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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, p. 139-149Article 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.
    Alila-Fersi, Olfa
    et al.
    Molecular and Functional Genetics Laboratory, Faculty of Science of Sfax, University of Sfax, Tunisia.
    Tabebi, Mouna
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Maalej, Marwa
    Molecular and Functional Genetics Laboratory, Faculty of Science of Sfax, University of Sfax, Tunisia.
    Belguith, Neila
    Department of Medical Genetics, Hédi Chaker Hospital, Sfax, Tunisia.
    Keskes, Leila
    Human Molecular Genetics Laboratory, Faculty of Medecine of Sfax, University of Sfax, Tunisia.
    Mkaouar-Rebai, Emna
    Molecular and Functional Genetics Laboratory, Faculty of Science of Sfax, University of Sfax, Tunisia.
    Fakhfakh, Faiza
    Molecular and Functional Genetics Laboratory, Faculty of Science of Sfax, University of Sfax, Tunisia.
    First description of a novel mitochondrial mutation in the MT-TI gene associated with multiple mitochondrial DNA deletion and depletion in family with severe dilated mitochondrial cardiomyopathy2018In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 497, no 4, p. 1049-1054Article in journal (Refereed)
    Abstract [en]

    Mitochondria are essential for early cardiac development and impaired mitochondria] function was described associated with heart diseases such as hypertrophic or dilated mitochondrial cardiomyopathy. In this study, we report a family including two individuals with severe dilated mitochondrial cardiomyopathy. The whole mitochondrial genome screening showed the presence of several variations and a novel homoplasmic mutation m.4318-4322deIC in the MT-TI gene shared by the two patients and their mother and leading to a disruption of the tRNA(IIe) secondary structure. In addition, a mitochondrial depletion was present in blood leucocyte of the two affected brother whereas a de novo heteroplasmic multiple deletion in the major arc of mtDNA was present in blood leucocyte and mucosa of only one of them. These deletions in the major arc of the mtDNA resulted to the loss of several protein-encoding genes and also some tRNA genes. The mtDNA deletion and depletion could result to an impairment of the oxidative phosphorylation and energy metabolism in the respiratory chain in the studied patients. Our report is the first description of a family with severe lethal dilated mitochondrial cardiomyopathy and presenting several mtDNA abnormalities including punctual mutation, deletion and depletion.

  • 3.
    Alkaissi, Hammoudi
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Identification of candidate genes involved in Mercury Toxicokinetics and Mercury Induced Autoimmunity2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    BACKGROUND: Autoimmune diseases require the involvement and activation of immune cells and occur when the body builds up an immune response against its own tissues. This process takes place due to the inability to distinguish self-antigen from foreign antigen. Systemic autoimmunity represents an important cause of morbidity and mortality in humans. The mechanisms triggering autoimmune responses are complex and involve a network of genetic factors. Genome wide association study (GWAS) is a powerful method, used to identify genetic risk factors in numerous diseases, such as systemic autoimmune diseases. The goal of GWAS is to identify these genetic risk factors in order to make predictions about who is at risk and investigate the biological process of disease susceptibility. There are several valuable mouse models to investigate the underlying mechanisms causing systemic autoimmune diseases in which mercury induced autoimmunity (HgIA) is a well- established and relevant model. HgIA in mice includes development of autoantibodies, immune complex glomerulonephritis, lymphocyte proliferation, hypergammaglobulinemia and polyclonal B cell activation. In humans, mercury exposure accumulates with considerable concentrations in kidney, liver, and brain. Toxicokinetics of Hg has been studied extensively but the key for inter-individual variation in humans are largely unclear. Differences in accumulation of renal Hg between inbred mouse strains suggest a genetic inter-strain variation regulating retention or/and excretion of Hg.

    OBJECTIVES: To find loci and candidate genes associated with phenotypes involved in the development of autoimmunity and find candidate genes involved in the regulation of renal Hg excretion.

    METHODS: MHC II (H-2s) mice were paired (A.SW x B10.S) to obtain F2 offspring exposed to 2.0 or 4.0 mg Hg in drinking water for 6 weeks. Mercury induced autoimmune phenotypes were studied with immunofluorescence (anti-nucleolar antibodies (ANoA)), ELISA anti-DNP/anti-ssDNA (polyclonal B cell activation), anti-chromatin antibodies (ACA) (4.0 mg Hg), and serum IgG1 concentrations. Mercury accumulation in kidney was performed previously and data was included as phenotype. F2 mice exposed to 2.0 mg Hg were genotyped with microsatellites for genome-wide scan with Ion Pair Reverse Phase High Performance Liquid Chromatography (IP RP HPLC). F2 mice exposed to 4.0 mg Hg were genotyped with single nucleotide polymorphisms for genomewide scan with SNP&SEQ technology platform. Quantitative trait loci (QTL) was established with R/QTL. Denaturing HPLC, next generation sequencing, conserved region analysis and genetic mouse strain comparison were used for haplotyping and fine mapping on QTLs associated with Hg concentration in kidney, development of ANoA and serum IgG1 hypergammaglobulinemia. Candidate genes (Pprc1, Bank1 and Nfkb1) verified by additional QTL were further investigated by real time polymerase chain reaction. Genes involved in the intracellular signaling together with candidate genes were included for gene expression analysis.

    RESULTS: F2 mice exposed to 2.0 mg Hg had low or no development of autoantibodies and showed no significant difference in polyclonal B cell activation in the B10.S and F2 strains. F2 mice exposed to 4.0 mg Hg developed autoantibodies and significantly increased IgG1 concentration and polyclonal B cell activation (anti-DNP). QTL analysis showed a logarithm of odds ratio (LOD) score between 2.9 – 4.36 on all serological phenotypes exposed to 4.0 mg Hg, and a LOD score of 5.78 on renal Hg concentration. Haplotyping and fine mapping associated the development of ANoA with Bank1 (B-cell scaffold protein with ankyrin repeats 1) and Nfkb1 (nuclear factor kappa B subunit 1). The serum IgG1 concentration was associated with a locus on chromosome 3, in which Rxfp4 (Relaxin Family Peptide/INSL5 Receptor 4) is a potential candidate gene. The renal Hg concentration was associated with Pprc1 (Peroxisome Proliferator-Activated Receptor Gamma, Co-activator-Related). Gene expression analysis revealed that the more susceptible A.SW strain expresses significantly higher levels of Nfkb1, Il6 and Tnf than the less susceptible B10.S strain. The A.SW strain expresses significantly lower levels of Pprc1 and cascade proteins than the B10.S strain. Development of ACA was associated with chromosomes 3, 6, 7 and 16 (LOD 3.1, 3.2, 3.4 and 6.8 respectively). Polyclonal B cell activation was associated with chromosome 2 with a LOD score of 2.9.

    CONCLUSIONS: By implementing a GWAS on HgIA in mice, several QTLs were discovered to be associated with the development of autoantibodies, polyclonal B cell activation and hypergammaglobulinemia. This thesis plausibly supports Bank1 and Nfkb1 as key regulators for ANoA development and HgIA seems to be initiated by B cells rather than T cells. GWAS on renal mercury excretion plausibly supports Pprc1 as key regulator and it seems that this gene has a protective role against Hg.

    List of papers
    1. Genome-Wide Association Study to Identify Genes Related to Renal Mercury Concentrations in Mice
    Open this publication in new window or tab >>Genome-Wide Association Study to Identify Genes Related to Renal Mercury Concentrations in Mice
    Show others...
    2016 (English)In: Journal of Environmental Health Perspectives, ISSN 0091-6765, E-ISSN 1552-9924, Vol. 124, no 7, p. 920-926Article in journal (Refereed) Published
    Abstract [en]

    BACKGROUND: Following human mercury (Hg) exposure, the metal accumulates in considerable concentrations in kidney, liver, and brain. Although the toxicokinetics of Hg have been studied extensively, factors responsible for interindividual variation in humans are largely unknown. Differences in accumulation of renal Hg between inbred mouse strains suggest a genetic interstrain variation regulating retention or/and excretion of Hg. A. SW, DBA/2 and BALB/C mouse strains accumulate higher amounts of Hg than B10.S.

    OBJECTIVES: We aimed to find candidate genes associated with regulation of renal Hg concentrations.

    METHODS: A. SW, B10.S and their F1 and F2 offspring were exposed for 6 weeks to 2.0 mg Hg/L drinking water. Genotyping with microsatellites was conducted on 84 F2 mice for genome-wide scanning with ion pair reverse-phase high-performance liquid chromatography (IP RP HPLC). Quantitative trait loci (QTL) were established. Denaturing HPLC was used to detect single nucleotide polymorphisms for haplotyping and fine mapping in 184 and 32 F2 mice, respectively. Candidate genes (Pprc1, Btrc and Nfkb2) verified by fine mapping and QTL were further investigated by real-time polymerase chain reaction. Genes enhanced by Pprc1 (Nrf1 and Nrf2) were included for gene expression analysis.

    RESULTS: Renal Hg concentrations differed significantly between A. SW and B10. S mice and between males and females within each strain. QTL analysis showed a peak logarithm of odds ratio score 5.78 on chromosome 19 (p = 0.002). Haplotype and fine mapping associated the Hg accumulation with Pprc1, which encodes PGC-1-related coactivator (PRC), a coactivator for proteins involved in detoxification. Pprc1 and two genes coactivated by Pprc1 (Nrf1 and Nrf2) had significantly lower gene expression in the A. SW strain than in the B10. S strain.

    CONCLUSIONS: This study supports Pprc1 as a key regulator for renal Hg excretion.

    Place, publisher, year, edition, pages
    U.S. Department of Health and Human Services * National Institute of Environmental Health Sciences, 2016
    National Category
    Other Biological Topics
    Identifiers
    urn:nbn:se:liu:diva-131584 (URN)10.1289/ehp.1409284 (DOI)000380749300012 ()26942574 (PubMedID)
    Note

    Funding Agencies|Swedish Research Council Branch of Medicine; County Council of Ostergotland; Linkoping University

    Available from: 2016-09-27 Created: 2016-09-27 Last updated: 2018-10-24Bibliographically approved
    2. Bank1 and NF-kappaB as key regulators in anti-nucleolar antibody development
    Open this publication in new window or tab >>Bank1 and NF-kappaB as key regulators in anti-nucleolar antibody development
    Show others...
    2018 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 13, no 7, article id e0199979Article in journal (Refereed) Published
    Abstract [en]

    Systemic autoimmune rheumatic disorders (SARD) represent important causes of morbidity and mortality in humans. The mechanisms triggering autoimmune responses are complex and involve a network of genetic factors. Mercury-induced autoimmunity (HgIA) in mice is an established model to study the mechanisms of the development of antinuclear antibodies (ANA), which is a hallmark in the diagnosis of SARD. A.SW mice with HgIA show a significantly higher titer of antinucleolar antibodies (ANoA) than the B10.S mice, although both share the same MHC class II (H-2). We applied a genome-wide association study (GWAS) to their Hg-exposed F2 offspring to investigate the non-MHC genes involved in the development of ANoA. Quantitative trait locus (QTL) analysis showed a peak logarithm of odds ratio (LOD) score of 3.05 on chromosome 3. Microsatellites were used for haplotyping, and fine mapping was conducted with next generation sequencing. The candidate genes Bank1 (B-cell scaffold protein with ankyrin repeats 1) and Nfkbl (nuclear factor kappa B subunit 1) were identified by additional QTL analysis. Expression of the Bank1 and Nfkb1 genes and their downstream target genes involved in the intracellular pathway (Tlr9,II6, Tnf) was investigated in mercury-exposed A.SW and B10.S mice by real-time PCR. Bank1 showed significantly lower gene expression in the A.SW strain after Hg-exposure, whereas the B10.S strain showed no significant difference. Nfkb1, Tlr9, II6 and Tnf had significantly higher gene expression in the A.SW strain after Hg-exposure, while the B10.S strain showed no difference. This study supports the roles of Bank1 (produced mainly in B-cells) and Nfkbl (produced in most immune cells) as key regulators of ANoA development in HgIA.

