10(-89)). This study provides a comprehensive layout for the genetic architecture of common variants for psoriasis.

  • 43.
    van Thuijl, Hinke F.
    et al.
    University of Calif San Francisco, CA 94143 USA; Vrije University of Amsterdam Medical Centre, Netherlands; Vrije University of Amsterdam Medical Centre, Netherlands.
    Mazor, Tali
    University of Calif San Francisco, CA 94143 USA.
    Johnson, Brett E.
    University of Calif San Francisco, CA 94143 USA.
    Fouse, Shaun D.
    University of Calif San Francisco, CA 94143 USA.
    Aihara, Koki
    University of Tokyo, Japan; University of Tokyo, Japan.
    Hong, Chibo
    University of Calif San Francisco, CA 94143 USA.
    Malmström, Annika
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Advanced Home Care in Linköping.
    Hallbeck, Martin
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Heimans, Jan J.
    Vrije University of Amsterdam Medical Centre, Netherlands.
    Kloezeman, Jenneke J.
    Erasmus MC, Netherlands.
    Stenmark Askmalm, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Lamfers, Martine L. M.
    Erasmus MC, Netherlands.
    Saito, Nobuhito
    University of Tokyo, Japan.
    Aburatani, Hiroyuki
    University of Tokyo, Japan.
    Mukasa, Akitake
    University of Tokyo, Japan.
    Berger, Mitchell S.
    University of Calif San Francisco, CA 94143 USA.
    Söderkvist, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Taylor, Barry S.
    Mem Sloan Kettering Cancer Centre, NY 10021 USA; Mem Sloan Kettering Cancer Centre, NY 10021 USA.
    Molinaro, Annette M.
    University of Calif San Francisco, CA 94143 USA; University of Calif San Francisco, CA 94143 USA.
    Wesseling, Pieter
    Vrije University of Amsterdam Medical Centre, Netherlands; Radboud University of Nijmegen, Netherlands.
    Reijneveld, Jaap C.
    Vrije University of Amsterdam Medical Centre, Netherlands; University of Amsterdam, Netherlands.
    Chang, Susan M.
    University of Calif San Francisco, CA 94143 USA.
    Ylstra, Bauke
    Vrije University of Amsterdam Medical Centre, Netherlands.
    Costello, Joseph F.
    University of Calif San Francisco, CA 94143 USA.
    Evolution of DNA repair defects during malignant progression of low-grade gliomas after temozolomide treatment2015In: Acta Neuropathologica, ISSN 0001-6322, E-ISSN 1432-0533, Vol. 129, no 4, 597-607 p.Article in journal (Refereed)
    Abstract [en]

    Temozolomide (TMZ) increases the overall survival of patients with glioblastoma (GBM), but its role in the clinical management of diffuse low-grade gliomas (LGG) is still being defined. DNA hypermethylation of the O (6) -methylguanine-DNA methyltransferase (MGMT) promoter is associated with an improved response to TMZ treatment, while inactivation of the DNA mismatch repair (MMR) pathway is associated with therapeutic resistance and TMZ-induced mutagenesis. We previously demonstrated that TMZ treatment of LGG induces driver mutations in the RB and AKT-mTOR pathways, which may drive malignant progression to secondary GBM. To better understand the mechanisms underlying TMZ-induced mutagenesis and malignant progression, we explored the evolution of MGMT methylation and genetic alterations affecting MMR genes in a cohort of 34 treatment-na less than ve LGGs and their recurrences. Recurrences with TMZ-associated hypermutation had increased MGMT methylation compared to their untreated initial tumors and higher overall MGMT methylation compared to TMZ-treated non-hypermutated recurrences. A TMZ-associated mutation in one or more MMR genes was observed in five out of six TMZ-treated hypermutated recurrences. In two cases, pre-existing heterozygous deletions encompassing MGMT, or an MMR gene, were followed by TMZ-associated mutations in one of the genes of interest. These results suggest that tumor cells with methylated MGMT may undergo positive selection during TMZ treatment in the context of MMR deficiency.

  • 44.
    Verma, Deepti
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Genetic variations in the NALP3 inflammasome: a susceptibility factor for inflammatory diseases2009Licentiate thesis, comprehensive summary (Other academic)
    Abstract [en]

    Innate immunity has received impressive attention in the past decade owing to the discovery of the Toll like receptors (TLRs) and the NOD-like receptors (NLRs). While the TLRs specialize in fighting microbes at the cell surface, the NLRs complement by detecting and responding to intracellular microbes. Recently, the non-microbe sensing NLR called inflammasomes, have been identified, which senses metabolic stress as well as certain pathogenic microbes and elicits host’s inflammatory response.

