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  • 51.
    Kissopoulou, Antheia
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Medicinska fakulteten. Cty Council Jonkoping, Sweden.
    Trinks, Cecilia
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk genetik.
    Gréen, Anna
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk genetik.
    Karlsson, Jan-Erik
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Medicinska fakulteten. Cty Council Jonkoping, Sweden.
    Jonasson, Jon
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk genetik.
    Gunnarsson, Cecilia
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk genetik. Region Östergötland, Centrum för verksamhetsstöd och utveckling.
    Homozygous missense MYBPC3 Pro873His mutation associated with increased risk for heart failure development in hypertrophic cardiomyopathy2018Ingår i: ESC Heart Failure, E-ISSN 2055-5822, Vol. 5, nr 4, s. 716-723Artikel i tidskrift (Refereegranskat)
    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.

  • 52.
    Kjellmo, Christian Abendstein
    et al.
    Nordland Hosp, Norway; Univ Tromso, Norway.
    Karlsson, Helen
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Hjärt- och Medicincentrum, Arbets- och miljömedicin.
    Nestvold, Torunn K.
    Nordland Hosp, Norway.
    Ljunggren, Stefan
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Hjärt- och Medicincentrum, Arbets- och miljömedicin.
    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 capacity2018Ingår i: Journal of Clinical Lipidology, ISSN 1933-2874, E-ISSN 1876-4789, Vol. 12, nr 1, s. 193-202Artikel i tidskrift (Refereegranskat)
    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.

  • 53.
    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.2014Ingår i: Journal of the American Medical Association (JAMA), ISSN 0098-7484, E-ISSN 1538-3598, Vol. 311, nr 22, s. 2279-2287Artikel i tidskrift (Refereegranskat)
    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.

  • 54.
    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
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Hjärt- och Medicincentrum, Reumatologiska kliniken i Östergötland.
    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.2015Ingår i: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 24, nr 2, s. 582-596Artikel i tidskrift (Refereegranskat)
    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.

  • 55.
    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 personalisation2006Ingår i: Expert opinion on therapeutic targets, ISSN 1472-8222, E-ISSN 1744-7631, ISSN 1472-8222, Vol. 10, nr 2, s. 289-302Artikel, forskningsöversikt (Refereegranskat)
    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.

  • 56.
    Langefeld, Carl D.
    et al.
    Wake Forest School Med, NC 27101 USA; Wake Forest School Med, NC 27101 USA.
    Ainsworth, Hannah C.
    Wake Forest School Med, NC 27101 USA; Wake Forest School Med, NC 27101 USA.
    Cunninghame Graham, Deborah S.
    Kings Coll London, England.
    Kelly, Jennifer A.
    Oklahoma Medical Research Fdn, OK 73104 USA.
    Comeau, Mary E.
    Wake Forest School Med, NC 27101 USA.
    Marion, Miranda C.
    Wake Forest School Med, NC 27101 USA.
    Howard, Timothy D.
    Wake Forest School Med, NC 27101 USA.
    Ramos, Paula S.
    Medical University of South Carolina, SC 29425 USA.
    Croker, Jennifer A.
    UAB School Med, AL 35294 USA.
    Morris, David L.
    Kings Coll London, England.
    Sandling, Johanna K.
    Uppsala University, Sweden; University of Nacl Mayor San Marcos, Peru.
    Carlsson Almlof, Jonas
    Uppsala University, Sweden; University of Nacl Mayor San Marcos, Peru.
    Acevedo-Vasquez, Eduardo M.
    University of Nacl Mayor San Marcos, Peru.
    Alarcon, Graciela S.
    UAB School of Medicine, Birmingham, Alabama, USA.
    Babini, Alejandra M.
    Hospital Italiano Cordoba, Argentina.
    Baca, Vicente
    Hospital Pediat Mexico City, Mexico.
    Bengtsson, Anders A.
    Lund University, Sweden.
    Berbotto, Guillermo A.
    Hospital Eva Peron, Argentina.
    Bijl, Marc
    Martini Hospital, Netherlands.
    Brown, Elizabeth E.
    UAB School of Medicine, Birmingham, Alabama, USA..
    Brunner, Hermine I.
    Cincinnati Childrens Hospital Medical Centre, OH 45229 USA; University of Cincinnati, OH 45229 USA.
    Cardiel, Mario H.
    Centre Invest Clin Morelia, Mexico.
    Catoggio, Luis
    Hospital Italiano Buenos Aires, Argentina.
    Cervera, Ricard
    University of Barcelona, Spain.
    Cucho-Venegas, Jorge M.
    University of Nacl Mayor San Marcos, Peru.
    Rantapaa Dahlqvist, Solbritt
    Umeå University, Sweden.
    DAlfonso, Sandra
    University of Piemonte Orientale, Italy.
    Martins Da Silva, Berta
    University of Porto, Portugal.
    de la Rua Figueroa, Inigo
    Hospital University of Gran Canaria Dr Negrin, Spain.
    Doria, Andrea
    University of Padua, Italy.
    Edberg, Jeffrey C.
    UAB School Med, AL 35294 USA.
    Endreffy, Emoke
    University of Szeged, Hungary; University of Szeged, Hungary.
    Esquivel-Valerio, Jorge A.
    Hospital University of Dr Jose Eleuterio Gonzalez University of Autonom, Mexico.
    Fortin, Paul R.
    University of Laval, Canada.
    Freedman, Barry I.
    Wake Forest School Med, NC 27101 USA; Wake Forest School Med, NC 27101 USA; Wake Forest School Med, NC 27101 USA.
    Frostegard, Johan
    Karolinska Institute, Sweden.
    Garcia, Mercedes A.
    Hospital Interzonal Gen Agudos Gen San Martin, Argentina.
    Garcia de la Torre, Ignacio
    University of Guadalajara, Mexico.
    Gilkeson, Gary S.
    Medical University of South Carolina, SC 29425 USA.
    Gladman, Dafna D.
    Toronto Western Hospital, Canada.
    Gunnarsson, Iva
    Karolinska University Hospital, Sweden.
    Guthridge, Joel M.
    Oklahoma Medical Research Fdn, OK 73104 USA.
    Huggins, Jennifer L.
    Cincinnati Childrens Hospital Medical Centre, OH 45229 USA; University of Cincinnati, OH 45229 USA.
    James, Judith A.
    Hospital Eva Peron, Argentina; University of Oklahoma, OK 73104 USA; University of Oklahoma, OK 73104 USA.
    Kallenberg, Cees G. M.
    University of Medical Centre Groningen, Netherlands.
    Kamen, Diane L.
    Medical University of South Carolina, Charleston, USA.
    Karp, David R.
    University of Texas Southwestern Medical Centre Dallas, TX 75235 USA.
    Kaufman, Kenneth M.
    Cincinnati Childrens Hospital Medical Centre, OH 45229 USA.
    Kottyan, Leah C.
    Cincinnati Childrens Hospital Medical Centre, OH 45229 USA.
    Kovacs, Laszlo
    University of Szeged, Hungary.
    Laustrup, Helle
    Odense University Hospital, Denmark.
    Lauwerys, Bernard R.
    Catholic University of Louvain, Belgium; Catholic University of Louvain, Belgium.
    Li, Quan-Zhen
    University of Texas Southwestern Medical Centre Dallas, TX 75235 USA.
    Maradiaga-Cecena, Marco A.
    Hospital Gen Culiacan, Mexico.
    Martin, Javier
    CSIC, Spain.
    McCune, Joseph M.
    University of Michigan, MI 48103 USA.
    McWilliams, David R.
    Wake Forest School Med, NC 27101 USA; Wake Forest School Med, NC 27101 USA.
    Merrill, Joan T.
    Oklahoma Medical Research Fdn, OK 73104 USA.
    Miranda, Pedro
    Centre Estudios Reumatol, Chile.
    Moctezuma, Jose F.
    Hospital Gen Mexico City, Mexico.
    Nath, Swapan K.
    Oklahoma Medical Research Fdn, OK 73104 USA.
    Niewold, Timothy B.
    Mayo Clin, MN 94158 USA.
    Orozco, Lorena
    Institute Nacl Medical Genom INMEGEN, Mexico.
    Ortego-Centeno, Norberto
    Hospital University of San Cecilio, Spain.
    Petri, Michelle
    Johns Hopkins University, MD 21218 USA.
    Pineau, Christian A.
    McGill University, Canada.
    Pons-Estel, Bernardo A.
    Sanatorio Parque, Argentina.
    Pope, Janet
    University of Western Ontario, Canada.
    Raj, Prithvi
    University of Texas Southwestern Medical Centre Dallas, TX 75235 USA.
    Ramsey-Goldman, Rosalind
    Northwestern University, IL 60611 USA.
    Reveille, John D.
    University of Texas Health Science Centre Houston UTHealth, TX 77030 USA.
    Russell, Laurie P.
    Wake Forest School Med, NC 27101 USA.
    Sabio, Jose M.
    Hospital University of Virgen de las Nieves, Spain.
    Aguilar-Salinas, Carlos A.
    Institute Nacl Ciencias Medical and Nutr Salvador Zubiran, Mexico.
    Scherbarth, Hugo R.
    Autoinmunes HIGA Dr Alende Mar Plata, Argentina.
    Scorza, Raffaella
    Fdn IRCCS CaGranda Osped Ma Repiore Policlin, Italy; University of Milan, Italy.
    Seldin, Michael F.
    UC Davis School Med, CA 95616 USA.
    Sjöwall, Christopher
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Hjärt- och Medicincentrum, Reumatologiska kliniken i Östergötland.
    Svenungsson, Elisabet
    Karolinska University Hospital, Sweden.
    Thompson, Susan D.
    Cincinnati Childrens Hospital Medical Centre, OH 45229 USA.
    Toloza, Sergio M. A.
    Minist Heatlh, Argentina.
    Truedsson, Lennart
    Lund University, Sweden.
    Tusie-Luna, Teresa
    UNAM Institute Nacl Ciencias Medical and Nutr Salvador Zubir, Mexico.
    Vasconcelos, Carlos
    University of Porto, Portugal.
    Vila, Luis M.
    University of Puerto Rico, PR 00936 USA.
    Wallace, Daniel J.
    Cedars Sinai Medical Centre, CA 90048 USA.
    Weisman, Michael H.
    Cedars Sinai Medical Centre, CA 90048 USA.
    Wither, Joan E.
    Toronto Western Hospital, Canada.
    Bhangale, Tushar
    Genentech Inc, CA 94080 USA.
    Oksenberg, Jorge R.
    University of Calif San Francisco, CA 94158 USA; University of Calif San Francisco, CA 94158 USA.
    Rioux, John D.
    University of Montreal, Canada; Montreal Heart Institute, Canada.
    Gregersen, Peter K.
    Feinstein Institute Medical Research, NY 11030 USA.
    Syvanen, Ann-Christine
    Uppsala University, Sweden; University of Nacl Mayor San Marcos, Peru.
    Ronnblom, Lars
    Uppsala University, Sweden.
    Criswell, Lindsey A.
    UCSF School Med, CA 94158 USA.
    Jacob, Chaim O.
    Keck School Medical USC, CA 90033 USA.
    Sivils, Kathy L.
    Oklahoma Medical Research Fdn, OK 73104 USA.
    Tsao, Betty P.
    Medical University of South Carolina, SC 29425 USA.
    Schanberg, Laura E.
    Duke University, NC 27708 USA.
    Behrens, Timothy W.
    Genentech Inc, CA 94080 USA.
    Silverman, Earl D.
    Hospital Sick Children, Canada; Hospital Sick Children, Canada; University of Toronto, Canada.
    Alarcon-Riquelme, Marta E.
    Oklahoma Medical Research Fdn, OK 73104 USA; University of Granada, Spain; Karolinska Institute, Sweden.
    Kimberly, Robert P.
    UAB School Med, AL 35294 USA.
    Harley, John B.
    Cincinnati Childrens Hospital Medical Centre, OH 45229 USA.
    Wakeland, Edward K.
    University of Texas Southwestern Medical Centre Dallas, TX 75235 USA.
    Graham, Robert R.
    Genentech Inc, CA 94080 USA.
    Gaffney, Patrick M.
    Oklahoma Medical Research Fdn, OK 73104 USA.
    Vyse, Timothy J.
    Kings Coll London, England.
    Transancestral mapping and genetic load in systemic lupus erythematosus2017Ingår i: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 8, artikel-id 16021Artikel i tidskrift (Refereegranskat)
    Abstract [en]