    Place, publisher, year, edition, pages
    PUBLIC LIBRARY SCIENCE, 2018
    National Category
    Genetics
    Identifiers
    urn:nbn:se:liu:diva-150265 (URN)10.1371/journal.pone.0199979 (DOI)000438866600014 ()30016332 (PubMedID)
    Note

    Funding Agencies|Swedish Research Council Branch of Medicine; County Council of Ostergotland; Linkoping University

    Available from: 2018-08-17 Created: 2018-08-17 Last updated: 2019-04-24
  • 4.
    Alvarez-Rodriguez, Manuel
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences.
    Atikuzzaman, Mohammad
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences. Department of Surgery and Theriogenology, Faculty of Veterinary Animal and Biomedical Sciences, Sylhet Agricultural University, Sylhet, Bangladesh.
    Venhoranta, Heli
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences. University of Helsinki, Department of Production Animal Medicine, Faculty of Veterinary Medicine, Saari, Finland.
    Wright, Dominic
    Linköping University, Department of Physics, Chemistry and Biology, Biology. Linköping University, Faculty of Science & Engineering.
    Rodriguez-Martinez, Heriberto
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences.
    Expression of Immune Regulatory Genes in the Porcine Internal Genital Tract Is Differentially Triggered by Spermatozoa and Seminal Plasma2019In: International Journal of Molecular Sciences, ISSN 1422-0067, E-ISSN 1422-0067, Vol. 20, no 3, article id 513Article in journal (Refereed)
    Abstract [en]

    Mating or cervical deposition of spermatozoa or seminal plasma (SP) modifies the expression of genes affecting local immune defense processes at the oviductal sperm reservoir in animals with internal fertilization, frequently by down-regulation. Such responses may occur alongside sperm transport to or even beyond the reservoir. Here, immune-related gene expression was explored with cDNA microarrays on porcine cervix-to-infundibulum tissues, pre-/peri-ovulation. Samples were collected 24 h post-mating or cervical deposition of sperm-peak spermatozoa or SP (from the sperm-peak fraction or the whole ejaculate). All treatments of this interventional study affected gene expression. The concerted action of spermatozoa and SP down-regulated chemokine and cytokine (P00031), interferon-gamma signaling (P00035), and JAK/STAT (P00038) pathways in segments up to the sperm reservoir (utero-tubal junction (UTJ)/isthmus). Spermatozoa in the vanguard sperm-peak fraction (P1-AI), uniquely displayed an up-regulatory effect on these pathways in the ampulla and infundibulum. Sperm-free SP, on the other hand, did not lead to major effects on gene expression, despite the clinical notion that SP mitigates reactivity by the female immune system after mating or artificial insemination.

  • 5.
    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.

  • 6.
    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, p. e8090-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.

  • 7.
    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, p. 1204-1212Article 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.

  • 8.
    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, p. 1-16Article 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.

  • 9.
    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, E-ISSN 1563-5260, Vol. 24, no Suppl. 1, p. 70-71Article in journal (Other academic)
    Abstract [en]

    n/a

  • 10.
    Björn, Niclas
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    Pradhananga, S.
    Science for Life Laboratory, School of Engineering Sciences in Chemistry, Biotechnology and Health, Division of Gene Technology, KTH Royal Institute of Technology, Solna, Sweden.
    Sigurgeirsson, B.
    Science for Life Laboratory, School of Engineering Sciences in Chemistry, Biotechnology and Health, Division of Gene Technology, KTH Royal Institute of Technology, Solna, Sweden; School of Engineering and Natural Sciences, University of Iceland, Reykjavík, Iceland.
    Lundberg, J.
    Science for Life Laboratory, School of Engineering Sciences in Chemistry, Biotechnology and Health, Division of Gene Technology, KTH Royal Institute of Technology, Solna, Sweden.
    Green, Henrik
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Science for Life Laboratory, School of Engineering Sciences in Chemistry, Biotechnology and Health, Division of Gene Technology, KTH Royal Institute of Technology, Solna, Sweden.
    Sahlén, P
    Science for Life Laboratory, School of Engineering Sciences in Chemistry, Biotechnology and Health, Division of Gene Technology, KTH Royal Institute of Technology, Solna, Sweden.
    Comparison of Variant Calls from Whole Genome and Whole Exome Sequencing Data Using Matched Samples2018In: Journal of Next Generation Sequencing & Applications, ISSN 2469-9853, Vol. 5, no 1, p. 1-8Article in journal (Refereed)
    Abstract [en]

    Whole exome sequencing (WES) has been extensively used in genomic research. As sequencing costs decline it is being replaced by whole genome sequencing (WGS) in large-scale genomic studies, but more comparative information on WES and WGS datasets would be valuable. Thus, we have extensively compared variant calls obtained from WGS and WES of matched germline DNA samples from 96 lung cancer patients. WGS provided more homogeneous coverage with higher genotyping quality, and identified more variants, than WES, regardless of exome coverage depth. It also called more reference variants, reflecting its power to call rare variants, and more heterozygous variants that met applied quality criteria, indicating that WGS is less prone to allelic drop outs. However, increasing WES coverage reduced the discrepancy between the WES and WGS results. We believe that as sequencing costs further decline WGS will become the method of choice even for research confined to the exome.

  • 11.
    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, p. 141-159Chapter 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).

  • 12.
    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.

     

  • 13.
    Bragde, Hanna
    et al.
    Division of Medical Diagnostics, Ryhov County Hospital, Sweden.
    Jansson, Ulf
    Department of Pediatrics, Ryhov County Hospital, Sweden.
    Jarlsfelt, Ingvar
    Division of Medical Diagnostics, Ryhov County Hospital, Sweden.
    Söderman, Jan
    Division of Medical Diagnostics, Ryhov County Hospital, Sweden.
    Gene Expression Profiling of Duodenal Biopsies Discriminates Celiac Disease Mucosa From Normal Mucosa2011In: Pediatric Research, ISSN 0031-3998, E-ISSN 1530-0447, Vol. 69, no 6, p. 530-537Article in journal (Refereed)
    Abstract [en]

    Celiac disease (CD) is identified by histopathologic changes in the small intestine which normalize during a gluten-free diet. The histopathologic assessment of duodenal biopsies is usually routine but can be difficult. This study investigated gene expression profiling as a diagnostic tool. A total of 109 genes were selected to reflect alterations in crypt-villi architecture, inflammatory response, and intestinal permeability and were examined for differential expression in normal mucosa compared with CD mucosa in pediatric patients. Biopsies were classified using discriminant analysis of gene expression. Fifty genes were differentially expressed, of which eight (APOC3, CYP3A4, OCLN, MAD2L1, MKI67, CXCL11, IL17A, and CTLA4) discriminated normal mucosa from CD mucosa without classification errors using leave-one-out cross-validation (n = 39) and identified the degree of mucosal damage. Validation using an independent set of biopsies (n = 27) resulted in four discrepant cases. Biopsies from two of these cases showed a patchy distribution of lesions, indicating that discriminant analysis based on single biopsies failed to identify CD mucosa. In the other two cases, serology support class according to discriminant analysis and histologic specimens were judged suboptimal but assessable. Gene expression profiling shows promise as a diagnostic tool and for follow-up of CD, but further evaluation is needed.

  • 14.
    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
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    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
    Keywords
    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: 2019-03-05Bibliographically 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
    Show others...
    2016 (English)In: Royal Society Open Science, E-ISSN 2054-5703, no 3, article id 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
    Keywords
    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: 2017-11-28
  • 15.
    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, p. 14-22Article 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: 2017-12-13Bibliographically 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
    Show others...
    2003 (English)In: Genes and Immunity, ISSN 1466-4879, E-ISSN 1476-5470, Vol. 4, no 8, p. 559-563Article 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: 2017-12-13Bibliographically 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
    Show others...
    2007 (English)In: Multiple Sclerosis, ISSN 1352-4585, E-ISSN 1477-0970, Vol. 13, no 4, p. 441-445Article 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: 2017-12-13Bibliographically 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, p. 1253-1262Article 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.

    Keywords
    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: 2017-12-12Bibliographically approved
  • 16.
    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, p. 352-360Conference 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

  • 17.
    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.

  • 18.
    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, article id 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.

  • 19.
    Carlsson Almlöf, Jonas Carlsson
    et al.
    Uppsala Univ, Sweden.
    Nystedt, Sara
    Uppsala Univ, Sweden.
    Leonard, Dag
    Uppsala Univ, Sweden.
    Eloranta, Maija-Leena
    Uppsala Univ, Sweden.
    Grosso, Giorgia
    Karolinska Univ Hosp, 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 Univ, Sweden.
    Jonsen, Andreas
    Lund Univ, Sweden.
    Gunnarsson, Iva
    Karolinska Univ Hosp, Sweden.
    Svenungsson, Elisabet
    Karolinska Univ Hosp, Sweden.
    Rönnblom, Lars
    Uppsala Univ, Sweden.
    Sandling, Johanna K.
    Uppsala Univ, Sweden.
    Syvanen, Ann-Christine
    Uppsala Univ, Sweden.
    Whole-genome sequencing identifies complex contributions to genetic risk by variants in genes causing monogenic systemic lupus erythematosus2019In: Human Genetics, ISSN 0340-6717, E-ISSN 1432-1203, Vol. 138, no 2, p. 141-150Article in journal (Refereed)
    Abstract [en]

    Systemic lupus erythematosus (SLE, OMIM 152700) is a systemic autoimmune disease with a complex etiology. The mode of inheritance of the genetic risk beyond familial SLE cases is currently unknown. Additionally, the contribution of heterozygous variants in genes known to cause monogenic SLE is not fully understood. Whole-genome sequencing of DNA samples from 71 Swedish patients with SLE and their healthy biological parents was performed to investigate the general genetic risk of SLE using known SLE GWAS risk loci identified using the ImmunoChip, variants in genes associated to monogenic SLE, and the mode of inheritance of SLE risk alleles in these families. A random forest model for predicting genetic risk for SLE showed that the SLE risk variants were mainly inherited from one of the parents. In the 71 patients, we detected a significant enrichment of ultra-rare (0.1%) missense and nonsense mutations in 22 genes known to cause monogenic forms of SLE. We identified one previously reported homozygous nonsense mutation in the C1QC (Complement C1q C Chain) gene, which explains the immunodeficiency and severe SLE phenotype of that patient. We also identified seven ultra-rare, coding heterozygous variants in five genes (C1S, DNASE1L3, DNASE1, IFIH1, and RNASEH2A) involved in monogenic SLE. Our findings indicate a complex contribution to the overall genetic risk of SLE by rare variants in genes associated with monogenic forms of SLE. The rare variants were inherited from the other parent than the one who passed on the more common risk variants leading to an increased genetic burden for SLE in the child. Higher frequency SLE risk variants are mostly passed from one of the parents to the offspring affected with SLE. In contrast, the other parent, in seven cases, contributed heterozygous rare variants in genes associated with monogenic forms of SLE, suggesting a larger impact of rare variants in SLE than hitherto reported.

  • 20.
    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, E-ISSN 2090-0430, 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.

  • 21.
    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, p. 4301-4313Article 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.