    The NLR, NALP3 (formerly known as cryopyrin) forms a large cytoplasmic complex called the ‘inflammasome’ when NALP3, activated by a stimuli, associates with the adaptor proteins ASC and CARD-8. This interaction leads to the activation of pro-inflammatory caspase-1 which subsequently results in the formation of Interleukin (IL)-1β and IL-18. Mutations in the gene encoding NALP3, termed NLRP3 can lead to its constitutive activation resulting in an uncontrolled production of IL-1β. These mutations have been implicated in hereditary inflammatory diseases, often grouped under cryopyrin associated periodic syndromes (CAPS).

    This thesis describes a patient with a long history of arthritis and antibiotic resistant fever, but without the typical symptoms of CAPS. The patient was found to be a heterozygous carrier of two common polymorphisms Q705K in NLRP3 and C10X in the CARD-8. Experimental studies showed elevated levels of caspase-1 and IL-1β in the patient, and a total clinical remission was achieved by IL-1β blockade. These two polymorphisms combined, were found to occur in approximately 4% of the control population, suggesting the possibility of a genetic predisposition for inflammation in these individuals. Therefore, a cohort of rheumatoid arthritis (RA) patients, where elevated IL-1β could be one of the reasons behind chronic inflammation, was investigated. We found that carrying the combined polymorphisms resulted in increased RA susceptibility and a more severe disease course. Hypothetically, this subgroup of patients might benefit from IL-1β blockade. Additional studies are warranted to elucidate the functional effects of the two polymorphisms and to determine whether they identify a subgroup of patients that could benefit from IL-1 targeted therapy. Given the structural similarity of NALP3 to other NALPs, the possibility of involvement of the alternative, homologous genes cannot be eliminated.

    List of papers
    1. Gene polymorphisms in the NALP3 inflammasome are associated with interleukin-1 production and severe inflammation: Relation to Common Inflammatory Diseases?
    Open this publication in new window or tab >>Gene polymorphisms in the NALP3 inflammasome are associated with interleukin-1 production and severe inflammation: Relation to Common Inflammatory Diseases?
    Show others...
    2008 (English)In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 58, no 3, 888-894 p.Article in journal (Refereed) Published
    Abstract [en]

    Objective: NALP3, ASC, and TUCAN are components of the NALP3 inflammasome, which triggers caspase 1-mediated interleukin-1β (IL-1β) release. Activating mutations in the gene encoding NALP3 (NLRP3) have recently been linked to familial periodic fever syndromes. We undertook this study to determine whether a patient with arthritis and antibiotic-resistant fever carried mutations in the genes encoding the NALP3 inflammasome.

    Methods: Genetic analysis of NLRP3 and the gene encoding TUCAN (CARD-8) was performed on genomic DNA from the patient and from a population-based collection of DNA (806 subjects). For in vitro studies of IL-1β production and caspase 1 activity, blood was obtained from the patient at different time points after administration of anakinra, an IL-1 receptor antagonist, as well as from 5 healthy age- and sex-matched control subjects.

    Results: Mutation analysis of the patient's genes encoding NALP3, ASC, and TUCAN revealed variations in the NLRP3 (Q705K) and CARD-8 (C10X) genes. The allele frequencies of these single-nucleotide polymorphisms (SNPs) in the population were 6.5% and 34%, respectively. The elevated activity of caspase 1 and the high levels of IL-1β measured in samples from the patient returned to normal levels after treatment with anakinra.

    Conclusion: Our results indicate that the patient's symptoms were due to elevated levels of IL-1β, since treatment with anakinra effectively abolished the symptoms. The compound SNPs may explain the increased IL-1β levels and inflammatory symptoms observed, but further studies are needed to reveal a functional relationship. The prevalence of the polymorphisms (4% of the population carry both SNPs) in the general population may suggest a genetic predisposition for common inflammatory disorders.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-19048 (URN)10.1002/art.23286 (DOI)
    Available from: 2009-06-11 Created: 2009-06-09 Last updated: 2013-10-25Bibliographically approved
    2. Genetic variation in proteins of the cryopyrin inflammasome influences susceptibility and severity of rheumatoid arthritis (the Swedish TIRA project)
    Open this publication in new window or tab >>Genetic variation in proteins of the cryopyrin inflammasome influences susceptibility and severity of rheumatoid arthritis (the Swedish TIRA project)
    Show others...
    2008 (English)In: Rheumatology, ISSN 1462-0324, Vol. 47, no 4, 415-417 p.Article in journal (Refereed) Published
    Abstract [en]

    Objectives: The genetic background to RA is incompletely understood.As new cytokine-targeted therapies emerge, early predictorsof disease severity are becoming increasingly important. Theinflammasomes are essential regulators of cytokine production.We investigated whether two polymorphisms in the genes encodingcryopyrin (CIAS1) and TUCAN (CARD8) influence susceptibilityand disease course in RA.