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

  • 57.
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    et al.
    University of Southern Calif, CA 90033 USA; Cedars Sinai Medical Centre, CA 90048 USA.
    Kar, Siddhartha
    University of Cambridge, England.
    McCue, Karen
    QIMR Berghofer Medical Research Institute, Australia.
    Kuchenbaeker, Karoline
    University of Cambridge, England.
    Michailidou, Kyriaki
    University of Cambridge, England.
    Tyrer, Jonathan
    University of Cambridge, England.
    Beesley, Jonathan
    QIMR Berghofer Medical Research Institute, Australia.
    Ramus, Susan J.
    University of Southern Calif, CA 90033 USA.
    Li, Qiyuan
    Xiamen University, Peoples R China; Dana Farber Cancer Institute, MA 02215 USA.
    Delgado, Melissa K.
    University of Southern Calif, CA 90033 USA.
    Lee, Janet M.
    University of Southern Calif, CA 90033 USA.
    Aittomaki, Kristiina
    University of Helsinki, Finland.
    Andrulis, Irene L.
    Mt Sinai Hospital, Canada; University of Toronto, Canada.
    Anton-Culver, Hoda
    University of Calif Irvine, CA 92697 USA.
    Arndt, Volker
    German Cancer Research Centre, Germany.
    Arun, Banu K.
    University of Texas MD Anderson Cancer Centre, TX 77030 USA.
    Arver, Brita
    Karolinska University Hospital, Sweden.
    Bandera, Elisa V.
    Rutgers Cancer Institute New Jersey, NJ 08903 USA.
    Barile, Monica
    Ist Europeo Oncol, Italy.
    Barkardottir, Rosa B.
    University of Iceland, Iceland; University of Iceland, Iceland.
    Barrowdale, Daniel
    University of Cambridge, England.
    Beckmann, Matthias W.
    University of Erlangen Nurnberg, Germany.
    Benitez, Javier
    Spanish National Cancer Research Centre, Spain; Centre Invest Red Enfermedades Raras, Spain.
    Berchuck, Andrew
    Duke University, NC 27710 USA.
    Bisogna, Maria
    Mem Sloan Kettering Cancer Centre, NY 10065 USA.
    Bjorge, Line
    Haukeland Hospital, Norway; University of Bergen, Norway.
    Blomqvist, Carl
    University of Helsinki, Finland.
    Blot, William
    Vanderbilt University, TN 37203 USA; Int Epidemiol Institute, MD 20850 USA.
    Bogdanova, Natalia
    Hannover Medical Sch, Germany.
    Bojesen, Anders
    Vejle Hospital, Denmark; Seoul National University, South Korea; Lunenfeld Tanenbaum Research Institute Mt Sinai Hospital, Canada.
    Bojesen, Stig E.
    University of Copenhagen, Denmark; Copenhagen University Hospital, Denmark; Copenhagen University Hospital, Denmark.
    Bolla, Manjeet K.
    University of Cambridge, England.
    Bonanni, Bernardo
    Ist Europeo Oncol, Italy.
    Borresen-Dale, Anne-Lise
    Oslo University Hospital, Norway; University of Oslo, Norway.
    Brauch, Hiltrud
    Dr Margarete Fischer Bosch Institute Clin Pharmacol, Germany; University of Tubingen, Germany; German Cancer Research Centre, Germany.
    Brennan, Paul
    Int Agency Research Canc, France.
    Brenner, Hermann
    German Cancer Research Centre, Germany; German Cancer Research Centre, Germany; German Cancer Research Centre, Germany.
    Bruinsma, Fiona
    Cancer Council Victoria, Australia.
    Brunet, Joan
    Catalan Institute Oncol, Spain.
    Ahmad Buhari, Shaik
    National University of Health Syst, Singapore.
    Burwinkel, Barbara
    German Cancer Research Centre, Germany; Heidelberg University, Germany.
    Butzow, Ralf
    University of Helsinki, Finland.
    Buys, Saundra S.
    University of Utah, UT 84112 USA.
    Cai, Qiuyin
    Vanderbilt University, TN 37203 USA.
    Caldes, Trinidad
    IdISSC El Institute Invest Sanitaria Hospital Clin San Car, Spain.
    Campbell, Ian
    Peter MacCallum Cancer Centre, Australia.
    Canniotto, Rikki
    Roswell Pk Cancer Institute, NY 14263 USA.
    Chang-Claude, Jenny
    German Cancer Research Centre, Germany; University of Medical Centre Hamburg Eppendorf, Germany.
    Chiquette, Jocelyne
    University of Quebec, Canada.
    Choi, Ji-Yeob
    Seoul National University, South Korea.
    Claes, Kathleen B. M.
    University of Ghent, Belgium.
    Cook, Linda S.
    University of New Mexico, NM 87131 USA.
    Cox, Angela
    University of Sheffield, England.
    Cramer, Daniel W.
    Harvard University, MA 02115 USA; Brigham and Womens Hospital, MA 02115 USA; Harvard University, MA 02115 USA.
    Cross, Simon S.
    University of Sheffield, England.
    Cybulski, Cezary
    Pomeranian Medical University, Poland.
    Czene, Kamila
    Karolinska Institute, Sweden.
    Daly, Mary B.
    Fox Chase Cancer Centre, PA 19111 USA.
    Damiola, Francesca
    University of Lyon, France.
    Dansonka-Mieszkowska, Agnieszka
    Maria Sklodowska Curie Mem Cancer Centre, Poland; Institute Oncol, Poland.
    Darabi, Hatef
    Karolinska Institute, Sweden.
    Dennis, Joe
    University of Cambridge, England.
    Devilee, Peter
    Leiden University, Netherlands.
    Diez, Orland
    University Hospital Vall Hebron, Spain; University of Autonoma Barcelona, Spain.
    Doherty, Jennifer A.
    Geisel School Medical Dartmouth, NH 03755 USA.
    Domchek, Susan M.
    University of Penn, PA 19104 USA.
    Dorfling, Cecilia M.
    University of Pretoria, South Africa.
    Doerk, Thilo
    Hannover Medical Sch, Germany.
    Dumont, Martine
    University of Laval, Canada.
    Ehrencrona, Hans
    Uppsala University, Sweden; University of Lund Hospital, Sweden.
    Ejlertsen, Bent
    Copenhagen University Hospital, Denmark.
    Ellis, Steve
    University of Cambridge, England.
    Engel, Christoph
    University of Leipzig, Germany.
    Lee, Eunjung
    University of Southern Calif, CA 90033 USA.
    Gareth Evans, D.
    University of Manchester, England.
    Fasching, Peter A.
    University of Erlangen Nurnberg, Germany; University of Calif Los Angeles, CA 90095 USA.
    Feliubadalo, Lidia
    Catalan Institute Oncol, Spain.
    Figueroa, Jonine
    NCI, MD 20892 USA.
    Flesch-Janys, Dieter
    University of Medical Centre Hamburg Eppendorf, Germany; University of Medical Centre Hamburg Eppendorf, Germany.
    Fletcher, Olivia
    Institute Cancer Research, England.
    Flyger, Henrik
    Copenhagen University Hospital, Denmark.
    Foretova, Lenka
    Masaryk Mem Cancer Institute, Czech Republic; Medical Fac MU, Czech Republic.
    Fostira, Florentia
    Aghia Paraskevi Attikis, Greece.
    Foulkes, William D.
    McGill University, Canada.
    Fridley, Brooke L.
    University of Kansas, KS 66103 USA.
    Friedman, Eitan
    Chaim Sheba Medical Centre, Israel.
    Frost, Debra
    University of Cambridge, England.
    Gambino, Gaetana
    University of and University Hospital Pisa, Italy.
    Ganz, Patricia A.
    Jonsson Comprehens Cancer Centre, CA 90024 USA.
    Garber, Judy
    Dana Farber Cancer Institute, MA 02215 USA.
    Garcia-Closas, Montserrat
    NCI, MD 20892 USA; Institute Cancer Research, England.
    Gentry-Maharaj, Aleksandra
    UCL EGA Institute Womens Heatlh, England.
    Ghoussaini, Maya
    University of Cambridge, England.
    Giles, Graham G.
    Cancer Council Victoria, Australia; University of Melbourne, Australia.
    Glasspool, Rosalind
    Beatson West Scotland Cancer Centre, Scotland.
    Godwin, Andrew K.
    University of Kansas, KS 66160 USA.
    Goldberg, Mark S.
    McGill University, Canada; McGill University, Canada.
    Goldgar, David E.
    University of Utah, UT 84132 USA.
    Gonzalez-Neira, Anna
    Spanish National Cancer Research Centre, Spain.
    Goode, Ellen L.
    Mayo Clin, MN 55902 USA.
    Goodman, Marc T.
    Cedars Sinai Medical Centre, CA 90048 USA; Cedars Sinai Medical Centre, CA 90048 USA.
    Greene, Mark H.
    NCI, MD 20892 USA.
    Gronwald, Jacek
    Pomeranian Medical University, Poland.
    Guenel, Pascal
    INSERM, France; University of Paris 11, France.
    Haiman, Christopher A.
    University of Southern Calif, CA 90033 USA.
    Hall, Per
    Karolinska Institute, Sweden.
    Hallberg, Emily
    Mayo Clin, MN 55902 USA.
    Hamann, Ute
    German Cancer Research Centre, Germany.
    Hansen, Thomas V. O.
    Copenhagen University Hospital, Denmark.
    Harrington, Patricia A.
    University of Cambridge, England.
    Hartman, Mikael
    National University of Health Syst, Singapore; National University of Singapore, Singapore.
    Hassan, Norhashimah
    University of Malaya, Malaysia; Cancer Research Initiat Fdn, Malaysia.
    Healey, Sue
    QIMR Berghofer Medical Research Institute, Australia.
    Heitz, Florian
    Kliniken Essen Mitte, Germany; Dr Horst Schmidt Kliniken Wiesbaden, Germany.
    Herzog, Josef
    City Hope Clin Cancer Genet Community Research Network, CA 91010 USA.
    Hogdall, Estrid
    University of Copenhagen, Denmark; Danish Cancer Soc Research Centre, Denmark.
    Hogdall, Claus K.
    University of Copenhagen, Denmark.
    Hogervorst, Frans B. L.
    Netherlands Cancer Institute, Netherlands.
    Hollestelle, Antoinette
    Erasmus MC Cancer Institute, Netherlands.
    Hopper, John L.
    University of Melbourne, Australia.
    Hulick, Peter J.
    NorthShore University of Health Syst, IL 60201 USA.
    Huzarski, Tomasz
    Pomeranian Medical University, Poland.
    Imyanitov, Evgeny N.
    NN Petrov Institute Oncol, Russia.
    Isaacs, Claudine
    Georgetown University, DC 20057 USA.
    Ito, Hidemi
    Aichi Cancer Centre, Japan.
    Jakubowska, Anna
    Pomeranian Medical University, Poland.
    Janavicius, Ramunas
    Centre Innovat Med, Lithuania.
    Jensen, Allan
    University of Copenhagen, Denmark.
    John, Esther M.
    Cancer Prevent Institute Calif, CA 94538 USA.
    Johnson, Nichola
    Institute Cancer Research, England.
    Kabisch, Maria
    German Cancer Research Centre, Germany.
    Kang, Daehee
    Seoul National University, South Korea.
    Kapuscinski, Miroslav
    University of Melbourne, Australia.
    Karlan, Beth Y.
    Cedars Sinai Medical Centre, CA 90048 USA.
    Khan, Sofia
    University of Helsinki, Finland.
    Kiemeney, Lambertus A.
    Radboud University of Nijmegen, Netherlands.
    Kruger Kjaer, Susanne
    Danish Cancer Soc Research Centre, Denmark; University of Copenhagen, Denmark.
    Knight, Julia A.
    Lunenfeld Tanenbaum Research Institute Mt Sinai Hospital, Canada; University of Toronto, Canada.
    Konstantopoulou, Irene
    Aghia Paraskevi Attikis, Greece.
    Kosma, Veli-Matti
    Kuopio University Hospital, Finland; University of Eastern Finland, Finland.
    Kristensen, Vessela
    Oslo University Hospital, Norway; University of Oslo, Norway; University of Oslo, Norway.
    Kupryjanczyk, Jolanta
    Maria Sklodowska Curie Mem Cancer Centre, Poland; Institute Oncol, Poland.
    Kwong, Ava
    Hong Kong Sanat and Hospital, Peoples R China; University of Hong Kong, Peoples R China.
    de la Hoya, Miguel