  • 22.
    Das, Jyotirmoy
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology, Infection and Inflammation. Linköping University, Faculty of Medicine and Health Sciences.
    Verma, Deepti
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Gustafsson, Mika
    Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics. Linköping University, Faculty of Science & Engineering.
    Lerm, Maria
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology, Infection and Inflammation. Linköping University, Faculty of Medicine and Health Sciences.
    Identification of DNA methylation patterns predisposing for an efficient response to BCG vaccination in healthy BCG-naive subjects2019In: Epigenetics, ISSN 1559-2294, E-ISSN 1559-2308, Vol. 14, no 6, p. 589-601Article in journal (Refereed)
    Abstract [en]

    The protection against tuberculosis induced by the Bacille Calmette Guerin (BCG) vaccine is unpredictable. In our previous study, altered DNA methylation pattern in peripheral blood mononuclear cells (PBMCs) in response to BCG was observed in a subgroup of individuals, whose macrophages killed mycobacteria effectively (responders). These macrophages also showed production of Interleukin-1 beta (IL-1 beta) in response to mycobacterial stimuli before vaccination. Here, we hypothesized that the propensity to respond to the BCG vaccine is reflected in the DNA methylome. We mapped the differentially methylated genes (DMGs) in PBMCs isolated from responders/non-responders at the time point before vaccination aiming to identify possible predictors of BCG responsiveness. We identified 43 DMGs and subsequent bioinformatic analyses showed that these were enriched for actin-modulating pathways, predicting differences in phagocytosis. This could be validated by experiments showing that phagocytosis of mycobacteria, which is an event preceding mycobacteria-induced IL-1 beta production, was strongly correlated with the DMG pattern.

  • 23.
    Davidsson, Josef
    et al.
    Skane Univ Hosp, Sweden; Lund Univ, Sweden.
    Puschmann, Andreas
    Lund Univ, Sweden.
    Tedgard, Ulf
    Skane Univ Hosp, Sweden.
    Bryder, David
    Lund Univ, Sweden.
    Nilsson, Lars
    Skane Univ Hosp, Sweden.
    Cammenga, Jörg
    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 Haematology.
    SAMD9 and SAMD9L in inherited predisposition to ataxia, pancytopenia, and myeloid malignancies2018In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 32, no 5, p. 1106-1115Article, review/survey (Refereed)
    Abstract [en]

    Germline mutations in the SAMD9 and SAMD9L genes, located in tandem on chromosome 7, are associated with a clinical spectrum of disorders including the MIRAGE syndrome, ataxia pancytopenia syndrome and myelodysplasia and leukemia syndrome with monosomy 7 syndrome. Germline gain-of-function mutations increase SAMD9 or SAMD9Ls normal antiproliferative effect. This causes pancytopenia and generally restricted growth and/or specific organ hypoplasia in non-hematopoietic tissues. In blood cells, additional somatic aberrations that reverse the germline mutations effect, and give rise to the clonal expansion of cells with reduced or no antiproliferative effect of SAMD9 or SAMD9L include complete or partial chromosome 7 loss or loss-of-function mutations in SAMD9 or SAMD9L. Furthermore, the complete or partial loss of chromosome 7q may cause myelodysplastic syndrome in these patients. SAMD9 mutations appear to associate with a more severe disease phenotype, including intrauterine growth restriction, developmental delay and hypoplasia of adrenal glands, testes, ovaries or thymus, and most reported patients died in infancy or early childhood due to infections, anemia and/or hemorrhages. SAMD9L mutations have been reported in a few families with balance problems and nystagmus due to cerebellar atrophy, and may lead to similar hematological disease as seen in SAMD9 mutation carriers, from early childhood to adult years. We review the clinical features of these syndromes, discuss the underlying biology, and interpret the genetic findings in some of the affected family members. We provide expert-based recommendations regarding diagnosis, follow-up, and treatment of mutation carriers.

  • 24.
    Dittrich, Lars
    et al.
    Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Sigmund-Freud-Str, 27 53127, Bonn, Germany.
    Petese, Alessandro
    Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Sigmund-Freud-Str, 27 53127, Bonn, Germany.
    Jackson, Walker S
    Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Sigmund-Freud-Str, 27 53127, Bonn, Germany.
    The natural Disc1-deletion present in several inbred mouse strains does not affect sleep2017In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, no 1, article id 5665Article in journal (Refereed)
    Abstract [en]

    The gene Disrupted in Schizophrenia-1 (DISC1) is linked to a range of psychiatric disorders. Two recent transgenic studies suggest DISC1 is also involved in homeostatic sleep regulation. Several strains of inbred mice commonly used for genome manipulation experiments, including several Swiss and likely all 129 substrains, carry a natural deletion mutation of Disc1. This constitutes a potential confound for studying sleep in genetically modified mice. Since disturbed sleep can also influence psychiatric and neurodegenerative disease models, this putative confound might affect a wide range of studies in several fields. Therefore, we asked to what extent the natural Disc1 deletion affects sleep. To this end, we first compared sleep and electroencephalogram (EEG) phenotypes of 129S4 mice carrying the Disc1 deletion and C57BL/6N mice carrying the full-length version. We then bred Disc1 from C57BL/6N into the 129S4 background, resulting in S4-Disc1 mice. The differences between 129S4 and C57BL/6N were not detected in the 129S4 to S4-Disc1 comparison. We conclude that the mutation has no effect on the measured sleep and EEG characteristics. Thus, it is unlikely the widespread Disc1 deletion has led to spurious results in previous sleep studies or that it alters sleep in mouse models of psychiatric or neurodegenerative diseases.

  • 25.
    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, p. 1774-1782Article 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.

  • 26.
    Elenis, Evangelia
    et al.
    Uppsala Univ, Sweden.
    Skalkidou, Alkistis
    Uppsala Univ, Sweden.
    Skoog-Svanberg, Agneta
    Uppsala Univ, Sweden.
    Sydsjö, Gunilla
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, Department of Gynaecology and Obstetrics in Linköping.
    Stavreus-Evers, Anneli
    Uppsala Univ, Sweden.
    Akerud, Helena
    Uppsala Univ, Sweden.
    HRG C633T polymorphism and risk of gestational hypertensive disorders: a pilot study2018In: BMC Medical Genetics, ISSN 1471-2350, E-ISSN 1471-2350, Vol. 19, article id 44Article in journal (Refereed)
    Abstract [en]

    Background: Preeclampsia and gestational hypertensive disorders are thought to occur due to endothelial cell dysfunction and abnormal placentation, triggered by angiogenesis-related factors yet undetermined. The aim of this study was to investigate whether a genetic polymorphism (SNP) of Histidine-rich glycoprotein (HRG), HRG C633T SNP, is associated with gestational hypertensive disorders. Methods: It was performed a nested case-control study from the BASIC Cohort of Uppsala University Hospital comprising 92 women diagnosed with gestational hypertensive disorders without other comorbidities and 200 women with full term uncomplicated pregnancies, all genotyped regarding HRG C633T SNP. Results: The genetic analysis of the study sample showed that C/C genotype was more prevalent among controls. The presence of the T-allele showed a tendency towards an increased risk of gestational hypertensive disorders. After clustering the study participants based on their genotype, it was observed that the odds for gestational hypertensive disorders among heterozygous C/T or homozygous T/T carriers were higher compared to homozygous C/C carriers [OR 1.72, 95% CI (1.04-2.84)]. The association remained significant even after adjustment for maternal age, BMI and parity. Conclusions: The HRG C633T genotype seems to be associated with gestational hypertensive disorders, and as part of a greater algorithm, might contribute in the future to the prediction of the individual susceptibility to the condition.

  • 27.
    Emmings, Edith
    et al.
    Univ Minnesota, MN 55455 USA.
    Mullany, Sally
    Univ Minnesota, MN 55455 USA.
    Chang, Zenas
    Univ Minnesota, MN 55455 USA.
    Landen, Charles N. Jr.
    Univ Virginia, VA 22908 USA.
    Linder, Stig
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Karolinska Inst, Sweden.
    Bazzaro, Martina
    Univ Minnesota, MN 55455 USA.
    Targeting Mitochondria for Treatment of Chemoresistant Ovarian Cancer2019In: International Journal of Molecular Sciences, ISSN 1422-0067, E-ISSN 1422-0067, Vol. 20, no 1, article id 229Article, review/survey (Refereed)
    Abstract [en]

    Ovarian cancer is the leading cause of death from gynecologic malignancy in the Western world. This is due, in part, to the fact that despite standard treatment of surgery and platinum/paclitaxel most patients recur with ultimately chemoresistant disease. Ovarian cancer is a unique form of solid tumor that develops, metastasizes and recurs in the same space, the abdominal cavity, which becomes a unique microenvironment characterized by ascites, hypoxia and low glucose levels. It is under these conditions that cancer cells adapt and switch to mitochondrial respiration, which becomes crucial to their survival, and therefore an ideal metabolic target for chemoresistant ovarian cancer. Importantly, independent of microenvironmental factors, mitochondria spatial redistribution has been associated to both tumor metastasis and chemoresistance in ovarian cancer while specific sets of genetic mutations have been shown to cause aberrant dependence on mitochondrial pathways in the most aggressive ovarian cancer subtypes. In this review we summarize on targeting mitochondria for treatment of chemoresistant ovarian cancer and current state of understanding of the role of mitochondria respiration in ovarian cancer. We feel this is an important and timely topic given that ovarian cancer remains the deadliest of the gynecological diseases, and that the mitochondrial pathway has recently emerged as critical in sustaining solid tumor progression.

  • 28.
    Enerbäck, Charlotta
    et al.
    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. Univ Michigan, MI 48109 USA.
    Sandin, Charlotta
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Lambert, S.
    Univ Michigan, MI 48109 USA.
    Zawistowski, M.
    Univ Michigan, MI 48109 USA.
    Stuart, P. E.
    Univ Michigan, MI 48109 USA.
    Verma, Deepti
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Tsoi, L. C.
    Univ Michigan, MI 48109 USA.
    Nair, R. P.
    Univ Michigan, MI 48109 USA.
    Johnston, A.
    Univ Michigan, MI 48109 USA.
    Elder, J. T.
    Univ Michigan, MI 48109 USA; Ann Arbor Vet Affairs Hlth Syst, MI USA.
    The psoriasis-protective TYK2 I684S variant impairs IL-12 stimulated pSTAT4 response in skin-homing CD4+and CD8+memory T-cells2018In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, article id 7043Article in journal (Refereed)
    Abstract [en]

    Tyrosine kinase 2 (TYK2) belongs to the Janus kinase (JAK) family of tyrosine kinases, which transmit signals from activated cytokine receptors. GWAS have consistently implicated TYK2 in psoriasis susceptibility. We performed an in-depth association analysis of TYK2 using GWAS and resequencing data. Strong genetic association of three nonsynonymous variants in the exonic regions of the TYK2 gene (rs34536443, rs12720356, and rs2304256) were found. rs12720356 encoding I684S is predicted to be deleterious based on its location in the pseudokinase domain. We analyzed PBMCs from 29 individuals representing the haplotypes containing each of the significantly associated signals. STAT4 phosphorylation was evaluated by phospho-flow cytometry after CD3/CD28 activation of cells followed by IL-12 stimulation. Individuals carrying the protective I684S variant manifested significantly reduced p-STAT4 levels in CD4 + CD25 + CD45RO + (mean Stimulation Index (S.I.) 48.08, n = 10) and CD8 + CD25 + CD45RO + cells (S.I. 55.71, n = 10), compared to controls homozygous for the ancestral haplotype (S.I. 68.19, n = 10 (p = 0.002) and 76.76 n = 10 (p = 0.0008) respectively). Reduced p-STAT4 levels were also observed in skin-homing, cutaneous lymphocyte associated antigen (CLA)-positive CD4 and CD8 cells from I684S carriers. No significant changes in p-STAT4 for the psoriasis-associated variant rs34536443 was found. These data establish the functional significance of the TYK2 I684S variant in psoriasis susceptibility.