    Methods: Genotype frequencies were assessed in 174 Swedish patientswith early RA and 360 population-based controls without rheumaticdisease. Genotypes were categorized according to the presence(+) or absence (–) of two wild-type alleles and comparedbetween patients and controls. In the RA patients, antibodiestowards cyclic citrullinated peptides (anti-CCP) and the ‘sharedepitope’ (SE) were assessed, and medication and measuresof disease activity were monitored regularly during 3 yrs.

    Results: The combination of CIAS1/TUCAN/–, ascompared with CIAS1/TUCAN +/+, was significantly more commonamong patients than in controls [odds ratio (OR) 2.2, 95% CI1.03–4.6]. This association was strengthened when patientswere divided into anti-CCP+ [OR 2.8 (1.1–6.7)] or presenceof 1 SE copy [OR 2.8 (1.3–6.2)]. At most time-points duringthe 3-yr follow-up, patients with CIAS1/TUCAN/–showed significantly higher disease activity. Furthermore, CIAS1/TUCAN/– patients proved to be much more likely to receiveTNF-blocking therapy [relative risk 20 (2.6–149)].

    Conclusions: Compound polymorphisms in CIAS1 and TUCAN associatewith RA susceptibility and severity. The cryopyrin inflammasomeneeds further attention regarding a possible aetiopathogeneticconnection with RA.

    Keyword
    Disease course, Genetics, Inflammasome, Rheumatoid arthritis
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-14380 (URN)10.1093/rheumatology/kem372 (DOI)
    Available from: 2007-04-20 Created: 2007-04-20 Last updated: 2015-08-31Bibliographically approved
  • 45.
    von Otter, Malin
    et al.
    University of Gothenburg, Sweden.
    Bergström, Petra
    University of Gothenburg, Sweden.
    Quattrone, Aldo
    Magna Graecia University of Catanzaro, Italy; CNR, Italy.
    Valeria De Marco, Elvira
    CNR, Italy.
    Annesi, Grazia
    CNR, Italy.
    Söderkvist, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Bezzina Wettinger, Stephanie
    University of Malta, Malta.
    Drozdzik, Marek
    Pomeranian Medical University, Poland.
    Bialecka, Monika
    Pomeranian Medical University, Poland.
    Nissbrandt, Hans
    University of Gothenburg, Sweden.
    Klein, Christine
    Medical University of Lubeck, Germany.
    Nilsson, Michael
    University of Gothenburg, Sweden; University of Newcastle, Australia.
    Hammarsten, Ola
    University of Gothenburg, Sweden.
    Nilsson, Staffan
    Chalmers, Sweden.
    Zetterberg, Henrik
    University of Gothenburg, Sweden; UCL Institute Neurol, England.
    Genetic associations of Nrf2-encoding NFE2L2 variants with Parkinson s disease a multicenter study2014In: BMC Medical Genetics, ISSN 1471-2350, Vol. 15, no 131Article in journal (Refereed)
    Abstract [en]