    IdISSC El Institute Invest Sanitaria Hospital Clin San Car, Spain.
    Laitman, Yael
    Chaim Sheba Medical Centre, Israel.
    Lambrechts, Diether
    VIB, Belgium; University of Leuven, Belgium.
    Le, Nhu
    University of Southern Calif, CA 90033 USA.
    De Leeneer, Kim
    University of Ghent, Belgium.
    Lester, Jenny
    Cedars Sinai Medical Centre, CA 90048 USA.
    Levine, Douglas A.
    Mem Sloan Kettering Cancer Centre, NY 10065 USA.
    Li, Jingmei
    Karolinska Institute, Sweden.
    Lindblom, Annika
    Karolinska Institute, Sweden.
    Long, Jirong
    Vanderbilt University, TN 37203 USA.
    Lophatananon, Artitaya
    University of Warwick, England.
    Loud, Jennifer T.
    NCI, MD 20892 USA.
    Lu, Karen
    University of Texas MD Anderson Cancer Centre, TX 77030 USA.
    Lubinski, Jan
    Pomeranian Medical University, Poland.
    Mannermaa, Arto
    Kuopio University Hospital, Finland; Kuopio University Hospital, Finland; University of Eastern Finland, Finland.
    Manoukian, Siranoush
    Ist Nazl Tumori, Italy.
    Le Marchand, Loic
    University of Hawaii, HI 96813 USA.
    Margolin, Sara
    Karolinska Institute, Sweden.
    Marme, Frederik
    Heidelberg University, Germany; Heidelberg University, Germany.
    Massuger, Leon F. A. G.
    Radboud University of Nijmegen, Netherlands.
    Matsuo, Keitaro
    Kyushu University, Japan.
    Mazoyer, Sylvie
    University of Lyon, France.
    McGuffog, Lesley
    University of Cambridge, England.
    McLean, Catriona
    Alfred Hospital, Australia.
    McNeish, Iain
    University of Glasgow, Scotland.
    Meindl, Alfons
    Technical University of Munich, Germany.
    Menon, Usha
    UCL EGA Institute Womens Heatlh, England.
    Mensenkamp, Arjen R.
    Radboud University of Nijmegen, Netherlands.
    Milne, Roger L.
    Cancer Council Victoria, Australia; University of Melbourne, Australia.
    Montagna, Marco
    IRCCS, Italy.
    Moysich, Kirsten B.
    Roswell Pk Cancer Institute, NY 14263 USA.
    Muir, Kenneth
    University of Warwick, England; University of Manchester, England.
    Mulligan, Anna Marie
    University of Health Network, Canada; University of Toronto, Canada.
    Nathanson, Katherine L.
    University of Penn, PA 19104 USA.
    Ness, Roberta B.
    University of Texas Houston, TX 77030 USA.
    Neuhausen, Susan L.
    Beckman Research Institute City Hope, CA 91010 USA.
    Nevanlinna, Heli
    University of Helsinki, Finland; University of Helsinki, Finland.
    Nord, Silje
    University of Oslo, Norway.
    Nussbaum, Robert L.
    University of Calif San Francisco, CA 94143 USA.
    Odunsi, Kunle
    Roswell Pk Cancer Institute, NY 14263 USA.
    Offit, Kenneth
    Mem Sloan Kettering Cancer Centre, NY 10065 USA.
    Olah, Edith
    National Institute Oncol, Hungary.
    Olopade, Olufunmilayo I.
    University of Chicago, IL 60637 USA.
    Olson, Janet E.
    Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, USA.
    Olswold, Curtis
    Mayo Clin, MN 55902 USA.
    OMalley, David
    Ohio State University, OH 43210 USA; James Graham Brown Cancer Centre, OH 43210 USA.
    Orlow, Irene
    Mem Sloan Kettering Cancer Centre, NY 10017 USA.
    Orr, Nick
    Institute Cancer Research, England.
    Osorio, Ana
    University of Copenhagen, Denmark; Spanish National Cancer Centre CNIO, Spain; Biomed Network Rare Disease CIBERER, Spain.
    Kyung Park, Sue
    Seoul National University, South Korea; Seoul National University, South Korea; Seoul National University, South Korea.
    Pearce, Celeste L.
    University of Southern Calif, CA 90033 USA.
    Pejovic, Tanja
    Oregon Health and Science University, OR 97239 USA; Oregon Health and Science University, OR 97239 USA.
    Peterlongo, Paolo
    FIRC Italian Fdn Cancer Research, Italy.
    Pfeiler, Georg
    Medical University of Vienna, Austria.
    Phelan, Catherine M.
    H Lee Moffitt Cancer Centre and Research Institute, FL 33606 USA.
    Poole, Elizabeth M.
    Harvard University, MA 02115 USA; Brigham and Womens Hospital, MA 02115 USA; Harvard University, MA 02115 USA.
    Pylkas, Katri
    Centre NordLab, Finland; University of Oulu, Finland.
    Radice, Paolo
    Ist Nazl Tumori, Italy.
    Rantala, Johanna
    Karolinska University Hospital, Sweden.
    Usman Rashid, Muhammad
    German Cancer Research Centre, Germany; Shaukat Khanum Mem Cancer Hospital and Research Centre SKMCH and RC, Pakistan.
    Rennert, Gad
    Clalit National Israeli Cancer Control Centre, Israel; Carmel Hospital, Israel.
    Rhenius, Valerie
    University of Cambridge, England.
    Rhiem, Kerstin
    University Hospital Cologne, Germany; University Hospital Cologne, Germany.
    Risch, Harvey A.
    Yale University, CT 06510 USA.
    Rodriguez, Gus
    NorthShore University of HealthSyst, IL 60201 USA.
    Anne Rossing, Mary
    Fred Hutchinson Cancer Research Centre, WA 98109 USA; University of Washington, WA 98109 USA.
    Rudolph, Anja
    German Cancer Research Centre, Germany.
    Salvesen, Helga B.
    Haukeland Hospital, Norway; University of Bergen, Norway.
    Sangrajrang, Suleeporn
    National Cancer Institute, Thailand.
    Sawyer, Elinor J.
    Kings Coll London, England.
    Schildkraut, Joellen M.
    Duke University, NC 27710 USA; Duke Cancer Institute, NC 27710 USA.
    Schmidt, Marjanka K.
    Netherlands Cancer Institute, Netherlands.
    Schmutzler, Rita K.
    University Hospital Cologne, Germany; University Hospital Cologne, Germany; University Hospital Cologne, Germany; University Hospital Cologne, Germany.
    Sellers, Thomas A.
    H Lee Moffitt Cancer Centre and Research Institute, FL 33606 USA.
    Seynaeve, Caroline
    Erasmus MC Cancer Institute, Netherlands.
    Shah, Mitul
    University of Cambridge, England.
    Shen, Chen-Yang
    Academic Sinica, Taiwan; China Medical University, Taiwan.
    Shu, Xiao-Ou
    Vanderbilt University, TN 37203 USA.
    Sieh, Weiva
    Stanford University, CA 94305 USA.
    Singer, Christian F.
    Medical University of Vienna, Austria.
    Sinilnikova, Olga M.
    Centre Leon Berard, France; University of Lyon 1, France.
    Slager, Susan
    Mayo Clin, MN 55902 USA.
    Song, Honglin
    University of Cambridge, England.
    Soucy, Penny
    University of Laval, Canada.
    Southey, Melissa C.
    University of Melbourne, Australia.
    Stenmark Askmalm, Marie
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk patologi och klinisk genetik. University of Lund Hospital, Sweden.
    Stoppa-Lyonnet, Dominique
    Institute Curie, France; Institute Curie, France; Sorbonne Paris Cite, France.
    Sutter, Christian
    University of Heidelberg Hospital, Germany.
    Swerdlow, Anthony
    Institute Cancer Research, England; Institute Cancer Research, England.
    Tchatchou, Sandrine
    Mt Sinai Hospital, Canada.
    Teixeira, Manuel R.
    Portuguese Oncology Institute, Portugal; University of Porto, Portugal.
    Teo, Soo H.
    University of Malaya, Malaysia; Cancer Research Initiat Fdn, Malaysia.
    Terry, Kathryn L.
    Harvard University, MA 02115 USA; Brigham and Womens Hospital, MA 02115 USA; Harvard University, MA 02115 USA.
    Beth Terry, Mary
    Columbia University, NY 10027 USA.
    Thomassen, Mads
    Odense University Hospital, Denmark.
    Grazia Tibiletti, Maria
    University of Insubria, Italy.
    Tihomirova, Laima
    Latvian Biomed Research and Study Centre, Latvia.
    Tognazzo, Silvia
    IRCCS, Italy.
    Ewart Toland, Amanda
    Vanderbilt University, TN 37203 USA; IdISSC El Institute Invest Sanitaria Hospital Clin San Car, Spain; Ohio State University, OH 43210 USA.
    Tomlinson, Ian
    University of Oxford, England; University of Oxford, England.
    Torres, Diana
    German Cancer Research Centre, Germany; Pontificia University of Javeriana, Colombia.
    Truong, Therese
    INSERM, France; University of Paris 11, France.
    Tseng, Chiu-chen
    University of Southern Calif, CA 90033 USA.
    Tung, Nadine
    Beth Israel Deaconess Medical Centre, MA 02215 USA.
    Tworoger, Shelley S.
    Harvard University, MA 02115 USA; Brigham and Womens Hospital, MA 02115 USA; Harvard University, MA 02115 USA.
    Vachon, Celine
    Mayo Clin, MN 55902 USA.
    van den Ouweland, Ans M. W.
    Erasmus University, Netherlands.
    van Doorn, Helena C.
    Erasmus MC Cancer Institute, Netherlands.
    van Rensburg, Elizabeth J.
    University of Pretoria, South Africa.
    Vant Veer, Laura J.
    Netherlands Cancer Institute, Netherlands.
    Vanderstichele, Adriaan
    University Hospital Leuven, Belgium.
    Vergote, Ignace
    University Hospital Leuven, Belgium.
    Vijai, Joseph
    Mem Sloan Kettering Cancer Centre, NY 10065 USA.
    Wang, Qin
    University of Cambridge, England.
    Wang-Gohrke, Shan
    University Hospital Ulm, Germany.
    Weitzel, Jeffrey N.
    City Hope Clin Cancer Genet Community Research Network, CA 91010 USA.
    Wentzensen, Nicolas
    NCI, MD 20892 USA.
    Whittemore, Alice S.
    Stanford University, CA 94305 USA.
    Wildiers, Hans
    University Hospital Leuven, Belgium.
    Winqvist, Robert
    Centre NordLab, Finland; University of Oulu, Finland.
    Wu, Anna H.
    University of Southern Calif, CA 90033 USA.
    Yannoukakos, Drakoulis
    National Centre Science Research Demokritos, Greece.
    Yoon, Sook-Yee
    Sime Darby Medical Centre, Malaysia; University of Malaya, Malaysia.
    Yu, Jyh-Cherng
    National Def Medical Centre, Taiwan.
    Zheng, Wei
    Vanderbilt University, TN 37203 USA.
    Zheng, Ying
    Shanghai Centre Disease Control and Prevent, Peoples R China.
    Kum Khanna, Kum
    QIMR Berghofer Medical Research Institute, Australia.
    Simard, Jacques
    University of Laval, Canada.
    Monteiro, Alvaro N.
    H Lee Moffitt Cancer Centre and Research Institute, FL 33612 USA.
    French, Juliet D.
    QIMR Berghofer Medical Research Institute, Australia.
    Couch, Fergus J.
    Mayo Clin, MN 55902 USA; Mayo Clin, MN 55905 USA.
    Freedman, Matthew L.
    Dana Farber Cancer Institute, MA 02215 USA.
    Easton, Douglas F.
    University of Cambridge, England; University of Cambridge, England.
    Dunning, Alison M.
    University of Cambridge, England.
    Pharoah, Paul D.
    University of Cambridge, England.
    Edwards, Stacey L.
    QIMR Berghofer Medical Research Institute, Australia.
    Chenevix-Trench, Georgia
    QIMR Berghofer Medical Research Institute, Australia.
    Antoniou, Antonis C.
    University of Cambridge, England.
    Gayther, Simon A.
    University of Southern Calif, CA 90033 USA; Cedars Sinai Medical Centre, CA 90048 USA.
    Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus2016Ingår i: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 7, artikel-id 12675Artikel i tidskrift (Refereegranskat)
    Abstract [en]