  • 29.
    Eriksson, Daniel
    et al.
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Bianchi, Matteo
    Uppsala Univ, Sweden.
    Landegren, Nils
    Karolinska Inst, Sweden; Uppsala Univ, Sweden.
    Dalin, Frida
    Karolinska Inst, Sweden; Uppsala Univ, Sweden.
    Skov, Jakob
    Karolinska Inst, Sweden.
    Hultin-Rosenberg, Lina
    Uppsala Univ, Sweden.
    Mathioudaki, Argyri
    Uppsala Univ, Sweden.
    Nordin, Jessika
    Uppsala Univ, Sweden.
    Hallgren, Asa
    Karolinska Inst, Sweden.
    Andersson, Goran
    Swedish Univ Agr Sci, Sweden.
    Tandre, Karolina
    Uppsala Univ, Sweden.
    Rantapaa Dahlqvist, Solbritt
    Umea Univ, 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, Clinical genetics.
    Ronnblom, Lars
    Uppsala Univ, Sweden.
    Hulting, Anna-Lena
    Not Found:[Eriksson, Daniel; Landegren, Nils; Dalin, Frida; Hallgren, Asa; Kampe, Olle] Karolinska Inst, Dept Med Solna, Ctr Mol Med, Stockholm, Sweden; [Eriksson, Daniel; Bensing, Sophie; Kampe, Olle] Karolinska Univ Hosp, Dept Endocrinol Metab and Diabet, Stockholm, Sweden; [Bianchi, Matteo; Hultin-Rosenberg, Lina; Mathioudaki, Argyri; Nordin, Jessika; Meadows, Jennifer R. S.; Lindblad-Toh, Kerstin; Pielberg, Gerli Rosengren] Uppsala Univ, Dept Med Biochem and Microbiol, Sci Life Lab, Uppsala, Sweden; [Landegren, Nils; Dalin, Frida; Tandre, Karolina; Ronnblom, Lars] Uppsala Univ, Dept Med Sci, Sci Life Lab, Uppsala, Sweden; [Skov, Jakob; Bensing, Sophie] Karolinska Inst, Dept Mol Med and Surg, Stockholm, Sweden; [Andersson, Goran] Swedish Univ Agr Sci, Dept Anim Breeding and Genet, Uppsala, Sweden; [Dahlqvist, Solbritt Rantapaa; Dahlqvist, Per] Umea Univ, Dept Publ Hlth and Clin Med, Umea, Sweden; [Soderkvist, Peter; Wahlberg, Jeanette] Linkoping Univ, Dept Clin and Expt Med, Linkoping, Sweden; [Wahlberg, Jeanette] Linkoping Univ, Dept Endocrinol, Linkoping, Sweden; [Wahlberg, Jeanette] Linkoping Univ, Dept Med and Hlth Sci, Linkoping, Sweden; [Ekwall, Olov] Univ Gothenburg, Sahlgrenska Acad, Inst Clin Sci, Dept Pediat, Gothenburg, Sweden; [Ekwall, Olov] Univ Gothenburg, Sahlgrenska Acad, Inst Med, Dept Rheumatol and Inflammat Res, Gothenburg, Sweden; [Lindblad-Toh, Kerstin] Broad Inst MIT and Harvard, Cambridge, MA USA; [Kampe, Olle] KG Jebsen Ctr Autoimmune Dis, Bergen, Norway;.
    Wahlberg, Jeanette
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Endocrinology.
    Dahlqvist, Per
    Umea Univ, Sweden.
    Ekwall, Olov
    Univ Gothenburg, Sweden; Univ Gothenburg, Sweden.
    Meadows, Jennifer R. S.
    Uppsala Univ, Sweden.
    Lindblad-Toh, Kerstin
    Uppsala Univ, Sweden; Broad Inst MIT and Harvard, MA USA.
    Bensing, Sophie
    Karolinska Univ Hosp, Sweden; Karolinska Inst, Sweden.
    Pielberg, Gerli Rosengren
    Uppsala Univ, Sweden.
    Kampe, Olle
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden; KG Jebsen Ctr Autoimmune Dis, Norway.
    Common genetic variation in the autoimmune regulator (AIRE) locus is associated with autoimmune Addisons disease in Sweden2018In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, article id 8395Article in journal (Refereed)
    Abstract [en]

    Autoimmune Addisons disease (AAD) is the predominating cause of primary adrenal failure. Despite its high heritability, the rarity of disease has long made candidate-gene studies the only feasible methodology for genetic studies. Here we conducted a comprehensive reinvestigation of suggested AAD risk loci and more than 1800 candidate genes with associated regulatory elements in 479 patients with AAD and 2394 controls. Our analysis enabled us to replicate many risk variants, but several other previously suggested risk variants failed confirmation. By exploring the full set of 1800 candidate genes, we further identified common variation in the autoimmune regulator (AIRE) as a novel risk locus associated to sporadic AAD in our study. Our findings not only confirm that multiple loci are associated with disease risk, but also show to what extent the multiple risk loci jointly associate to AAD. In total, risk loci discovered to date only explain about 7% of variance in liability to AAD in our study population.

  • 30.
    Fardell, Camilla
    et al.
    Univ Gothenburg, Sweden.
    Zettergren, Anna
    Univ Gothenburg, Sweden.
    Ran, Caroline
    Karolinska Inst, Sweden.
    Belin, Andrea Carmine
    Karolinska Inst, Sweden.
    Ekman, Agneta
    Univ Gothenburg, Sweden.
    Sydow, Olof
    Karolinska Univ Hosp, Sweden.
    Backman, Lars
    Karolinska Inst, Sweden.
    Holmberg, Bjorn
    Univ Gothenburg, Sweden.
    Dizdar Segrell, Nil
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Neurology.
    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, Clinical genetics.
    Nissbrandt, Hans
    Univ Gothenburg, Sweden.
    S100B polymorphisms are associated with age of onset of Parkinsons disease2018In: BMC Medical Genetics, ISSN 1471-2350, E-ISSN 1471-2350, Vol. 19, article id 42Article in journal (Refereed)
    Abstract [en]

    Background: In this study we investigated the association between SNPs in the S100B gene and Parkinsons disease (PD) in two independent Swedish cohorts. The SNP rs9722 has previously been shown to be associated with higher S100B concentrations in serum and frontal cortex in humans. S100B is widely expressed in the central nervous system and has many functions such as regulating calcium homeostasis, inflammatory processes, cytoskeleton assembly/disassembly, protein phosphorylation and degradation, and cell proliferation and differentiation. Several of these functions have been suggested to be of importance for the pathophysiology of PD. Methods: The SNPs rs9722, rs2239574, rs881827, rs9984765, and rs1051169 of the S100B gene were genotyped using the KASPar (R) PCR SNP genotyping system in a case-control study of two populations (431 PD patients and 465 controls, 195 PD patients and 378 controls, respectively). The association between the genotype and allelic distributions and PD risk was evaluated using Chi-Square and Cox proportional hazards test, as well as logistic regression. Linear regression and Cox proportional hazards tests were applied to assess the effect of the rs9722 genotypes on age of disease onset. Results: The S100B SNPs tested were not associated with the risk of PD. However, in both cohorts, the T allele of rs9722 was significantly more common in early onset PD patients compared to late onset PD patients. The SNP rs9722 was significantly related to age of onset, and each T allele lowered disease onset with 4.9 years. In addition, allelic variants of rs881827, rs9984765, and rs1051169, were significantly more common in early-onset PD compared to late-onset PD in the pooled population. Conclusions: rs9722, a functional SNP in the 3-UTR of the S100B gene, was strongly associated with age of onset of PD.

  • 31.
    Franco, Irene
    et al.
    Karolinska Inst, Sweden.
    Johansson, Anna
    Uppsala Univ, Sweden.
    Olsson, Karl
    Karolinska Inst, Sweden.
    Vrtacnik, Peter
    Karolinska Inst, Sweden.
    Lundin, Par
    Karolinska Inst, Sweden; Stockholm Univ, Sweden.
    Helgadottir, Hafdis T.
    Karolinska Inst, Sweden.
    Larsson, Malin
    Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics. Linköping University, Faculty of Science & Engineering.
    Revechon, Gwladys
    Karolinska Inst, Sweden.
    Bosia, Carla
    IIGM, Italy; Politecn Torino, Italy.
    Pagnani, Andrea
    IIGM, Italy; Politecn Torino, Italy.
    Provero, Paolo
    Mol Biotechnol Ctr, Italy; Ist Sci San Raffaele, Italy.
    Gustafsson, Thomas
    Karolinska Inst, Sweden.
    Fischer, Helene
    Karolinska Inst, Sweden.
    Eriksson, Maria
    Karolinska Inst, Sweden.
    Somatic mutagenesis in satellite cells associates with human skeletal muscle aging2018In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 9, article id 800Article in journal (Refereed)
    Abstract [en]

    Human aging is associated with a decline in skeletal muscle (SkM) function and a reduction in the number and activity of satellite cells (SCs), the resident stem cells. To study the connection between SC aging and muscle impairment, we analyze the whole genome of single SC clones of the leg muscle vastus lateralis from healthy individuals of different ages (21-78 years). We find an accumulation rate of 13 somatic mutations per genome per year, consistent with proliferation of SCs in the healthy adult muscle. SkM-expressed genes are protected from mutations, but aging results in an increase in mutations in exons and promoters, targeting genes involved in SC activity and muscle function. In agreement with SC mutations affecting the whole tissue, we detect a missense mutation in a SC propagating to the muscle. Our results suggest somatic mutagenesis in SCs as a driving force in the age-related decline of SkM function.

  • 32.
    Gawel, Danuta R.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences.
    Identification of genes and regulators that are shared across T cell associated diseases2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Genome-wide association studies (GWASs) of hundreds of diseases and millions of patients have led to the identification of genes that are associated with more than one disease. The aims of this PhD thesis were to a) identify a group of genes important in multiple diseases (shared disease genes), b) identify shared up-stream disease regulators, and c) determine how the same genes can be involved in the pathogenesis of different diseases. These aims have been tested on CD4+ T cells because they express the T helper cell differentiation pathway, which was the most enriched pathway in analyses of all disease associated genes identified with GWASs.

    Combining information about known gene-gene interactions from the protein-protein interaction (PPI) network with gene expression changes in multiple T cell associated diseases led to the identification of a group of highly interconnected genes that were miss-expressed in many of those diseases – hereafter called ‘shared disease genes’. Those genes were further enriched for inflammatory, metabolic and proliferative pathways, genetic variants identified by all GWASs, as well as mutations in cancer studies and known diagnostic and therapeutic targets. Taken together, these findings supported the relevance of the shared disease genes.

    Identification of the shared upstream disease regulators was addressed in the second project of this PhD thesis. The underlying hypothesis assumed that the determination of the shared upstream disease regulators is possible through a network model showing in which order genes activate each other. For that reason a transcription factor–gene regulatory network (TF-GRN) was created. The TF-GRN was based on the time-series gene expression profiling of the T helper cell type 1 (Th1), and T helper cell type 2 (Th2) differentiation from Native T-cells. Transcription factors (TFs) whose expression changed early during polarization and had many downstream predicted targets (hubs) that were enriched for disease associated single nucleotide polymorphisms (SNPs) were prioritised as the putative early disease regulators. These analyses identified three transcription factors: GATA3, MAF and MYB. Their predicted targets were validated by ChIP-Seq and siRNA mediated knockdown in primary human T-cells. CD4+ T cells isolated from seasonal allergic rhinitis (SAR) and multiple sclerosis (MS) patients in their non-symptomatic stages were analysed in order to demonstrate predictive potential of those three TFs. We found that those three TFs were differentially expressed in symptom-free stages of the two diseases, while their TF-GRN{predicted targets were differentially expressed during symptomatic disease stages. Moreover, using RNA-Seq data we identified a disease associated SNP that correlated with differential splicing of GATA3.