    Background: The transcription factor Nrf2, encoded by the NFE2L2 gene, is an important regulator of the cellular protection against oxidative stress. Parkinson s disease is a neurodegenerative disease highly associated with oxidative stress. In a previously published study, we reported associations of NFE2L2 haplotypes with risk and age at onset of idiopathic Parkinson s disease in a Swedish discovery material and a Polish replication material. Here, we have extended the replication study and performed meta-analyses including the Polish material and four new independent European patient-control materials. Furthermore, all SNPs included in the haplotype windows were investigated individually for associations with Parkinson s disease in meta-analyses including all six materials. Methods: Totally 1038 patients and 1600 control subjects were studied. Based on previous NFE2L2 haplotype associations with Parkinson s disease, five NFE2L2 tag SNPs were genotyped by allelic discrimination and three functional NFE2L2 promoter SNPs were genotyped by sequencing. The impact of individual SNPs and haplotypes on risk and age at onset of Parkinson s disease were investigated in each material individually and in meta-analyses of the obtained results. Results: Meta-analyses of NFE2L2 haplotypes showed association of haplotype GAGCAAAA, including the fully functional promoter haplotype AGC, with decreased risk (OR = 0.8 per allele, p = 0.012) and delayed onset (+ 1.1 years per allele, p = 0.048) of Parkinson s disease. These results support the previously observed protective effect of this haplotype in the first study. Further, meta-analyses of the SNPs included in the haplotypes revealed four NFE2L2 SNPs associated with age at onset of Parkinson s disease (rs7557529 G greater than A, -1.0 years per allele, p = 0.042; rs35652124 A greater than G, -1.1 years per allele, p = 0.045; rs2886161 A greater than G, -1.2 years per allele, p = 0.021; rs1806649 G greater than A, + 1.2 years per allele, p = 0.029). One of these (rs35652124) is a functional SNP located in the NFE2L2 promoter. No individual SNP was associated with risk of Parkinson s disease. Conclusion: Our results support the hypothesis that variation in the NFE2L2 gene, encoding a central protein in the cellular protection against oxidative stress, may contribute to the pathogenesis of Parkinson s disease. Functional studies are now needed to explore these results further.

  • 46.
    Willander, Kerstin
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology.
    Jakobsen Falk, Ingrid
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medical and Health Sciences, Division of Drug Research.
    Chaireti, Roza
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Acute Internal Medicine.
    Paul, Esbjörn
    Division of Hematology, Department of Medicine, Karolinska Institutet, Huddinge, Stockholm, Sweden.
    Monica, Hermanson
    Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.
    Gréen, Henrik
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences. Department of Forensic Genetics and Forensic Toxicology, National Board of Forensic Medicine, Linköping, Sweden.
    Lotfi, Kourosh
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Pharmacology.
    Söderkvist, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Mutations in the isocitrate dehydrogenase 1/2 genes and IDH1 SNP 105C>T have a prognostic value in acute myeloid leukemia2014In: Biomarker Research, ISSN 2050-7771, Vol. 2, no 18Article in journal (Refereed)
    Abstract [en]

    The isocitrate dehydrogenase (IDH1/IDH2) genes are frequently mutated and reported to associate with poor prognosis in acute myeloid leukemia (AML). We have investigated the frequency and outcome of the acquired IDH1/IDH2 mutations and the IDH1 SNP  105C>T (rs11554137) in 207 unselected de novo AML patients. IDH1 codon 132 mutations were present in 7.7%, whereas IDH2 mutations were more frequent and mutations were identified in codon 140 and 172 in a frequency of 10.1% and 2.9%, respectively. The SNP 105C>T was present in 10.1% of the patients, similar to the normal population. A significantly reduced overall survival (OS) for patients carrying IDH2 codon 140 mutation compared with patients carrying wild-type IDH2 gene (p=0.009) was observed in the intermediate risk patient group with cytogenetically normal karyotype (CN-AML). Neither in the entire patient group nor subdivided in different risk groups, IDH1 mutations had any significance on OS compared to the wild-type IDH1 patients. A significant difference in OS between the heterozygous SNP variant and the homozygous wild-type was observed in the intermediate risk FLT3 negative CN-AML, (p=0.007). Our results indicate that IDH2 mutations and the IDH1 SNP 105C>T variant may represent a new subgroup for risk stratification and may indicate new treatment options.

  • 47.
    Willems, Els
    et al.
    KU Leuven, Department of Biosystems, Laboratory of Livestock Physiology, Kasteelpark Arenberg 30 box 2456, 3001 Leuven, Belgium.
    Guerrero-Bosagna, Carlos
    Linköping University, Department of Physics, Chemistry and Biology, Biology. Linköping University, Faculty of Science & Engineering.
    Decuypere, Eddy
    KU Leuven, Department of Biosystems, Laboratory of Livestock Physiology, Kasteelpark Arenberg 30 box 2456, 3001 Leuven, Belgium.
    Janssens, Steven
    KU Leuven, Department of Biosystems, Research Group Livestock Genetics, Kasteelpark Arenberg 30 box 2456, 3001 Leuven, Belgium.
    Buyse, Johan
    KU Leuven, Department of Biosystems, Laboratory of Livestock Physiology, Kasteelpark Arenberg 30 box 2456, 3001 Leuven, Belgium.
    Buys, Nadine
    KU Leuven, Department of Biosystems, Research Group Livestock Genetics, Kasteelpark Arenberg 30 box 2456, 3001 Leuven, Belgium.
    Jensen, Per
    Linköping University, Department of Physics, Chemistry and Biology, Biology. Linköping University, Faculty of Science & Engineering.
    Everaert, Nadia
    4University of Liège, Gembloux Agro-Bio Tech, Precision Livestock and Nutrition Unit, Passage des Déportés 2, 5030 Gembloux, Belgium.
    Differential Expression of Genes and DNA Methylation associated with Prenatal Protein Undernutrition by Albumen Removal in an avian model2016In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6Article in journal (Refereed)
    Abstract [en]