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

  • 58.
    Leandro-Garcia, Luis J.
    et al.
    Spanish National Cancer Research Centre, Spain .
    Inglada-Perez, Lucia
    Spanish National Cancer Research Centre, Spain .
    Pita, Guillermo
    Spanish National Cancer Research Centre, Spain .
    Hjerpe, Elisabet
    Karolinska University Hospital, Sweden .
    Leskelae, Susanna
    Spanish National Cancer Research Centre, Spain .
    Jara, Carlos
    Fdn Hospital Alcorcon, Spain .
    Mielgo, Xabier
    Fdn Hospital Alcorcon, Spain .
    Gonzalez-Neira, Anna
    Spanish National Cancer Research Centre, Spain .
    Robledo, Mercedes
    Spanish National Cancer Research Centre, Spain .
    Åvall-Lundqvist, Elisabeth
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Hälsouniversitetet. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US. Karolinska University Hospital, Sweden .
    Green, Henrik
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Hälsouniversitetet.
    Rodriguez-Antona, Cristina
    Spanish National Cancer Research Centre, Spain .
    Genome-wide association study identifies ephrin type A receptors implicated in paclitaxel induced peripheral sensory neuropathy2013Ingår i: Journal of Medical Genetics, ISSN 0022-2593, E-ISSN 1468-6244, Vol. 50, nr 9, s. 599-605Artikel i tidskrift (Refereegranskat)
    Abstract [en]

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

  • 59.
    Li, He
    et al.
    Oklahoma Medical Research Fdn, OK 73104 USA; University of Oklahoma, OK USA; University of Calif San Diego, CA 92093 USA.
    Ragna Reksten, Tove
    Oklahoma Medical Research Fdn, OK 73104 USA; University of Bergen, Norway.
    Ice, John A.
    Oklahoma Medical Research Fdn, OK 73104 USA.
    Kelly, Jennifer A.
    Oklahoma Medical Research Fdn, OK 73104 USA.
    Adrianto, Indra
    Oklahoma Medical Research Fdn, OK 73104 USA.
    Rasmussen, Astrid
    Oklahoma Medical Research Fdn, OK 73104 USA.
    Wang, Shaofeng
    Oklahoma Medical Research Fdn, OK 73104 USA.
    He, Bo
    Oklahoma Medical Research Fdn, OK 73104 USA; University of Oklahoma, OK USA.
    Grundahl, Kiely M.
    Oklahoma Medical Research Fdn, OK 73104 USA.
    Glenn, Stuart B.
    Oklahoma Medical Research Fdn, OK 73104 USA.
    Miceli-Richard, Corinne
    University of Paris Sud, France.
    Bowman, Simon
    University Hospital Birmingham, England.
    Lester, Sue
    Queen Elizabeth Hospital, Australia.
    Eriksson, Per
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Region Östergötland, Hjärt- och Medicincentrum, Reumatologiska kliniken i Östergötland. Linköpings universitet, Medicinska fakulteten.
    Eloranta, Maija-Leena
    Uppsala University, Sweden.
    Brun, Johan G.
    University of Bergen, Norway; Haukeland Hospital, Norway.
    Goransson, Lasse G.
    Stavanger University Hospital, Norway.
    Harboe, Erna
    Stavanger University Hospital, Norway.
    Guthridge, Joel M.
    Oklahoma Medical Research Fdn, OK 73104 USA.
    Kaufman, Kenneth M.
    Cincinnati Childrens Hospital Medical Centre, OH 45229 USA; US Department Vet Affairs, OH USA.
    Kvarnstrom, Marika
    Karolinska Institute, Sweden.
    Cunninghame Graham, Deborah S.
    Kings Coll London, England.
    Patel, Ketan
    University of Minnesota, MN 55455 USA; North Mem Medical Centre, MN USA.
    Adler, Adam J.
    Oklahoma Medical Research Fdn, OK 73104 USA.
    Darise Farris, A.
    Oklahoma Medical Research Fdn, OK 73104 USA; University of Oklahoma, OK USA.
    Brennan, Michael T.
    Carolinas Medical Centre, NC 28203 USA.
    Chodosh, James
    Harvard Medical Sch, MA USA.
    Gopalakrishnan, Rajaram
    University of Minnesota, MN 55455 USA.
    Weisman, Michael H.
    Cedars Sinai Medical Centre, CA 90048 USA.
    Venuturupalli, Swamy
    Cedars Sinai Medical Centre, CA 90048 USA.
    Wallace, Daniel J.
    Cedars Sinai Medical Centre, CA 90048 USA.
    Hefner, Kimberly S.
    Cedars Sinai Medical Centre, CA 90048 USA; Hefner Eye Care and Opt Centre, OK USA.
    Houston, Glen D.
    University of Oklahoma, OK USA; Heartland Pathol Consultants, OK USA.
    Huang, Andrew J. W.
    Washington University, MO 63130 USA.
    Hughes, Pamela J.
    University of Minnesota, MN 55455 USA.
    Lewis, David M.
    University of Oklahoma, OK USA.
    Radfar, Lida
    University of Oklahoma, OK USA.
    Vista, Evan S.
    Oklahoma Medical Research Fdn, OK 73104 USA; University of Santo Tomas Hospital, Philippines.
    Edgar, Contessa E.
    Oklahoma Baptist University, OK USA.
    Rohrer, Michael D.
    University of Minnesota, MN 55455 USA.
    Stone, Donald U.
    Johns Hopkins University, MD USA.
    Vyse, Timothy J.
    Kings Coll London, England.
    Harley, John B.
    Cincinnati Childrens Hospital Medical Centre, OH 45229 USA; US Department Vet Affairs, OH USA.
    Gaffney, Patrick M.
    Oklahoma Medical Research Fdn, OK 73104 USA.
    James, Judith A.
    Oklahoma Medical Research Fdn, OK 73104 USA; University of Oklahoma, OK USA; University of Oklahoma, OK USA.
    Turner, Sean
    Oklahoma Medical Research Fdn, OK 73104 USA.
    Alevizos, Ilias
    National Institute Dent and Craniofacial Research, MD USA.
    Anaya, Juan-Manuel
    University of Rosario, Colombia.
    Rhodus, Nelson L.
    University of Minnesota, MN 55455 USA.
    Segal, Barbara M.
    University of Minnesota, MN 55455 USA.
    Montgomery, Courtney G.
    Oklahoma Medical Research Fdn, OK 73104 USA.
    Hal Scofield, R.
    Oklahoma Medical Research Fdn, OK 73104 USA; University of Oklahoma, OK USA; US Department Vet Affairs, OK USA.
    Kovats, Susan
    Oklahoma Medical Research Fdn, OK 73104 USA.
    Mariette, Xavier
    University of Paris Sud, France.
    Ronnblom, Lars
    Uppsala University, Sweden.
    Witte, Torsten
    Hannover Medical Sch, Germany.
    Rischmueller, Maureen
    Queen Elizabeth Hospital, Australia; University of Adelaide, Australia.
    Wahren-Herlenius, Marie
    Karolinska Institute, Sweden.
    Omdal, Roald
    Stavanger University Hospital, Norway.
    Jonsson, Roland
    University of Bergen, Norway; Haukeland Hospital, Norway.
    Ng, Wan-Fai
    Newcastle University, England; Newcastle University, England.
    Nordmark, Gunnel
    Uppsala University, Sweden.
    Lessard, Christopher J.
    Oklahoma Medical Research Fdn, OK 73104 USA; University of Oklahoma, OK USA.
    Sivils, Kathy L.
    Oklahoma Medical Research Fdn, OK 73104 USA; University of Oklahoma, OK USA.
    Identification of a Sjögrens syndrome susceptibility locus at OAS1 that influences isoform switching, protein expression, and responsiveness to type I interferons2017Ingår i: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 13, nr 6, artikel-id e1006820Artikel i tidskrift (Refereegranskat)
    Abstract [en]