    A limitation of the above study is that it concentrated on TFs as main regulators in cells, excluding other potential regulators such as microRNAs. To this end, a microRNA{gene regulatory network (mGRN) of human CD4+ T cell differentiation was constructed. Within this network, we defined regulatory clusters (groups of microRNAs that are regulating groups of mRNAs). One regulatory cluster was differentially expressed in all of the tested diseases, and was highly enriched for GWAS SNPs. Although the microRNA processing machinery was dynamically upregulated during early T-cell activation, the majority of microRNA modules showed specialisation in later time-points.

    In summary this PhD thesis shows the relevance of shared genes and up-stream disease regulators. Putative mechanisms of why shared genes can be involved in pathogenesis of different diseases have also been demonstrated: a) differential gene expression in different diseases; b) alternative transcription factor splicing variants may affect different downstream gene target group; and c) SNPs might cause alternative splicing.

    List of papers
    1. Integrated genomic and prospective clinical studies show the importance of modular pleiotropy for disease susceptibility, diagnosis and treatment
    Open this publication in new window or tab >>Integrated genomic and prospective clinical studies show the importance of modular pleiotropy for disease susceptibility, diagnosis and treatment
    Show others...
    2014 (English)In: Genome Medicine, ISSN 1756-994X, E-ISSN 1756-994X, Vol. 6, no 17Article in journal (Refereed) Published
    Abstract [en]

    Background: Translational research typically aims to identify and functionally validate individual, disease-specific genes. However, reaching this aim is complicated by the involvement of thousands of genes in common diseases, and that many of those genes are pleiotropic, that is, shared by several diseases. Methods: We integrated genomic meta-analyses with prospective clinical studies to systematically investigate the pathogenic, diagnostic and therapeutic roles of pleiotropic genes. In a novel approach, we first used pathway analysis of all published genome-wide association studies (GWAS) to find a cell type common to many diseases. Results: The analysis showed over-representation of the T helper cell differentiation pathway, which is expressed in T cells. This led us to focus on expression profiling of CD4(+) T cells from highly diverse inflammatory and malignant diseases. We found that pleiotropic genes were highly interconnected and formed a pleiotropic module, which was enriched for inflammatory, metabolic and proliferative pathways. The general relevance of this module was supported by highly significant enrichment of genetic variants identified by all GWAS and cancer studies, as well as known diagnostic and therapeutic targets. Prospective clinical studies of multiple sclerosis and allergy showed the importance of both pleiotropic and disease specific modules for clinical stratification. Conclusions: In summary, this translational genomics study identified a pleiotropic module, which has key pathogenic, diagnostic and therapeutic roles.

    Place, publisher, year, edition, pages
    BioMed Central, 2014
    National Category
    Clinical Medicine Basic Medicine
    Identifiers
    urn:nbn:se:liu:diva-106873 (URN)10.1186/gm534 (DOI)000334631300002 ()
    Available from: 2014-05-28 Created: 2014-05-23 Last updated: 2018-04-10
    2. A validated gene regulatory network and GWAS identifies early regulators of T cell-associated diseases
    Open this publication in new window or tab >>A validated gene regulatory network and GWAS identifies early regulators of T cell-associated diseases
    Show others...
    2015 (English)In: Science Translational Medicine, ISSN 1946-6234, E-ISSN 1946-6242, Vol. 7, no 313, article id 313ra178Article in journal (Refereed) Published
    Abstract [en]

    Early regulators of disease may increase understanding of disease mechanisms and serve as markers for presymptomatic diagnosis and treatment. However, early regulators are difficult to identify because patients generally present after they are symptomatic. We hypothesized that early regulators of T cell-associated diseases could be found by identifying upstream transcription factors (TFs) in T cell differentiation and by prioritizing hub TFs that were enriched for disease-associated polymorphisms. A gene regulatory network (GRN) was constructed by time series profiling of the transcriptomes and methylomes of human CD4(+) T cells during in vitro differentiation into four helper T cell lineages, in combination with sequence-based TF binding predictions. The TFs GATA3, MAF, and MYB were identified as early regulators and validated by ChIP-seq (chromatin immunoprecipitation sequencing) and small interfering RNA knockdowns. Differential mRNA expression of the TFs and their targets in T cell-associated diseases supports their clinical relevance. To directly test if the TFs were altered early in disease, T cells from patients with two T cell-mediated diseases, multiple sclerosis and seasonal allergic rhinitis, were analyzed. Strikingly, the TFs were differentially expressed during asymptomatic stages of both diseases, whereas their targets showed altered expression during symptomatic stages. This analytical strategy to identify early regulators of disease by combining GRNs with genome-wide association studies may be generally applicable for functional and clinical studies of early disease development.

    Place, publisher, year, edition, pages
    AMER ASSOC ADVANCEMENT SCIENCE, 2015
    National Category
    Biological Sciences Clinical Medicine
    Identifiers
    urn:nbn:se:liu:diva-123522 (URN)10.1126/scitranslmed.aad2722 (DOI)000365237400003 ()26560356 (PubMedID)
    Note

    Funding Agencies|Cancer fund, Swedish Medical Research Council [K2013-61X-22310-01-04, 2012-3168]; Academy of Finland Centre of Excellence in Molecular Systems Immunology and Physiology Research [250114]; Sigrid Juselius Foundation; Generalitat de Catalunya AGAUR [2014-SGR364]; Spanish Association Against Cancer; Spanish Ministry of Health ISCIII FIS [PI12/01528]; RTICC [RD12/0036/0008]

    Available from: 2015-12-22 Created: 2015-12-21 Last updated: 2018-04-10Bibliographically approved
  • 33.
    Gawel, Danuta
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences.
    Serra-Musach, Jordi
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences.
    Lilja, Sandra
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences.
    Aagesen, Jesper
    Reg Jonkoping Cty, Sweden.
    Arenas, Alex
    Univ Rovira and Virgili, Spain.
    Asking, Bengt
    Reg Jonkoping Cty, Sweden.
    Bengner, Malin
    Reg Jonkoping Cty, Sweden.
    Bjorkander, Janne
    Reg Jonkoping Cty, Sweden.
    Biggs, Sophie
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Ernerudh, Jan
    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 Immunology and Transfusion Medicine.
    Hjortswang, Henrik
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Gastroentorology.
    Karlsson, Jan-Erik
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Reg Jonkoping Cty, Sweden.
    Köpsén, Mattias
    Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics. Linköping University, Faculty of Science & Engineering.
    Jung Lee, Eun Jung
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences. Yonsei Univ, South Korea.
    Lentini, Antonio
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences.
    Li, Xinxiu
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences.
    Magnusson, Mattias
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Martinez, David
    Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics. Linköping University, Faculty of Science & Engineering.
    Matussek, Andreas
    Reg Jonkoping Cty, Sweden; Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Nestor, Colm
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences.
    Schafer, Samuel
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Seifert, Oliver
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Reg Jonkoping Cty, Sweden.
    Sonmez, Ceylan
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    Stjernman, Henrik
    Reg Jonkoping Cty, Sweden.
    Tjärnberg, Andreas
    Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics. Linköping University, Faculty of Science & Engineering.
    Wu, Simon
    Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics. Linköping University, Faculty of Science & Engineering.
    Åkesson, Karin
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences. Reg Jonkoping Cty, Sweden.
    Shalek, Alex K.
    MIT, MA 02139 USA; Broad Inst MIT and Harvard, MA 02142 USA; Ragon Inst MGH MIT and Harvard, MA USA.
    Stenmarker, Margaretha
    Reg Jonkoping Cty, Sweden; Inst Clin Sci, Sweden.
    Zhang, Huan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences.
    Gustafsson, Mika
    Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics. Linköping University, Faculty of Science & Engineering.
    Benson, Mikael
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, H.K.H. Kronprinsessan Victorias barn- och ungdomssjukhus.
    A validated single-cell-based strategy to identify diagnostic and therapeutic targets in complex diseases2019In: Genome Medicine, ISSN 1756-994X, E-ISSN 1756-994X, Vol. 11, article id 47Article in journal (Refereed)
    Abstract [en]

    Background

    Genomic medicine has paved the way for identifying biomarkers and therapeutically actionable targets for complex diseases, but is complicated by the involvement of thousands of variably expressed genes across multiple cell types. Single-cell RNA-sequencing study (scRNA-seq) allows the characterization of such complex changes in whole organs.

    Methods

    The study is based on applying network tools to organize and analyze scRNA-seq data from a mouse model of arthritis and human rheumatoid arthritis, in order to find diagnostic biomarkers and therapeutic targets. Diagnostic validation studies were performed using expression profiling data and potential protein biomarkers from prospective clinical studies of 13 diseases. A candidate drug was examined by a treatment study of a mouse model of arthritis, using phenotypic, immunohistochemical, and cellular analyses as read-outs.

    Results

    We performed the first systematic analysis of pathways, potential biomarkers, and drug targets in scRNA-seq data from a complex disease, starting with inflamed joints and lymph nodes from a mouse model of arthritis. We found the involvement of hundreds of pathways, biomarkers, and drug targets that differed greatly between cell types. Analyses of scRNA-seq and GWAS data from human rheumatoid arthritis (RA) supported a similar dispersion of pathogenic mechanisms in different cell types. Thus, systems-level approaches to prioritize biomarkers and drugs are needed. Here, we present a prioritization strategy that is based on constructing network models of disease-associated cell types and interactions using scRNA-seq data from our mouse model of arthritis, as well as human RA, which we term multicellular disease models (MCDMs). We find that the network centrality of MCDM cell types correlates with the enrichment of genes harboring genetic variants associated with RA and thus could potentially be used to prioritize cell types and genes for diagnostics and therapeutics. We validated this hypothesis in a large-scale study of patients with 13 different autoimmune, allergic, infectious, malignant, endocrine, metabolic, and cardiovascular diseases, as well as a therapeutic study of the mouse arthritis model.

    Conclusions

    Overall, our results support that our strategy has the potential to help prioritize diagnostic and therapeutic targets in human disease.

  • 34.
    Gray, J. D.
    et al.
    Rockefeller Univ, NY 10021 USA.
    Rubin, T. G.
    Albert Einstein Coll Med, NY 10467 USA.
    Kogan, J. F.
    Rockefeller Univ, NY 10021 USA.
    Marrocco, J.
    Rockefeller Univ, NY 10021 USA.
    Weidmann, J.
    Linköping University.
    Lindkvist, S.
    Linköping University.
    Lee, F. S.
    Weill Cornell Med Coll, NY USA.
    Schmidt, E. F.
    Rockefeller Univ, NY 10021 USA.
    McEwen, B. S.
    Rockefeller Univ, NY 10021 USA.
    Translational profiling of stress-induced neuroplasticity in the CA3 pyramidal neurons of BDNF Val66Met mice2018In: Molecular Psychiatry, ISSN 1359-4184, E-ISSN 1476-5578, Vol. 23, no 4, p. 904-913Article in journal (Refereed)
    Abstract [en]

    Genetic susceptibility and environmental factors (such as stress) can interact to affect the likelihood of developing a mood disorder. Stress-induced changes in the hippocampus have been implicated in mood disorders, and mutations in several genes have now been associated with increased risk, such as brain-derived neurotrophic factor (BDNF). The hippocampus has important anatomical subdivisions, and pyramidal neurons of the vulnerable CA3 region show significant remodeling after chronic stress, but the mechanisms underlying their unique plasticity remain unknown. This study characterizes stress-induced changes in the in vivo translating mRNA of this cell population using a CA3-specific enhanced green fluorescent protein (EGFP) reporter fused to the L10a large ribosomal subunit (EGFPL10a). RNA-sequencing after isolation of polysome-bound mRNAs allows for cell-type-specific, genome-wide characterization of translational changes after stress. The data demonstrate that acute and chronic stress produce unique translational profiles and that the stress history of the animal can alter future reactivity of CA3 neurons. CA3-specific EGFPL10a mice were then crossed to the stress-susceptible BDNF Val66Met mouse line to characterize how a known genetic susceptibility alters both baseline translational profiles and the reactivity of CA3 neurons to stress. Not only do Met allele carriers exhibit distinct levels of baseline translation in genes implicated in ion channel function and cytoskeletal regulation, but they also activate a stress response profile that is highly dissimilar from wild-type mice. Closer examination of genes implicated in the mechanisms of neuroplasticity, such as the NMDA and AMPA subunits and the BDNF pathway, reveal how wild-type mice upregulate many of these genes in response to stress, but Met allele carriers fail to do so. These profiles provide a roadmap of stress-induced changes in a genetically homogenous population of hippocampal neurons and illustrate the profound effects of gene-environment interactions on the translational profile of these cells.