    Previously, long-term effects on body weight and reproductive performance have been demonstrated in the chicken model of prenatal protein undernutrition by albumen removal. Introduction of such persistent alterations in phenotype suggests stable changes in gene expression. Therefore, a genome-wide screening of the hepatic transcriptome by RNA-Seq was performed in adult hens. The albumen-deprived hens were created by partial removal of the albumen from eggs and replacement with saline early during embryonic development. Results were compared to sham-manipulated hens and non-manipulated hens. Grouping of the differentially expressed (DE) genes according to biological functions revealed the involvement of processes such as 'embryonic and organismal development' and 'reproductive system development and function'. Molecular pathways that were altered were 'amino acid metabolism', 'carbohydrate metabolism' and 'protein synthesis'. Three key central genes interacting with many DE genes were identified: UBC, NR3C1, and ELAVL1. The DNA methylation of 9 DE genes and 3 key central genes was examined by MeDIP-qPCR. The DNA methylation of a fragment (UBC_3) of the UBC gene was increased in the albumen-deprived hens compared to the non-manipulated hens. In conclusion, these results demonstrated that prenatal protein undernutrition by albumen removal leads to long-term alterations of the hepatic transcriptome in the chicken.

  • 48.
    Yamamoto, Toshiyuki
    et al.
    Tokyo Womens Medical University, Japan .
    Wilsdon, Anna
    Nottingham City Hospital, UK.
    Joss, Shelagh
    Southern General Hospital, Glasgow, UK.
    Isidor, Bertrand
    Centre Hospital University of Nantes 7, France Institute Thorax, France .
    Erlandsson, Anna
    Sahlgrenska University Hospital, Gothenburg, Sweden.
    Suri, Mohnish
    Nottingham City Hospital, UK.
    Sangu, Noriko
    Tokyo Womens Medical University, Japan .
    Shimada, Shino
    Tokyo Womens Medical University, Japan .
    Shimojima, Keiko
    Tokyo Womens Medical University, Japan .
    Le Caignec, Cedric
    Centre Hospital University of Nantes 7, France Institute Thorax, France .
    Samuelsson, Lena
    Sahlgrenska University Hospital, Gothenburg, Sweden.
    Stefanova, Margarita
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics. Sahlgrenska University Hospital, Gothenburg, Sweden.
    An emerging phenotype of Xq22 microdeletions in females with severe intellectual disability, hypotonia and behavioral abnormalities2014In: Journal of Human Genetics, ISSN 1434-5161, E-ISSN 1435-232X, Vol. 59, no 6, 300-306 p.Article in journal (Refereed)
    Abstract [en]

    The majority of Xq22 duplications seen in patients with Pelizaeus-Merzbacher disease (PMD) include proteolipid protein 1 (PLP1), the gene responsible for PMD, and neighboring genes. Some cases result from larger duplications up to 7 Mb in size. In comparison, the deletions including PLP1 seen in PMD patients are small. In this study, we present the genetic and clinical information for five female patients with deletions involving the Xq22 region, and review the correlation between the genotype and phenotype. Three of the five patients show similar large deletions (greater than3 Mb) ranging from Xq22.1 to Xq22.3 and all manifest severe intellectual disability, hypotonia and behavioral abnormalities. The most striking similarity among them are the behavioral problems, including poor eye contact and sleep disturbance. We propose that this represents an emerging distinctive microdeletion syndrome encompassing PLP1 in female patients. The possible candidate region responsible for such distinctive features has been narrowed down to the neighboring region for PLP1, including the interleukin 1 receptor accessory protein-like 2 (IL1RAPL2) gene and the clustered brain expressed X-linked (BEX) genes. The gene(s) responsible for severe neurological features in the patients in this study would be located in the regions proximate to PLP1; thus, males with the deletions involving the gene(s) would be lethal, and finally, the sizes of the deletions in PMD patients would be smaller than those of the duplications.

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