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

  • 60.
    Lidell, Martin E.
    et al.
    Medicinsk genetik, Göteborgs universitet.
    Betz, Matthias J.
    Medicinsk genetik, Göteborgs universitet.
    Dahlqvist Leinhard, Olof
    Linköpings universitet, Centrum för medicinsk bildvetenskap och visualisering, CMIV. Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för radiologiska vetenskaper. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Radiofysikavdelningen US.
    Heglind, Mikael
    Medicinsk genetik, Göteborgs universitet.
    Elander, Louise
    Linköpings universitet, Centrum för medicinsk bildvetenskap och visualisering, CMIV. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Slawik, Marc
    Klinikum der Ludwig Maximilians University (LMU), Munich, Germany.
    Mussack, Thomas
    Klinikum der LMU, Munich, Germany.
    Nilsson, Daniel
    Medicinsk genetik, Göteborgs universitet.
    Romu, Thobias
    Linköpings universitet, Centrum för medicinsk bildvetenskap och visualisering, CMIV. Linköpings universitet, Institutionen för medicinsk teknik, Medicinsk informatik. Linköpings universitet, Tekniska högskolan.
    Nuutila, Pirjo
    University of Turku, Turku, Finland.
    Virtanen, Kirsi A.
    University of Turku, Turku, Finland.
    Beuschlein, Felix
    Klinikum der Ludwig Maximilians University (LMU), Munich, Germany.
    Persson, Anders
    Linköpings universitet, Centrum för medicinsk bildvetenskap och visualisering, CMIV. Linköpings universitet, Institutionen för medicin och hälsa, Medicinsk radiologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Röntgenkliniken i Linköping.
    Borga, Magnus
    Linköpings universitet, Centrum för medicinsk bildvetenskap och visualisering, CMIV. Linköpings universitet, Institutionen för medicinsk teknik, Medicinsk informatik. Linköpings universitet, Tekniska högskolan.
    Enerbäck, Sven
    Medicinsk genetik, Göteborgs universitet.
    Evidence for two types of brown adipose tissue in humans2013Ingår i: Nature Medicine, ISSN 1078-8956, E-ISSN 1546-170X, Vol. 19, nr 5, s. 631-634Artikel i tidskrift (Refereegranskat)
    Abstract [en]

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

  • 61.
    Lilljebjorn, Henrik
    et al.
    Lund University, Sweden.
    Henningsson, Rasmus
    Lund University, Sweden.
    Hyrenius-Wittsten, Axel
    Lund University, Sweden.
    Olsson, Linda
    Lund University, Sweden.
    Orsmark-Pietras, Christina
    Lund University, Sweden.
    von Palffy, Sofia
    Lund University, Sweden.
    Askmyr, Maria
    Lund University, Sweden.
    Rissler, Marianne
    Lund University, Sweden.
    Schrappe, Martin
    University Hospital Schleswig Holstein, Germany.
    Cario, Gunnar
    University Hospital Schleswig Holstein, Germany.
    Castor, Anders
    Lund University, Sweden.
    Pronk, Cornelis J. H.
    Lund University, Sweden.
    Behrendtz, Mikael
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Region Östergötland, Barn- och kvinnocentrum, Barn- och ungdomskliniken i Linköping. Linköpings universitet, Medicinska fakulteten.
    Mitelman, Felix
    Lund University, Sweden.
    Johansson, Bertil
    Lund University, Sweden; University of and Regional Labs Regional Skåne, Sweden.
    Paulsson, Kajsa
    Lund University, Sweden.
    Andersson, Anna K.
    Lund University, Sweden.
    Fontes, Magnus
    Lund University, Sweden.
    Fioretos, Thoas
    Lund University, Sweden; University of and Regional Labs Regional Skåne, Sweden.
    Identification of ETV6-RUNX1-like and DUX4-rearranged subtypes in paediatric B-cell precursor acute lymphoblastic leukaemia2016Ingår i: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 7, nr 11790Artikel i tidskrift (Refereegranskat)
    Abstract [en]

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

  • 62.
    Lindqvist, Maria
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för hälso- och vårdutveckling, Vårdhygien.
    Isaksson, Barbro
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för hälso- och vårdutveckling, Vårdhygien. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk mikrobiologi.
    Nilsson, Lennart
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Hälsouniversitetet.
    Wistedt, Annika
    Department of Clinical Microbiology and Infection Control, Kalmar County Hospital, Kalmar, Sweden.
    Swanberg, Jonas
    Clinical Microbiology Laboratory, Ryhov Hospital, Jönköping, Sweden.
    Skov, Robert
    Staphylococcus Laboratory, Department of Microbiology and Infection Control, Statens Serum Institut, Copenhagen, Denmark.
    Rhod Larsen, Anders
    Staphylococcus Laboratory, Department of Microbiology and Infection Control, Statens Serum Institut, Copenhagen, Denmark.
    Larsen, Jesper
    Staphylococcus Laboratory, Department of Microbiology and Infection Control, Statens Serum Institut, Copenhagen, Denmark.
    Petersen, Andreas
    Staphylococcus Laboratory, Department of Microbiology and Infection Control, Statens Serum Institut, Copenhagen, Denmark.
    Hällgren, Anita
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Hjärt- och Medicincentrum, Infektionskliniken i Östergötland.
    Genetic relatedness of multi-resistant methicillin-susceptible Staphylococcus aureus in southeast Sweden2014Manuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

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

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

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

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

  • 63.
    Ljunggren, Stefan
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten.
    Lipoproteomics: Environmental and Genetic Factors Affecting High-Density Lipoprotein (HDL)2016Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

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

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

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

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

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

    Delarbeten
    1. ApoA-I mutations, L202P and K131del, in HDL from heterozygotes with low HDL-C
    Öppna denna publikation i ny flik eller fönster >>ApoA-I mutations, L202P and K131del, in HDL from heterozygotes with low HDL-C
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    2014 (Engelska)Ingår i: PROTEOMICS - Clinical Applications, ISSN 1862-8346, E-ISSN 1862-8354, Vol. 8, nr 3-4, s. 241-250Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

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

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

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

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

    Ort, förlag, år, upplaga, sidor
    Wiley-Blackwell, 2014
    Nationell ämneskategori
    Cell- och molekylärbiologi Biokemi och molekylärbiologi
    Identifikatorer
    urn:nbn:se:liu:diva-105992 (URN)10.1002/prca.201300014 (DOI)000334251600013 ()24273187 (PubMedID)
    Tillgänglig från: 2014-04-16 Skapad: 2014-04-16 Senast uppdaterad: 2020-02-20
    2. Lipoprotein profiles in human heterozygote carriers of a functional mutation P297S in scavenger receptor class B1.
    Öppna denna publikation i ny flik eller fönster >>Lipoprotein profiles in human heterozygote carriers of a functional mutation P297S in scavenger receptor class B1.
    Visa övriga...
    2015 (Engelska)Ingår i: Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids, ISSN 1388-1981, E-ISSN 1879-2618, Vol. 1851, nr 12, s. 1587-1595Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

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

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

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

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

    Ort, förlag, år, upplaga, sidor
    Elsevier, 2015
    Nyckelord
    ApoE; ApoL-1; HDL; LDL/VLDL; P297S; SR-B1
    Nationell ämneskategori
    Biokemi och molekylärbiologi
    Identifikatorer
    urn:nbn:se:liu:diva-122723 (URN)10.1016/j.bbalip.2015.09.006 (DOI)000364252800008 ()26454245 (PubMedID)
    Anmärkning

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

    Tillgänglig från: 2015-11-18 Skapad: 2015-11-18 Senast uppdaterad: 2020-02-20
    3. Persistent organic pollutants distribution in lipoprotein fractions in relation to cardiovascular disease and cancer.
    Öppna denna publikation i ny flik eller fönster >>Persistent organic pollutants distribution in lipoprotein fractions in relation to cardiovascular disease and cancer.
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    2014 (Engelska)Ingår i: Environment International, ISSN 0160-4120, E-ISSN 1873-6750, Vol. 65, s. 93-9Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

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

    Ort, förlag, år, upplaga, sidor
    Elsevier, 2014
    Nationell ämneskategori
    Klinisk medicin Annan medicinsk grundvetenskap
    Identifikatorer
    urn:nbn:se:liu:diva-104755 (URN)10.1016/j.envint.2013.12.017 (DOI)000334728500010 ()24472825 (PubMedID)
    Tillgänglig från: 2014-02-25 Skapad: 2014-02-25 Senast uppdaterad: 2020-02-20
  • 64.
    Montelius, Kerstin
    et al.
    National Board of Forensic Medicine, Linköping, Sweden.
    Karlsson, Andreas O
    National Board of Forensic Medicine, Linköping, Sweden.
    Holmlund, Gunilla
    National Board of Forensic Medicine, Linköping, Sweden.
    STR data for the AmpFlSTR Identifiler loci from Swedish population in comparison to European, as well as with non-European population2008Ingår i: Forensic Science International: Genetics, ISSN 1872-4973, E-ISSN 1878-0326, Vol. 2, nr 3, s. e49-e52Artikel i tidskrift (Refereegranskat)
    Abstract [en]

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

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

  • 65.
    Mosrati, Mohamed Ali
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Medicinska fakulteten.
    Malmström, Annika
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Region Östergötland, Närsjukvården i centrala Östergötland, LAH Linköping. Linköpings universitet, Medicinska fakulteten.
    Lysiak, Malgorzata
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Krysztofiak, Adam
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Medicinska fakulteten.
    Hallbeck, Martin
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk patologi och klinisk genetik.
    Milos, Peter
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Region Östergötland, Sinnescentrum, Neurokirurgiska kliniken US. Linköpings universitet, Medicinska fakulteten.
    Hallbeck, Anna-Lotta
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US. Linköpings universitet, Medicinska fakulteten.
    Bratthall, Charlotte
    Dist Hospital, Sweden.
    Strandeus, Michael
    Ryhov Hospital, Sweden.
    Stenmark Askmalm, Marie
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk patologi och klinisk genetik.
    Söderkvist, Peter
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk patologi och klinisk genetik.
    TERT promoter mutations and polymorphisms as prognostic factors in primary glioblastoma2015Ingår i: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 6, nr 18, s. 16663-16673Artikel i tidskrift (Refereegranskat)
    Abstract [en]

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

  • 66.
    Mukwaya, Anthony
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten.
    Mirabelli, Pierfrancesco
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Sinnescentrum, Ögonkliniken US/LiM.
    Lennikov, Anton
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten.
    Xeroudaki, Maria
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Sinnescentrum, Ögonkliniken US/LiM.
    Schaupper, Mira
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten.
    Peebo, Beatrice
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Sinnescentrum, Ögonkliniken US/LiM.
    Lagali, Neil
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Sinnescentrum, Ögonkliniken US/LiM.
    Genome-wide expression datasets of anti-VEGF and dexamethasone treatment of angiogenesis in the rat cornea2017Ingår i: Scientific Data, E-ISSN 2052-4463, Vol. 4, artikel-id 170111Artikel i tidskrift (Refereegranskat)
    Abstract [en]