  • 35.
    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, p. 366-373Article 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.

  • 36.
    Gunnarsson, Rebeqa
    et al.
    Lund Univ, Sweden.
    Dilorenzo, Sebastian
    Uppsala Univ, Sweden; Uppsala Univ, Sweden.
    Lundin-Strom, Kristina B.
    Lund Univ, Sweden.
    Olsson, Linda
    Lund Univ, Sweden; Dept Clin Genet and Pathol, Sweden.
    Biloglav, Andrea
    Lund Univ, Sweden.
    Lilljebjorn, Henrik
    Lund Univ, Sweden.
    Rissler, Marianne
    Lund Univ, Sweden.
    Wahlberg, Per
    Uppsala Univ, Sweden.
    Lundmark, Anders
    Uppsala Univ, Sweden.
    Castor, Anders
    Skane Univ Hosp, Sweden.
    Behrendtz, Mikael
    Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, H.K.H. Kronprinsessan Victorias barn- och ungdomssjukhus. Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences.
    Fioretos, Thoas
    Lund Univ, Sweden; Dept Clin Genet and Pathol, Sweden.
    Paulsson, Kajsa
    Lund Univ, Sweden.
    Isaksson, Anders
    Uppsala Univ, Sweden.
    Johansson, Bertil
    Lund Univ, Sweden; Dept Clin Genet and Pathol, Sweden.
    Mutation, methylation, and gene expression profiles in dup(1q)-positive pediatric B-cell precursor acute lymphoblastic leukemia2018In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 32, no 10, p. 2117-2125Article in journal (Refereed)
    Abstract [en]

    High-throughput sequencing was applied to investigate the mutation/methylation patterns on 1q and gene expression profiles in pediatric B-cell precursor acute lymphoblastic leukemia (BCP ALL) with/without (w/wo) dup(1q). Sequencing of the breakpoint regions and all exons on 1q in seven dup(1q)-positive cases revealed non-synonymous somatic single nucleotide variants (SNVs) in BLZF1, FMN2, KCNT2, LCE1C, NES, and PARP1. Deep sequencing of these in a validation cohort w (n = 17)/wo (n = 94) dup(1q) revealed similar SNV frequencies in the two groups (47% vs. 35%; P = 0.42). Only 0.6% of the 36,259 CpGs on 1q were differentially methylated between cases w (n = 14)/wo (n = 13) dup(1q). RNA sequencing of high hyperdiploid (HeH) and t(1;19)(q23;p13)-positive cases w (n = 14)/wo (n = 52) dup(1q) identified 252 and 424 differentially expressed genes, respectively; only seven overlapped. Of the overexpressed genes in the HeH and t(1;19) groups, 23 and 31%, respectively, mapped to 1q; 60-80% of these encode nucleic acid/protein binding factors or proteins with catalytic activity. We conclude that the pathogenetically important consequence of dup(1q) in BCP ALL is a gene-dosage effect, with the deregulated genes differing between genetic subtypes, but involving similar molecular functions, biological processes, and protein classes.

  • 37.
    Gustafsson Bragde, Hanna
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences. Laboratory Medicine, Region Jönköping County.
    Biomarkers of Inflammation and Intestinal Mucosa Pathology in Celiac Disease2019Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Celiac disease (CD) is a chronic small intestinal immune-mediated enteropathy triggered by gluten. The only currently available treatment is complying with a lifelong gluten-free diet, which should not be commenced before a CD diagnosis has been established by diagnostic test results (including histopathologic assessment of small intestinal biopsies and CD-specific antibody levels). This makes diagnostic swiftness and accuracy important. In cases with low CD-specific antibody levels and/or low-grade intestinal injuries the diagnosis can be difficult to establish. The main objective of this thesis was to complement and improve CD diagnostics by identifying and implementing new biomarkers, mainly based on gene expression, in small intestinal biopsies and blood. In paper I, genes were selected to reflect villous height, crypt elongation, immune response, and epithelial integrity. The results showed that a subset of those genes could discriminate active CD mucosa from mucosa without CD-related changes and grade the intestinal injury. In paper III, an unbiased investigation of gene expression in CD mucosa was performed using transcriptome analysis. Active CD and non-CD mucosa showed differential expression in a subset of genes, and some were differentially expressed in CD mucosa before histopathologic assessment could confirm intestinal alterations compatible with a CD diagnosis. Gene set analysis revealed that there are many biological processes affected in CD mucosa, including those associated with immune response, microbial infection, phagocytosis, intestinal barrier function, metabolism, and transportation.

    In parallel, gene expression was investigated in stabilised whole blood. Blood is a more accessible sampling material than intestinal biopsies, and stabilised blood is suitable for routine diagnostics since transcript levels are preserved at sampling. In paper II, expressions from a selection of genes were quantified in stabilised whole blood (RNA) and/or plasma (protein). Three genes with differential expression in CD were identified. Compared to the CD-specific autoantibodies against tissue transglutaminase (anti-TG2) alone, the addition of the information from the new potential markers resulted in a nonsignificant contribution to the diagnostic capacity of anti-TG2. An unbiased investigation using transcriptome analysis (paper IV) showed that gene level expression differences in stabilised whole blood were small between CD and non-CD. However, expression differences on a gene set level could potentially be used in CD diagnostics. CD-associated biological processes suggested by the results included a pro-inflammatory response, negative regulation of viral replication, proliferation, differentiation, cell migration, cell survival, translation, and haemostasis.

    Expression analysis using real-time polymerase chain reaction (PCR) is easy to perform, with instrumentation available at most clinical laboratories. Although select solitary biomarkers could be very useful in the diagnosis of CD, basing gene expression profiles on pathway information instead of single genes might also disclose disease heterogeneity between patients and add stability to a diagnostic method based on gene expressions. In conclusion, the results of this work demonstrate that analysing the expression of a few small intestinal genes can complement CD diagnostics. The application of gene expression analysis in cases with minor small intestine histopathological changes shows promising results, but needs further investigations. Additionally, gene expressions in other inflammatory diseases of the small intestine need to be investigated and compared with CD to complete the picture. Moreover, the findings from this work give clues about the biological contexts in which CD resides, and the potential of gene expression in blood at a gene set level is of interest for further investigations.

    List of papers
    1. Gene Expression Profiling of Duodenal Biopsies Discriminates Celiac Disease Mucosa From Normal Mucosa
    Open this publication in new window or tab >>Gene Expression Profiling of Duodenal Biopsies Discriminates Celiac Disease Mucosa From Normal Mucosa
    2011 (English)In: Pediatric Research, ISSN 0031-3998, E-ISSN 1530-0447, Vol. 69, no 6, p. 530-537Article in journal (Refereed) Published
    Abstract [en]

    Celiac disease (CD) is identified by histopathologic changes in the small intestine which normalize during a gluten-free diet. The histopathologic assessment of duodenal biopsies is usually routine but can be difficult. This study investigated gene expression profiling as a diagnostic tool. A total of 109 genes were selected to reflect alterations in crypt-villi architecture, inflammatory response, and intestinal permeability and were examined for differential expression in normal mucosa compared with CD mucosa in pediatric patients. Biopsies were classified using discriminant analysis of gene expression. Fifty genes were differentially expressed, of which eight (APOC3, CYP3A4, OCLN, MAD2L1, MKI67, CXCL11, IL17A, and CTLA4) discriminated normal mucosa from CD mucosa without classification errors using leave-one-out cross-validation (n = 39) and identified the degree of mucosal damage. Validation using an independent set of biopsies (n = 27) resulted in four discrepant cases. Biopsies from two of these cases showed a patchy distribution of lesions, indicating that discriminant analysis based on single biopsies failed to identify CD mucosa. In the other two cases, serology support class according to discriminant analysis and histologic specimens were judged suboptimal but assessable. Gene expression profiling shows promise as a diagnostic tool and for follow-up of CD, but further evaluation is needed.

    Place, publisher, year, edition, pages
    Nature Publishing Group, 2011
    National Category
    Medical Genetics
    Identifiers
    urn:nbn:se:liu:diva-156089 (URN)10.1203/PDR.0b013e318217ecec (DOI)000290831700011 ()21378598 (PubMedID)2-s2.0-79955855027 (Scopus ID)
    Available from: 2019-04-03 Created: 2019-04-03 Last updated: 2019-07-01Bibliographically approved
    2. Potential blood-based markers of celiac disease
    Open this publication in new window or tab >>Potential blood-based markers of celiac disease
    Show others...
    2014 (English)In: BMC Gastroenterology, ISSN 1471-230X, E-ISSN 1471-230X, Vol. 14, no 176Article in journal (Refereed) Published
    Abstract [en]

    Background: Blood-based diagnostics has the potential to simplify the process of diagnosing celiac disease (CD). Although high levels of autoantibodies against tissue transglutaminase (anti-TG2) are strongly indicative of active CD, several other scenarios involve a need for additional blood-based CD markers. Methods: We investigated the levels of messenger RNA (mRNA) in whole blood (n = 49) and protein in plasma (n = 22) from cases with active CD (n = 20), with confirmed CD and normalized histology (n = 15), and without a CD diagnosis (n = 14). Group differences were analyzed using Kruskal-Wallis one-way analysis of variance by ranks. We also investigated correlations between levels of potential markers, histopathology according to the modified Marsh scale, and CD risk gradient based on HLA type, using Spearman rank correlation. The relation between HLA-DQ2 gene dose effect and the expression levels of selected blood-based markers was investigated using the Mann-Whitney U test. Finally, the diagnostic performance of anti-TG2, potential blood-based CD markers, and logistic regression models of combined markers was evaluated using receiver operating characteristic (ROC) curve analysis. Results: CXCL11 protein levels and TNFRSF9 and TNFSF13B mRNA levels were identified as potential CD markers. These are all affected by or involved in the regulation of the NF-kappa B complex. CXCL11 protein levels and IL21 and IL15 mRNA levels were correlated with histopathology according to the modified Marsh scale, as were the established CD markers. HLA genotype risk and HLA-DQ2 gene dose effect did not show any significant relations with either the potential CD markers or the established CD markers. ROC curve analysis revealed a slight, non-significant increase in the area under the curve for the combined use of anti-TG2 and different constellations of potential blood-based CD markers compared to anti-TG2 alone. Conclusions: The CD markers identified in this study further emphasize the significance of components related to NF-kappa B regulation in relation to CD. However, the relevance of CXCL11, TNFSF13B, TNFRSF9, and other NF-kappa B interacting proteins recognized by pathway analysis, needs to be further investigated in relation to diagnosis and monitoring of CD.