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

  • 67.
    Nazaryan-Petersen, Lusine
    et al.
    Univ Copenhagen, Denmark.
    Eisfeldt, Jesper
    Karolinska Inst, Sweden; Karolinska Inst Sci Pk, Sweden.
    Pettersson, Maria
    Karolinska Inst, Sweden.
    Lundin, Johanna
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Nilsson, Daniel
    Karolinska Inst, Sweden; Karolinska Inst Sci Pk, Sweden; Karolinska Univ Hosp, Sweden.
    Wincent, Josephine
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Lieden, Agne
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Lovmar, Lovisa
    Sahlgrens Univ Hosp, Sweden.
    Ottosson, Jesper
    Sahlgrens Univ Hosp, Sweden.
    Gacic, Jelena
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk genetik.
    Makitie, Outi
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden; Univ Helsinki, Finland; Helsinki Univ Hosp, Finland; Folkhalsan Inst Genet, Finland.
    Nordgren, Ann
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Vezzi, Francesco
    Stockholm Univ, Sweden; Devyser AB, Sweden.
    Wirta, Valtteri
    KTH Royal Inst Technol, Sweden; Karolinska Inst, Sweden.
    Kaller, Max
    KTH Royal Inst Technol, Sweden; Karolinska Inst, Sweden.
    Hjortshoj, Tina Duelund
    Rigshosp, Denmark.
    Jespersgaard, Cathrine
    Rigshosp, Denmark.
    Houssari, Rayan
    Rigshosp, Denmark.
    Pignata, Laura
    Rigshosp, Denmark.
    Bak, Mads
    Univ Copenhagen, Denmark.
    Tommerup, Niels
    Univ Copenhagen, Denmark.
    Lundberg, Elisabeth Syk
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Tumer, Zeynep
    Rigshosp, Denmark; Univ Copenhagen, Denmark.
    Lindstrand, Anna
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Replicative and non-replicative mechanisms in the formation of clustered CNVs are indicated by whole genome characterization2018Ingår i: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 14, nr 11, artikel-id e1007780Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Clustered copy number variants (CNVs) as detected by chromosomal microarray analysis (CMA) are often reported as germline chromothripsis. However, such cases might need further investigations by massive parallel whole genome sequencing (WGS) in order to accurately define the underlying complex rearrangement, predict the occurrence mechanisms and identify additional complexities. Here, we utilized WGS to delineate the rearrangement structure of 21 clustered CNV carriers first investigated by CMA and identified a total of 83 breakpoint junctions (BPJs). The rearrangements were further sub-classified depending on the patterns observed: I) Cases with only deletions (n = 8) often had additional structural rearrangements, such as insertions and inversions typical to chromothripsis; II) cases with only duplications (n = 7) or III) combinations of deletions and duplications (n = 6) demonstrated mostly interspersed duplications and BPJs enriched with microhomology. In two cases the rearrangement mutational signatures indicated both a breakage-fusion-bridge cycle process and haltered formation of a ring chromosome. Finally, we observed two cases with Alu- and LINE-mediated rearrangements as well as two unrelated individuals with seemingly identical clustered CNVs on 2p25.3, possibly a rare European founder rearrangement. In conclusion, through detailed characterization of the derivative chromosomes we show that multiple mechanisms are likely involved in the formation of clustered CNVs and add further evidence for chromoanagenesis mechanisms in both "simple" and highly complex chromosomal rearrangements. Finally, WGS characterization adds positional information, important for a correct clinical interpretation and deciphering mechanisms involved in the formation of these rearrangements.

  • 68.
    Okuyama, Kazuki
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Medicinska fakulteten.
    Strid, Tobias
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för hematopoes och utvecklingsbiologi. Linköpings universitet, Medicinska fakulteten. Lund Univ, Sweden.
    Kuruvilla, Jacob
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för hematopoes och utvecklingsbiologi. Linköpings universitet, Medicinska fakulteten. Lund Univ, Sweden.
    Somasundaram, Rajesh
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för hematopoes och utvecklingsbiologi. Linköpings universitet, Medicinska fakulteten.
    Cristobal, Susana
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Smith, Emma
    Lund Univ, Sweden.
    Prasad, Mahadesh
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Medicinska fakulteten.
    Fioretos, Thoas
    Lund Univ, Sweden.
    Lilljebjorn, Henrik
    Lund Univ, Sweden.
    Soneji, Shamit
    Lund Univ, Sweden.
    Lang, Stefan
    Lund Univ, Sweden.
    Ungerback, Jonas
    Lund Univ, Sweden.
    Sigvardsson, Mikael
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för hematopoes och utvecklingsbiologi. Linköpings universitet, Medicinska fakulteten. Lund Univ, Sweden.
    PAX5 is part of a functional transcription factor network targeted in lymphoid leukemia2019Ingår i: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 15, nr 8, artikel-id e1008280Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    One of the most frequently mutated proteins in human B-lineage leukemia is the transcription factor PAX5. These mutations often result in partial rather than complete loss of function of the transcription factor. While the functional dose of PAX5 has a clear connection to human malignancy, there is limited evidence for that heterozygote loss of PAX5 have a dramatic effect on the development and function of B-cell progenitors. One possible explanation comes from the finding that PAX5 mutated B-ALL often display complex karyotypes and additional mutations. Thus, PAX5 might be one component of a larger transcription factor network targeted in B-ALL. To investigate the functional network associated with PAX5 we used BioID technology to isolate proteins associated with this transcription factor in the living cell. This identified 239 proteins out of which several could be found mutated in human B-ALL. Most prominently we identified the commonly mutated IKZF1 and RUNX1, involved in the formation of ETV6-AML1 fusion protein, among the interaction partners. ChIP- as well as PLAC-seq analysis supported the idea that these factors share a multitude of target genes in human B-ALL cells. Gene expression analysis of mouse models and primary human leukemia suggested that reduced function of PAX5 increased the ability of an oncogenic form of IKZF1 or ETV6-AML to modulate gene expression. Our data reveals that PAX5 belong to a regulatory network frequently targeted by multiple mutations in B-ALL shedding light on the molecular interplay in leukemia cells. Author summary The use of modern high throughput DNA-sequencing has dramatically increased our ability to identify genetic alterations associated with cancer. However, while the mutations per se are rather easily identified, our understanding of how these mutations impact cellular functions and drive malignant transformation is more limited. We have explored the function of the transcription factor PAX5, commonly mutated in human B-lymphocyte leukemia, to identify a regulatory network of transcription factors often targeted in human disease. Hence, we propose that malignant conversion of B-lymphocyte progenitors involves multiple targeting of a central transcription factor network aggravating the impact of the individual mutations. These data increase our understanding for how individual mutations collaborate to drive the formation of B-lineage leukemia.

  • 69.
    Olsson, Linda
    et al.
    Div Lab Med, Sweden.
    Lundin-Ström, Kristina B.
    Lund Univ, Sweden.
    Castor, Anders
    Skåne Univ Hosp, Sweden.
    Behrendtz, Mikael
    Region Östergötland, Barn- och kvinnocentrum, H.K.H. Kronprinsessan Victorias barn- och ungdomssjukhus. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för barns och kvinnors hälsa. Linköpings universitet, Medicinska fakulteten.
    Biloglav, Andrea
    Lund Univ, Sweden.
    Noren-Nyström, Ulrika
    Umeå Univ, Sweden.
    Paulsson, Kajsa
    Lund Univ, Sweden.
    Johansson, Bertil
    Div Lab Med, Sweden; Lund Univ, Sweden.
    Improved cytogenetic characterization and risk stratification of pediatric acute lymphoblastic leukemia using single nucleotide polymorphism array analysis: A single center experience of 296 cases2018Ingår i: Genes, Chromosomes and Cancer, ISSN 1045-2257, E-ISSN 1098-2264, Vol. 57, nr 11, s. 604-607Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Single nucleotide polymorphism array (SNP-A) analyses are increasingly being introduced in routine genetic diagnostics of acute lymphoblastic leukemia (ALL). Despite this, only few studies that have compared the diagnostic value of SNP-A with conventional chromosome banding have been published. We here report such a comparison of 296 ALL cases, the largest series to date. Only genomic imbalances amp;gt;5Mb and microdeletions targeting the BTG1, CDKN2A/B, EBF1, ERG, ETV6, IKZF1, PAX5, and RB1 genes and the pseudoautosomal region 1 (PAR1) were ascertained, in agreement with recent guidelines. Of 36 T-cell ALL cases, the karyotypes of 24 cases (67%) were revised by SNP-A analyses that either revealed additional imbalances amp;gt;5Mb or better characterized the changes found by G-banding. Of 260 B-cell precursor (BCP) ALL cases, SNP-A analyses identified additional copy number alterations, including the above-mentioned microdeletions, or better characterized the imbalances found by G-banding in 236 (91%) cases. Furthermore, the cytogenetic subtype classification of 41/260 (16%) BCP ALL cases was revised based on the SNP-A findings. Of the subtype revisions, 12/41 (29%) had clinical implications as regards risk stratifying cytogenetic groups or genotype-specific minimal residual disease stratification. We conclude that SNP-A analyses dramatically improve the cytogenetic characterization of both T-cell and BCP ALL and also provide important information pertinent to risk stratification of BCP ALL.

  • 70.
    Onengut-Gumuscu, Suna
    et al.
    Center for Public Health Genomics, Univ Department of Medicine, Division of Endocrinology, University of Virginia, Charlottesville, Virginia, USA.
    Chen, Wei-Min
    Center for Public Health Genomics, Department of Public Health Sciences, Division of Biostatistics and Epidemiology, University of Virginia, Charlottesville, Virginia, USA.
    Burren, Oliver
    Juvenile Diabetes Research Foundation (JDRF)/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, Cambridge Institute for Medical Research, National Institute for Health Research (NIHR) Biomedical Research Centre, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK.
    Cooper, Nick J
    Juvenile Diabetes Research Foundation (JDRF)/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, Cambridge Institute for Medical Research, National Institute for Health Research (NIHR) Biomedical Research Centre, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK.
    Quinlan, Aaron R
    Center for Public Health Genomics, Department of Public Health Sciences, Division of Biostatistics and Epidemiology, University of Virginia, Charlottesville, Virginia, USA.
    Mychaleckyj, Josyf C
    Center for Public Health Genomics, Department of Public Health Sciences, Division of Biostatistics and Epidemiology, University of Virginia, Charlottesville, Virginia, USA.
    Farber, Emily
    Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia, USA.
    Bonnie, Jessica K
    Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia, USA.
    Szpak, Michal
    Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia, USA.
    Schofield, Ellen
    Juvenile Diabetes Research Foundation (JDRF)/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, Cambridge Institute for Medical Research, National Institute for Health Research (NIHR) Biomedical Research Centre, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK.
    Achuthan, Premanand
    Juvenile Diabetes Research Foundation (JDRF)/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, Cambridge Institute for Medical Research, National Institute for Health Research (NIHR) Biomedical Research Centre, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK.
    Guo, Hui
    Juvenile Diabetes Research Foundation (JDRF)/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, Cambridge Institute for Medical Research, National Institute for Health Research (NIHR) Biomedical Research Centre, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK.
    Fortune, Mary D
    Juvenile Diabetes Research Foundation (JDRF)/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, Cambridge Institute for Medical Research, National Institute for Health Research (NIHR) Biomedical Research Centre, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK.
    Stevens, Helen
    Juvenile Diabetes Research Foundation (JDRF)/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, Cambridge Institute for Medical Research, National Institute for Health Research (NIHR) Biomedical Research Centre, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK.
    Walker, Neil M
    Juvenile Diabetes Research Foundation (JDRF)/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, Cambridge Institute for Medical Research, National Institute for Health Research (NIHR) Biomedical Research Centre, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK.
    Ward, Lucas D
    Department of Computer Science, Massachusetts Institute of Technology (MIT), Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
    Kundaje, Anshul
    Department of Computer Science, Massachusetts Institute of Technology (MIT), Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA / Department of Genetics, Stanford University, Stanford, California, USA / Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, USA.
    Kellis, Manolis
    Department of Computer Science, Massachusetts Institute of Technology (MIT), Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
    Daly, Mark J
    Broad Institute of MIT and Harvard, Cambridge, Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, USA.
    Barrett, Jeffrey C
    Wellcome Trust Sanger Institute, Hinxton, UK.
    Cooper, Jason D
    Juvenile Diabetes Research Foundation (JDRF)/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, Cambridge Institute for Medical Research, National Institute for Health Research (NIHR) Biomedical Research Centre, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK.
    Deloukas, Panos
    Wellcome Trust Sanger Institute, Hinxton, UK.
    Todd, John A
    Juvenile Diabetes Research Foundation (JDRF)/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, Cambridge Institute for Medical Research, National Institute for Health Research (NIHR) Biomedical Research Centre, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK.
    Wallace, Chris
    Juvenile Diabetes Research Foundation (JDRF)/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, Cambridge Institute for Medical Research, National Institute for Health Research (NIHR) Biomedical Research Centre, University of Cambridge, Addenbrooke's Hospital, Medical Research Council (MRC) Biostatistics Unit, Institute of Public Health, University Forvie Site, Cambridge, UK.
    Concannon, Patrick
    Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia, USA.
    Rich, Stephen S
    Center for Public Health Genomics, University of Virginia, Department of Public Health Sciences, Division of Biostatistics and Epidemiology, Charlottesville, Virginia, USA.
    Fine mapping of type 1 diabetes susceptibility loci and evidence for colocalization of causal variants with lymphoid gene enhancers.2015Ingår i: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 47, nr 4, s. 381-386Artikel i tidskrift (Refereegranskat)
    Abstract [en]

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

  • 71.
    Parenti, I.
    et al.
    University of Lubeck, Germany; University of Milan, Italy.
    Gervasini, C.
    University of Milan, Italy.
    Pozojevic, J.
    University of Lubeck, Germany.
    Wendt, K. S.
    Erasmus MC, Netherlands.
    Watrin, E.
    UMR6290 CNRS, France.
    Azzollini, J.
    University of Milan, Italy.
    Braunholz, D.
    University of Lubeck, Germany.
    Buiting, K.
    University of Dusseldorf, Germany.
    Cereda, A.
    AOS Gerardo, Italy.
    Engels, H.
    University of Bonn, Germany.
    Garavelli, L.
    IRCCS S Maria Nuova Hospital, Italy.
    Glazar, R.
    Centre Medical Genet GENESIS Poznan, Poland.
    Graffmann, B.
    Region Östergötland, Barn- och kvinnocentrum, Barn- och ungdomskliniken i Linköping.
    Larizza, L.
    IRCCS Ist Auxol Italiano, Italy.
    Luedecke, H. J.
    University of Dusseldorf, Germany.
    Mariani, M.
    AOS Gerardo, Italy.
    Masciadri, M.
    IRCCS Ist Auxol Italiano, Italy.
    Pie, J.
    University of Zaragoza, Spain; University of Zaragoza, Spain; ISS Aragon, Spain.
    Ramos, F. J.
    University of Zaragoza, Spain; University of Zaragoza, Spain; ISS Aragon, Spain; Hospital Clin University of Lozano Blesa, Spain.
    Russo, S.
    IRCCS Ist Auxol Italiano, Italy.
    Selicorni, A.
    AOS Gerardo, Italy.
    Stefanova, Margarita
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk patologi och klinisk genetik.
    Strom, T. M.
    Technical University of Munich, Germany; German Research Centre Environm Heatlh, Germany.
    Werner, R.
    University of Lubeck, Germany.
    Wierzba, J.
    Medical University of Gdansk, Poland; Medical University of Gdansk, Poland.
    Zampino, G.
    University of Cattolica Sacro Cuore, Italy.
    Gillessen-Kaesbach, G.
    University of Lubeck, Germany.
    Wieczorek, D.
    University of Dusseldorf, Germany.
    Kaiser, F. J.
    University of Lubeck, Germany.
    Expanding the clinical spectrum of the "HDAC8-phenotype - implications for molecular diagnostics, counseling and risk prediction2016Ingår i: Clinical Genetics, ISSN 0009-9163, E-ISSN 1399-0004, Vol. 89, nr 5, s. 564-573Artikel i tidskrift (Refereegranskat)
    Abstract [en]

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

  • 72.
    Paulsson, Johan O.
    et al.
    Karolinska University Hospital, Sweden.
    Svahn, F.
    Karolinska University Hospital, Sweden.
    Welander, Jenny
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Brunaud, L.
    University of Lorraine, France.
    Söderkvist, Peter
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk patologi och klinisk genetik.
    Gimm, Oliver
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Kirurgiska kliniken US.
    Stenman, A.
    Karolinska University Hospital, Sweden.
    Juhlin, C. C.
    Karolinska University Hospital, Sweden.
    Editorial Material: Absence of the BRAF V600E mutation in pheochromocytoma in JOURNAL OF ENDOCRINOLOGICAL INVESTIGATION, vol 39, issue 6, pp 715-7162016Ingår i: Journal of Endocrinological Investigation, ISSN 0391-4097, E-ISSN 1720-8386, Vol. 39, nr 6, s. 715-716Artikel i tidskrift (Övrigt vetenskapligt)
    Abstract [en]

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

  • 73.
    Pestoff, Rebecka
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk genetik.
    Moldovan, R.
    Babes Bolyai Univ, Romania.
    Cordier, C.
    Synlab Genet, Switzerland.
    Serra-Juhe, C.
    Univ Pompeu Fabra Hosp Mar Res Inst IMIM, Spain; Inst Salud Carlos III, Spain.
    Paneque, M.
    Univ Porto, Portugal; Univ Porto, Portugal.
    Ingvoldstad, C. M.
    Uppsala Univ, Sweden; Karolinska Inst, Sweden; Uppsala Univ, Sweden.
    How practical experiences, educational routes and multidisciplinary teams influence genetic counselors clinical practice in Europe2018Ingår i: Clinical Genetics, ISSN 0009-9163, E-ISSN 1399-0004, Vol. 93, nr 4, s. 891-898Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The main objective of our study was to explore whether, and to what extent, genetic counselors characteristics impact on their tasks in practice. Specifically, we explored the complementariness between genetic counselors and medical geneticists and therefore looked at the most relevant tasks of genetic counselors, according to genetic counselors themselves and according to the medical geneticists they work with. A total of 104 genetic counselors and 29 medical geneticists from 15 countries completed a purposefully designed questionnaire. Results showed that most genetic counselors in Europe perform similar tasks, irrespective of their backgrounds. When looking at the factors influencing genetic counselors roles data showed that the type of tasks performed by genetic counselors is associated with the years of experience in the field, not with their background or education. Of particular interest was the consensus between genetic counselors and medical geneticists regarding the genetic counselors role. Not surprisingly, tasks with more psychosocial implications were seen as genetic counselors eligibility while tasks with more medical implications were seen as medical geneticists attribution. Our study shows that most genetic counselors work in tune with international recommendations and seem to be supportive of multidisciplinary teams. Corroborating our data with previous research, we discuss potential implications for practice and training in genetic counseling.

  • 74.
    Petaros, Anja
    et al.
    National Board Forens Med, Department Forens Med, Artillerigatan 12, S-58758 Linkoping, Sweden; Rijeka University, Croatia.
    Garvi, Heather M.
    Mercyhurst University, PA 16546 USA; Des Moines University, IA 50312 USA.
    Sholts, Sabrina B.
    Smithsonian Institute, DC 20560 USA.
    Schlager, Stefan
    University of Freiburg, Germany.
    Wärmländer, Sebastian
    Linköpings universitet, Institutionen för ekonomisk och industriell utveckling, Affärsrätt. Linköpings universitet, Filosofiska fakulteten. UCLA, CA USA; Stockholm University, Sweden.
    Sexual dimorphism and regional variation in human frontal bone inclination measured via digital 3D models2017Ingår i: Legal Medicine, ISSN 1344-6223, E-ISSN 1873-4162, Vol. 29, s. 53-61Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The frontal bone is one of the most sexually dimorphic elements of the human skull, due to features such as the glabella, frontal eminences, and frontal inclination. While glabella is frequently evaluated in procedures to estimate sex in unknown human skeletal remains, frontal inclination has received less attention. In this study we present a straightforward, quick, and reproducible method for measuring frontal inclination angles from glabella and supraglabella. Using a sample of 413 human crania from four different populations (U.S. Whites, U.S. Blacks, Portuguese, and Chinese), we test the usefulness of the inclination angles for sex estimation and compare their performance to traditional methods of frontal inclination assessment. Accuracy rates in the range 75-81% were achieved for the U.S. White, U.S. Black, and Portuguese groups. For Chinese the overall accuracy was lower, i.e. 66%. Although some regional variation was observed, a cut-off value of 78.2 for glabellar inclination angles separates female and male crania from all studied populations with good accuracy. As inclination angles measured from glabella captures two sexually dimorphic features (i.e. glabellar prominence and frontal inclination) in a single measure, the observed clear male/female difference is not unexpected. Being continuous variables, inclination angles are suitable for use in statistical methods for sex estimations.