    Place, publisher, year, edition, pages
    BioMed Central, 2014
    Keywords
    Celiac disease; Molecular diagnostics; Blood-based biological markers
    National Category
    Clinical Medicine
    Identifiers
    urn:nbn:se:liu:diva-112037 (URN)10.1186/1471-230X-14-176 (DOI)000342782900001 ()25298177 (PubMedID)
    Note

    Funding Agencies|Futurum - the Academy for Healthcare; Jonkoping County Council; Medical Research Council of Southeast Sweden

    Available from: 2014-11-17 Created: 2014-11-13 Last updated: 2019-04-03
    3. Celiac disease biomarkers identified by transcriptome analysis of small intestinal biopsies
    Open this publication in new window or tab >>Celiac disease biomarkers identified by transcriptome analysis of small intestinal biopsies
    Show others...
    2018 (English)In: Cellular and Molecular Life Sciences (CMLS), ISSN 1420-682X, E-ISSN 1420-9071, Vol. 75, no 23, p. 4385-4401Article in journal (Refereed) Published
    Abstract [en]

    Establishing a celiac disease (CD) diagnosis can be difficult, such as when CD-specific antibody levels are just above cutoff or when small intestinal biopsies show low-grade injuries. To investigate the biological pathways involved in CD and select potential biomarkers to aid in CD diagnosis, RNA sequencing of duodenal biopsies from subjects with either confirmed Active CD (n=20) or without any signs of CD (n=20) was performed. Gene enrichment and pathway analysis highlighted contexts, such as immune response, microbial infection, phagocytosis, intestinal barrier function, metabolism, and transportation. Twenty-nine potential CD biomarkers were selected based on differential expression and biological context. The biomarkers were validated by real-time polymerase chain reaction of eight RNA sequencing study subjects, and further investigated using an independent study group (n=43) consisting of subjects not affected by CD, with a clear diagnosis of CD on either a gluten-containing or a gluten-free diet, or with low-grade intestinal injury. Selected biomarkers were able to classify subjects with clear CD/non-CD status, and a subset of the biomarkers (CXCL10, GBP5, IFI27, IFNG, and UBD) showed differential expression in biopsies from subjects with no or low-grade intestinal injury that received a CD diagnosis based on biopsies taken at a later time point. A large number of pathways are involved in CD pathogenesis, and gene expression is affected in CD mucosa already in low-grade intestinal injuries. RNA sequencing of low-grade intestinal injuries might discover pathways and biomarkers involved in early stages of CD pathogenesis.

    Place, publisher, year, edition, pages
    SPRINGER BASEL AG, 2018
    Keywords
    RNA-seq; RNA sequencing; Molecular biomarkers; Gene expression profiling; Gene ontology enrichment analysis
    National Category
    Biochemistry and Molecular Biology
    Identifiers
    urn:nbn:se:liu:diva-152799 (URN)10.1007/s00018-018-2898-5 (DOI)000449307300008 ()30097691 (PubMedID)
    Note

    Funding Agencies|Futurum-the Academy for Health and Care, Region Jonkoping County; Medical Research Council of Southeast Sweden; National Genomics Infrastructure - Swedish Research Council

    Available from: 2018-11-22 Created: 2018-11-22 Last updated: 2019-04-10
  • 38.
    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
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    2001 (English)In: Human Mutation, ISSN 1059-7794, E-ISSN 1098-1004, Vol. 18, no 6, p. 516-525Article 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.

    Keywords
    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: 2017-12-14Bibliographically 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
    Show others...
    2003 (English)In: Genetic Testing, ISSN 1090-6576, E-ISSN 1557-7473, Vol. 7, no 1, p. 13-20Article 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: 2017-12-14Bibliographically 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, p. 417-425Article 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.

    Keywords
    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: 2017-12-14Bibliographically 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, p. 769-776Article 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
  • 39.
    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, E-ISSN 1932-6203, Vol. 8, no 1, p. e53075-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.

  • 40.
    Hedberg-Oldfors, Carola
    et al.
    Univ Gothenburg, Sweden.
    Abramsson, Alexandra
    Univ Gothenburg, Sweden.
    Osborn, Daniel P. S.
    St Georges Univ London, England.
    Danielsson, Olof
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Neurology.
    Fazlinezhad, Afsoon
    Imam Reza Int Univ, Iran.
    Nilipour, Yalda
    Shahid Beheshti Univ Med Sci, Iran.
    Hübbert, Laila
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Cardiology in Norrköping.
    Nennesmo, Inger
    Karolinska Univ Hosp, Sweden.
    Visuttijai, Kittichate
    Univ Gothenburg, Sweden.
    Bharj, Jaipreet
    St Georges Univ London, England.
    Petropoulou, Evmorfia
    St Georges Univ London, England.
    Shoreim, Azza
    St Georges Univ London, England.
    Vona, Barbara
    Julius Maximilians Univ Wurzburg, Germany.
    Ahangari, Najmeh
    Mashhad Univ Med Sci, Iran.
    Lopez, Marcela Davila
    Univ Gothenburg, Sweden.
    Doosti, Mohammad
    Next Generat Genet Polyclin, Iran.
    Banote, Rakesh Kumar
    Univ Gothenburg, Sweden.
    Maroofian, Reza
    St Georges Univ London, England.
    Edling, Malin
    Univ Gothenburg, Sweden.
    Taherpour, Mehdi
    Imam Reza Int Univ, Iran.
    Zetterberg, Henrik
    Univ Gothenburg, Sweden; Sahlgrens Univ Hosp, Sweden; UCL Inst Neurol, England.
    Karimiani, Ehsan Ghayoor
    Imam Reza Int Univ, Iran; Islamic Azad Univ, Iran.
    Oldfors, Anders
    Univ Gothenburg, Sweden.
    Jamshidi, Yalda
    St Georges Univ London, England.
    Cardiomyopathy with lethal arrhythmias associated with inactivation of KLHL242019In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 28, no 11, p. 1919-1929Article in journal (Refereed)
    Abstract [en]

    Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiovascular disorder, yet the genetic cause of up to 50% of cases remains unknown. Here, we show that mutations in KLHL24 cause HCM in humans. Using genome-wide linkage analysis and exome sequencing, we identified homozygous mutations in KLHL24 in two consanguineous families with HCM. Of the 11 young affected adults identified, 3 died suddenly and 1 had a cardiac transplant due to heart failure. KLHL24 is a member of the Kelch-like protein family, which acts as substrate-specific adaptors to Cullin E3 ubiquitin ligases. Endomyocardial and skeletal muscle biopsies from affected individuals of both families demonstrated characteristic alterations, including accumulation of desmin intermediate filaments. Knock-down of the zebrafish homologue klhl24a results in heart defects similar to that described for other HCM-linked genes providing additional support for KLHL24 as a HCM-associated gene. Our findings reveal a crucial role for KLHL24 in cardiac development and function.

  • 41.
    Henström, Maria
    et al.
    Karolinska Institute, Sweden.
    Diekmann, Lena
    University of Vet Medical Hannover, Germany.
    Bonfiglio, Ferdinando
    Karolinska Institute, Sweden.
    Hadizadeh, Fatemeh
    Karolinska Institute, Sweden.
    Kuech, Eva-Maria
    University of Vet Medical Hannover, Germany.
    von Koeckritz-Blickwede, Maren
    University of Vet Medical Hannover, Germany.
    Thingholm, Louise B.
    Christian Albrechts University of Kiel, Germany.
    Zheng, Tenghao
    Karolinska Institute, Sweden.
    Assadi, Ghazaleh
    Karolinska Institute, Sweden.
    Dierks, Claudia
    University of Vet Medical Hannover, Germany.
    Heine, Martin
    University of Vet Medical Hannover, Germany.
    Philipp, Ute
    University of Vet Medical Hannover, Germany.
    Distl, Ottmar
    University of Vet Medical Hannover, Germany.
    Money, Mary E.
    University of Maryland, MD 21201 USA; Meritus Medical Centre, MD USA.
    Belheouane, Meriem
    Max Planck Institute Evolutionary Biol, Germany; Christian Albrechts University of Kiel, Germany.
    Heinsen, Femke-Anouska
    Christian Albrechts University of Kiel, Germany.
    Rafter, Joseph
    Karolinska Institute, Sweden.
    Nardone, Gerardo
    Federico II University Hospital, Italy.
    Cuomo, Rosario
    Federico II University Hospital, Italy.
    Usai-Satta, Paolo
    Azienda Osped G Brotzu, Italy.
    Galeazzi, Francesca
    Padova University Hospital, Italy.
    Neri, Matteo
    GDAnnunzio University, Italy; University of GDAnnunzio, Italy.
    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. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Simren, Magnus
    University of Gothenburg, Sweden; University of N Carolina, NC USA.
    Karling, Pontus
    Umeå University, Sweden.
    Ohlsson, Bodil
    Skåne University Hospital, Sweden; Lund University, Sweden.
    Schmidt, Peter T.
    Karolinska University Hospital, Sweden.
    Lindberg, Greger
    Karolinska University Hospital, Sweden.
    Dlugosz, Aldona
    Karolinska University Hospital, Sweden.
    Agreus, Lars
    Karolinska Institute, Sweden.
    Andreasson, Anna
    Karolinska Institute, Sweden; Stockholm University, Sweden.
    Mayer, Emeran
    University of Calif Los Angeles, CA USA.
    Baines, John F.
    Max Planck Institute Evolutionary Biol, Germany; Christian Albrechts University of Kiel, Germany.
    Engstrand, Lars
    Karolinska Institute, Sweden.
    Portincasa, Piero
    University of Bari Aldo Moro, Italy.
    Bellini, Massimo
    University of Pisa, Italy.
    Stanghellini, Vincenzo
    University of Bologna, Italy.
    Barbara, Giovanni
    University of Bologna, Italy.
    Chang, Lin
    University of Calif Los Angeles, CA USA.
    Camilleri, Michael
    Mayo Clin, MN USA.
    Franke, Andre
    Christian Albrechts University of Kiel, Germany.
    Naim, Hassan Y.
    University of Vet Medical Hannover, Germany.
    DAmato, Mauro
    Karolinska Institute, Sweden; BioDonostia Health Research Institute, Spain; Basque Science Fdn, Spain; Karolinska Institute, Sweden.
    Functional variants in the sucrase-isomaltase gene associate with increased risk of irritable bowel syndrome2018In: Gut, ISSN 0017-5749, E-ISSN 1468-3288, Vol. 67, no 2, p. 263-270Article in journal (Refereed)
    Abstract [en]

    Objective IBS is a common gut disorder of uncertain pathogenesis. Among other factors, genetics and certain foods are proposed to contribute. Congenital sucraseisomaltase deficiency (CSID) is a rare genetic form of disaccharide malabsorption characterised by diarrhoea, abdominal pain and bloating, which are features common to IBS. We tested sucrase-isomaltase (SI) gene variants for their potential relevance in IBS. Design We sequenced SI exons in seven familial cases, and screened four CSID mutations (p.Val557Gly, p. Gly1073Asp, p.Arg1124Ter and p.Phe1745Cys) and a common SI coding polymorphism (p.Val15Phe) in a multicentre cohort of 1887 cases and controls. We studied the effect of the 15Val to 15Phe substitution on SI function in vitro. We analysed p.Val15Phe genotype in relation to IBS status, stool frequency and faecal microbiota composition in 250 individuals from the general population. Results CSID mutations were more common in patients than asymptomatic controls (p=0.074; OR=1.84) and Exome Aggregation Consortium reference sequenced individuals (p=0.020; OR=1.57). 15Phe was detected in 6/7 sequenced familial cases, and increased IBS risk in case-control and population-based cohorts, with best evidence for diarrhoea phenotypes (combined p=0.00012; OR=1.36). In the population-based sample, 15Phe allele dosage correlated with stool frequency (p=0.026) and Parabacteroides faecal microbiota abundance (p=0.0024). The SI protein with 15Phe exhibited 35% reduced enzymatic activity in vitro compared with 15Val (pamp;lt;0.05). Conclusions SI gene variants coding for disaccharidases with defective or reduced enzymatic activity predispose to IBS. This may help the identification of individuals at risk, and contribute to personalising treatment options in a subset of patients.

  • 42.
    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, p. 578-582Article 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.

  • 43.
    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, article id 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: 2017-12-06Bibliographically approved
  • 44.
    Karlsson, Anna
    et al.
    Division of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, Medicon Village, Lund, Sweden.
    Cirenajwis, Helena
    Division of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, Medicon Village, Lund, Sweden.
    Ericson-Lindquist, Kajsa
    Division of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden; Department of Pathology, Regional Laboratories Region Skåne, Lund, Sweden.
    Brunnstrom, Hans
    Division of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden; Department of Pathology, Regional Laboratories Region Skåne, Lund, Sweden.
    Reutersward, Christel
    Division of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, Medicon Village, Lund, Sweden.
    Jönsson, Mats
    Division of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, Medicon Village, Lund, Sweden.
    Ortiz-Villalon, Cristian
    Department of Pathology, Karolinska University Hospital, Stockholm, Sweden.
    Hussein, Aziz
    Department of Pathology and cytology, Sahlgrenska university hospital, Gothenburg, Sweden.
    Bergman, Bengt
    Department of Respiratory Medicine, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Vikström, Anders
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Respiratory Medicine.
    Monsef, Nastaran
    Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical pathology.
    Branden, Eva
    Respiratory Medicine Unit, Department of Medicine Solna and CMM, Karolinska Institutet and Karolinska University Hospital Solna, Stockholm, Sweden; Centre for Research and Development, Uppsala University/Region Gävleborg, Gävle, Sweden.
    Koyi, Hirsh
    Respiratory Medicine Unit, Department of Medicine Solna and CMM, Karolinska Institutet and Karolinska University Hospital Solna, Stockholm, Sweden; Centre for Research and Development, Uppsala University/Region Gävleborg, Gävle, Sweden.
    de Petris, Luigi
    Thoracic Oncology Unit, Karolinska University Hospital and Department Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.
    Micke, Patrick
    Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
    Patthey, Annika
    Department of Pathology, Umeå University Hospital, Umeå, Sweden.
    Behndig, Annelie F.
    Department of Public Health and Clinical Medicine, Division of Medicine, Umeå University, Umeå, Sweden.
    Johansson, Mikael
    Department of Radiation Sciences, Oncology, Umeå University, Umeå, Sweden.
    Planck, Maria
    Division of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, Medicon Village, Lund, Sweden; Department of Respiratory Medicine and Allergology, Skåne University Hospital, Lund, Sweden.
    Staaf, Johan
    Division of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, Medicon Village, Lund, Sweden.
    A combined gene expression tool for parallel histological prediction and gene fusion detection in non-small cell lung cancer2019In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 9, article id 5207Article in journal (Refereed)
    Abstract [en]

    Accurate histological classification and identification of fusion genes represent two cornerstones of clinical diagnostics in non-small cell lung cancer (NSCLC). Here, we present a NanoString gene expression platform and a novel platform-independent, single sample predictor (SSP) of NSCLC histology for combined, simultaneous, histological classification and fusion gene detection in minimal formalin fixed paraffin embedded (FFPE) tissue. The SSP was developed in 68 NSCLC tumors of adenocarcinoma (AC), squamous cell carcinoma (SqCC) and large-cell neuroendocrine carcinoma (LCNEC) histology, based on NanoString expression of 11 (CHGA, SYP, CD56, SFTPG, NAPSA, TTF-1, TP73L, KRT6A, KRT5, KRT40, KRT16) relevant genes for IHC-based NSCLC histology classification. The SSP was combined with a gene fusion detection module (analyzing ALK, RET, ROS1, MET, NRG1, and NTRK1) into a multicomponent NanoString assay. The histological SSP was validated in six cohorts varying in size (n = 11-199), tissue origin (early or advanced disease), histological composition (including undifferentiated cancer), and gene expression platform. Fusion gene detection revealed five EML4-ALK fusions, four KIF5B-RET fusions, two CD74-NRG1 fusion and three MET exon 14 skipping events among 131 tested cases. The histological SSP was successfully trained and tested in the development cohort (mean AUC = 0.96 in iterated test sets). The SSP proved successful in predicting histology of NSCLC tumors of well-defined subgroups and difficult undifferentiated morphology irrespective of gene expression data platform. Discrepancies between gene expression prediction and histologic diagnosis included cases with mixed histologies, true large cell carcinomas, or poorly differentiated adenocarcinomas with mucin expression. In summary, we present a proof-of-concept multicomponent assay for parallel histological classification and multiplexed fusion gene detection in archival tissue, including a novel platform-independent histological SSP classifier. The assay and SSP could serve as a promising complement in the routine evaluation of diagnostic lung cancer biopsies.

  • 45.
    Khabou, Boudour
    et al.
    Univ Sfax, Tunisia.
    Tababi, Mouna
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Siala-Sahnoun, Olfa
    Univ Sfax, Tunisia.
    Mkaouar-Rebai, Emna
    Univ Sfax, Tunisia.
    Rebai, Ahmed
    Ctr Biotechnol Sfax, Tunisia.
    Fakhfakh, Faiza
    Univ Sfax, Tunisia.
    Potential dysfunctional effects of synonymous variants: Insights from an exhaustive in silico analysis of the ABCB4 gene2018In: Annals of Human Genetics, ISSN 0003-4800, E-ISSN 1469-1809, Vol. 82, no 6, p. 457-468Article in journal (Refereed)
    Abstract [en]

    The multiple drug resistance 3 (MDR3) protein is a canalicular phospholipid translocator involved in the bile secretion and encoded by the ABCB4 gene. Its deficiency is related to a large spectrum of liver diseases. Taking into account the increased evidence about the involvement of synonymous variants in inherited diseases, this study aims to explore the putative effects of silent genetic variants on the ABCB4 expression. We performed an exhaustive computational approach using ESE finder, RegRNA 2.0, MFOLD, SNPfold, and %MinMax software added to the measurement of the Relative Synonymous Codon Usage. This analysis included 216 synonymous variants distributed throughout the ABCB4 gene. Results have shown that 11 synonymous coding SNPs decrease the ESE activity, while 8 of them change the codon frequency. Besides, the c.24Camp;gt;T variation, located 21 nucleotides downstream the start A (Adenine) U (Uracil) G (Glutamine) AUG causes an increase in the local stability. Moreover, the computational analysis of the 3UTR region showed that six of the eight variants located in this region affected the Wild Type (WT) pattern of the miRNA targets sites and/or their proper display. The 26 sSNPs retained as putatively functional possessed a very low allele frequency, supporting their pathogenicity. In conclusion, the obtained results suggest that some synonymous SNPs in the ABCB4 gene, considered up to now as neutral, may be involved in the MDR3 deficiency.

  • 46.
    Kissopoulou, Antheia
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Cty Council Jonkoping, Sweden.
    Trinks, Cecilia
    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, Clinical genetics.
    Gréen, Anna
    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, Clinical genetics.
    Karlsson, Jan-Erik
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Cty Council Jonkoping, Sweden.
    Jonasson, Jon
    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, Clinical genetics.
    Gunnarsson, Cecilia
    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, Clinical genetics. Region Östergötland, Center for Business support and Development.
    Homozygous missense MYBPC3 Pro873His mutation associated with increased risk for heart failure development in hypertrophic cardiomyopathy2018In: ESC Heart Failure, E-ISSN 2055-5822, Vol. 5, no 4, p. 716-723Article in journal (Refereed)
    Abstract [en]

    Hypertrophic cardiomyopathy (HCM) is a primary autosomal-dominant disorder of the myocardium with variable expressivity and penetrance. Occasionally, homozygous sarcomere genetic variants emerge while genotyping HCM patients. In these cases, a more severe HCM phenotype is generally seen. Here, we report a case of HCM that was diagnosed clinically at 39years of age. Initial symptoms were shortness of breath during exertion. Successively, he developed a wide array of severe clinical manifestations, which progressed to an ominous end-stage heart failure that resulted in heart transplantation. Genotype analysis revealed a missense MYBPC3 variant NM_000256.3:c.2618Camp;gt;A,p.(Pro873His) that presented in the homozygous form. Conflicting interpretations of pathogenicity have been reported for the Pro873His MYBPC3 variant described here. Our patient, presenting with two copies of the variant and devoid of a normal allele, progressed to end-stage heart failure, which supports the notion of a deleterious effect of this variant in the homozygous form.

  • 47.
    Kjellmo, Christian Abendstein
    et al.
    Nordland Hosp, Norway; Univ Tromso, Norway.
    Karlsson, Helen
    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, Occupational and Environmental Medicine Center.
    Nestvold, Torunn K.
    Nordland Hosp, Norway.
    Ljunggren, Stefan
    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, Occupational and Environmental Medicine Center.
    Cederbrant, Karin
    Swedish Toxicol Sci Res Ctr, Sweden.
    Marcusson-Stahl, Maritha
    Swedish Toxicol Sci Res Ctr, Sweden.
    Mathisen, Monica
    Nordland Hosp, Norway.
    Lappegard, Knut Tore
    Nordland Hosp, Norway; Univ Tromso, Norway.
    Hovland, Anders
    Nordland Hosp, Norway; Univ Tromso, Norway.
    Bariatric surgery improves lipoprotein profile in morbidly obese patients by reducing LDL cholesterol, apoB, and SAA/PON1 ratio, increasing HDL cholesterol, but has no effect on cholesterol efflux capacity2018In: Journal of Clinical Lipidology, ISSN 1933-2874, E-ISSN 1876-4789, Vol. 12, no 1, p. 193-202Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Bariatric surgery has been shown to reduce cardiovascular events and cause specific mortality for coronary artery disease in obese patients. Lipoprotein biomarkers relating to low-density lipoprotein (LDL), high-density lipoprotein (HDL), their subfractions, and macrophage cholesterol efflux have all been hypothesized to be of value in cardiovascular risk assessment. OBJECTIVES: The objective of this study was to examine the effect of a lifestyle intervention followed by bariatric surgery on the lipid profile of morbidly obese patients. METHODS: Thirty-four morbidly obese patients were evaluated before and after lifestyle changes and then 1 year after bariatric surgery. They were compared with 17 lean subjects. Several lipoprotein metrics, serum amyloid A (SAA), serum paraoxonase-1 (PON1), and macrophage cholesterol efflux capacity (CEC) were assessed. RESULTS: Average weight loss after the lifestyle intervention was 10.5% and 1 year after bariatric surgery was 33.9%. The lifestyle intervention significantly decreased triglycerides (TGs; 28.7 mg/dL, P amp;lt; .05), LDL cholesterol (LDL-C; 32.3 mg/dL, P amp;lt; .0001), and apolipoprotein B (apoB; 62.9 mu g/mL, P amp;lt; .001). Bariatric surgery further reduced TGs (-36.7 mg/dL, P amp;lt; .05), increased HDL cholesterol (+12 mg/dL, P amp;lt; .0001), and reductions in LDL-C and apoB were sustained. Bariatric surgery reduced large, buoyant LDL (P amp;lt; .0001), but had no effect on the small, dense LDL.The large HDL subfractions increased (P amp;lt; .0001), but there was no effect on the smaller HDL sub fractions. The ratio for SAA/PON1 was reduced after the lifestyle intervention (P amp;lt; .01) and further reduced after bariatric surgery (P amp;lt; .0001). Neither the lifestyle intervention nor bariatric surgery had any effect on CEC. CONCLUSIONS: Lifestyle intervention followed by bariatric surgery in 34 morbidly obese patients showed favorable effects on TGs, LDL-C, and apoB. HDL cholesterol and apoA1 was increased, apoB/apoA1 ratio as well as SAA/PON1 ratio reduced, but bariatric surgery did not influence CEC. (C) 2017 National Lipid Association. All rights reserved.

  • 48.
    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, p. 2279-2287Article 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.

  • 49.
    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, p. 582-596Article 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.

  • 50.
    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, p. 289-302Article, 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.

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