  • 75.
    Ran, Caroline
    et al.
    Karolinska Institute, Sweden.
    Brodin, Lovisa
    Karolinska University Hospital, Sweden.
    Forsgren, Lars
    Umeå University, Sweden.
    Westerlund, Marie
    Karolinska Institute, Sweden.
    Ramezani, Mehrafarin
    Karolinska Institute, Sweden.
    Gellhaar, Sandra
    Karolinska Institute, Sweden.
    Xiang, Fengqing
    Karolinska University Hospital, Sweden.
    Fardell, Camilla
    University of Gothenburg, Sweden.
    Nissbrandt, Hans
    University of Gothenburg, Sweden.
    Söderkvist, Peter
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk patologi och klinisk genetik.
    Puschmann, Andreas
    Skåne University Hospital, Sweden; Lund University, Sweden.
    Ygland, Emil
    Lund University, Sweden.
    Olson, Lars
    Karolinska Institute, Sweden.
    Willows, Thomas
    Karolinska University Hospital, Sweden.
    Johansson, Anders
    Karolinska University Hospital, Sweden.
    Sydow, Olof
    Karolinska University Hospital, Sweden.
    Wirdefeldt, Karin
    Karolinska University Hospital, Sweden; Karolinska Institute, Sweden.
    Galter, Dagmar
    Karolinska Institute, Sweden.
    Svenningsson, Per
    Karolinska University Hospital, Sweden.
    Carmine Belin, Andrea
    Karolinska Institute, Sweden.
    Strong association between glucocerebrosidase mutations and Parkinsons disease in Sweden2016Ingår i: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 45, nr 212.e5Artikel i tidskrift (Refereegranskat)
    Abstract [en]

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

  • 76.
    Sahlin, Ellika
    et al.
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Gréen, Anna
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Gustavsson, Peter
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Lieden, Agne
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Nordenskjold, Magnus
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Papadogiannakis, Nikos
    Karolinska Univ Hosp, Sweden; Karolinska Inst, Sweden.
    Pettersson, Karin
    Karolinska Univ Hosp, Sweden; Karolinska Inst, Sweden.
    Nilsson, Daniel
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Jonasson, Jon
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk patologi och klinisk genetik.
    Iwarsson, Erik
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Identification of putative pathogenic single nucleotide variants (SNVs) in genes associated with heart disease in 290 cases of stillbirth2019Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 14, nr 1, artikel-id e0210017Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The incidence of stillbirth in Sweden has essentially remained constant since the 1980s, and despite thorough investigation, many cases remain unexplained. It has been suggested that a proportion of stillbirth cases is caused by heart disease, mainly channelopathies. The aim of this study was to analyze DNA from 290 stillbirth cases without chromosomal abnormalities for pathogenic single nucleotide variants (SNVs) in 70 genes associated with cardiac channelopathies and cardiomyopathies. The HaloPlex Target Enrichment System (Agilent Technologies) was utilized to prepare sequencing libraries which were sequenced on the Illumina NextSeq platform. We found that 12.1% of the 290 investigated stillbirth cases had one (n = 31) or two (n = 4) variants with evidence supporting pathogenicity, i.e. loss-of-function variants (nonsense, frameshift, splice site substitutions), evidence from functional studies, or previous identification of the variants in affected individuals. Regarding identified putative pathogenic variants in genes associated with channelopathies, the prevalence was significantly higher in the stillbirth cohort (n = 23, 7.93%) than the corresponding prevalence of the same variants in the non-Finnish European population of the Exome Aggregation Consortium (2.70%, pamp;lt;0.001) and SweGen, (2.30%, pamp;lt;0.001). Our results give further support to the hypothesis that cardiac channelopathies might contribute to stillbirth. Screening for pathogenic SNVs in genes associated with heart disease might be a valuable complement for stillbirth cases where todays conventional investigation does not reveal the underlying cause of fetal demise.

  • 77.
    Sandestig, Anna
    et al.
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Engström, Karolina
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Pepler, Alexander
    CeGaT GmbH, Germany; Praxis Humangenet, Germany.
    Danielsson, Ingela
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Medicinska fakulteten.
    Odelberg-Johnson, Per
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för barns och kvinnors hälsa. Linköpings universitet, Medicinska fakulteten.
    Biskup, Saskia
    CeGaT GmbH, Germany; Praxis Humangenet, Germany.
    Holz, Anja
    CeGaT GmbH, Germany; Praxis Humangenet, Germany.
    Stefanova, Margarita
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk genetik.
    NUP188 Biallelic Loss of Function May Underlie a New Syndrome: Nucleoporin 188 Insufficiency Syndrome?2020Ingår i: Molecular Syndromology, ISSN 1661-8769, E-ISSN 1661-8777, Vol. 10, nr 6, s. 313-319Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    There is no clearly established association between the gene NUP188 and human pathology. Only a few reports of patients with different clinical presentation and different heterozygous or compound heterozygous missense or splice region variants have been identified in several sequencing projects; however, a causative association between the clinical features and the identified variants has not been established. For the first time, we report 2 unrelated patients with 2 different homozygous nonsense gene variants of NUP188, p.Tyr96* and p.Gln113*, respectively. Although having different supposedly truncating mutations, the patients presented with strikingly comparable phenotypes including pre- and postnatal microcephaly, trigonocephaly, congenital bilateral cataract, microphthalmia, cleft lip and palate or high-arched palate, camptodactyly, rocker-bottom feet, heart anomalies, specific brain changes (such as loss of periventricular white matter), thin corpus callosum, and delayed myelinization. Both patients showed very similar facial features such as laterally extended arched eyebrows, wide convex nose with a wide prominent nasal bridge, and prominent angulated antihelix. They were both born small for gestational age and died shortly after birth at the age of 67 and 140 days, respectively, as a result of central respiratory failure. Our findings strongly suggest a correlation between the homozygous nonsense gene variants of NUP188 and a severe phenotype of a new developmental syndrome with poor prognosis resulting from nucleoporin 188 homolog protein insufficiency.

  • 78.
    Sandestig, Anna
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk genetik.
    Gréen, Anna
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk genetik.
    Aronsson, Johan
    Ryhov Cty Hosp, Sweden.
    Ellnebo-Svedlund, Katarina
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk genetik.
    Stefanova, Margarita
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk genetik.
    A Novel DLG3 Mutation Expanding the Phenotype of X-Linked Intellectual Disability Caused by DLG3 Nonsense Variants2019Ingår i: Molecular Syndromology, ISSN 1661-8769, E-ISSN 1661-8777, Vol. 10, nr 5, s. 281-285Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The DLG3 gene is located at Xq13.1 and encodes SAP102, a member of the MAGUK protein family, extensively expressed in the brain and involved in synaptic function. Mutations in DLG3 are associated with a rare nonsyndromic form of X-linked intellectual disability (XLID) and have been described in 11 families to date. All affected males presented with intellectual disability, and some showed additional clinical features. The majority of female carriers were reported asymptomatic or mildly affected, due to skewed X-inactivation, rarely severely affected. We report a family, a boy and his mother, with a novel nonsense mutation in the DLG3 gene, c.1720Camp;gt;T; p.Arg574*. The boy, hemizygous for the variant, showed intellectual disability, short stature due to growth hormone deficiency, dysmorphic features, and pectus excavatum. The mother, who presented with learning disabilities and borderline cognitive development, is a heterozygous carrier of the variant, which had arisen de novo. X-inactivation test was noninformative. This case report broadens the phenotypic spectrum of XLID caused by DLG3 nonsense variants. The dysmorphic features of the affected males may be more frequent than previously thought.

  • 79.
    Sandestig, Anna
    et al.
    Region Östergötland, Diagnostikcentrum, Klinisk genetik.
    Gréen, Anna
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk genetik.
    Jonasson, Jon
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk genetik.
    Vogt, Hartmut
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för barns och kvinnors hälsa. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Barn- och kvinnocentrum, H.K.H. Kronprinsessan Victorias barn- och ungdomssjukhus.
    Wahlström, Johan
    Region Östergötland, Barn- och kvinnocentrum, H.K.H. Kronprinsessan Victorias barn- och ungdomssjukhus.
    Pepler, Alexander
    Department of CeGaT GmbH, Tübingen, Germany.
    Ellnebo, Katarina
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk genetik.
    Biskup, Saskia
    Department of CeGaT GmbH, Tübingen, Germany.
    Stefanova, Margarita
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk genetik.
    Could Dissimilar Phenotypic Effects of ACTB Missense Mutations Reflect the Actin Conformational Change?: Two Novel Mutations and Literature Review2019Ingår i: Molecular Syndromology, ISSN 1661-8769, E-ISSN 1661-8777, Vol. 9, nr 5, s. 259-265Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The beta-actin gene encodes 1 of 6 different actin proteins. De novo heterozygous missense mutations in ACTB have been identified in patients with Baraitser-Winter syndrome (BRWS) and also in patients with developmental disorders other than BRWS, such as deafness, dystonia, and neutrophil dysfunction. We describe 2 different novel de novo missense ACTB mutations, c.208Camp;gt;G (p.Pro70Ala) and c.511Camp;gt;T (p.Leu171Phe), found by trio exome sequencing analysis of 2 unrelated patients: an 8-year-old boy with a suspected BRWS and a 4-year-old girl with unclear developmental disorder. The mutated residue in the first case is situated in the actin H-loop, which is involved in actin polymerization. The mutated residue in the second case (p.Leu171Phe) is found at the actin barbed end in the W-loop, important for binding to profilin and other actin-binding molecules. While the boy presented with a typical BRWS facial appearance, the girl showed facial features not recognizable as a BRWS gestalt as well as ventricular arrhythmia, cleft palate, thrombocytopenia, and gray matter heterotopia. We reviewed previously published ACTB missense mutations and ascertained that a number of them do not cause typical BRWS. By comparing clinical and molecular data, we speculate that the phenotypic differences found in ACTB missense mutation carriers might supposedly be dependent on the conformational change of ACTB.

  • 80.
    Sandin, Linnea
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Bergkvist, Liza
    Linköpings universitet, Tekniska fakulteten. Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi.
    Nath, Sangeeta
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Kielkopf, Claudia
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Janefjord, Camilla
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten.
    Helmfors, Linda
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska fakulteten.
    Zetterberg, Henrik
    Clinical Neurochemistry Laboratory, Department of Neuroscience and Physiology, Sahlgrenska University Hospital, Mölndal, Sweden / UCL Institute of Neurology, London, UK.
    Blennow, Kaj
    Clinical Neurochemistry Laboratory, Department of Neuroscience and Physiology, Sahlgrenska University Hospital, Mölndal, Sweden.
    Li, Hongyun
    Illawarra Health and Medical Research Institute, University of Wollongong, Australia.
    Nilsberth, Camilla
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Närsjukvården i centrala Östergötland, Medicinska och geriatriska akutkliniken.
    Garner, Brett
    Illawarra Health and Medical Research Institute, University of Wollongong, Australia / School of Biological Sciences, University of Wollongong, Australia.
    Brorsson, Ann-Christin
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska fakulteten.
    Kågedal, Katarina
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Beneficial effects of increased lysozyme levels in Alzheimer’s disease modelled in Drosophila melanogaster2016Ingår i: The FEBS Journal, ISSN 1742-464X, E-ISSN 1742-4658, Vol. 283, nr 19, s. 3508-3522Artikel i tidskrift (Refereegranskat)
    Abstract [en]

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

  • 81.
    Smol, T.
    et al.
    CHU Lille, France; Univ Lille, France.
    Petit, F.
    Univ Lille, France; CHU Lille, France.
    Piton, A.
    Hop Univ Strasbourg, France.
    Keren, B.
    Grp Hosp Pitie Salpetriere, France.
    Sanlaville, D.
    Hosp Civils Lyon, France.
    Afenjar, A.
    Hop Enfants Armand Trousseau, France.
    Baker, S.
    Childrens Hosp Philadelphia, PA 19104 USA.
    Bedoukian, E. C.
    Childrens Hosp Philadelphia, PA 19104 USA.
    Bhoj, E. J.
    Childrens Hosp Philadelphia, PA 19104 USA.
    Bonneau, D.
    CHU Angers, France.
    Boudry-Labis, E.
    CHU Lille, France.
    Bouquillon, S.
    CHU Lille, France.
    Boute-Benejean, O.
    Univ Lille, France; CHU Lille, France.
    Caumes, R.
    CHU Lille, France.
    Chatron, N.
    Hosp Civils Lyon, France.
    Colson, C.
    Univ Lille, France; CHU Lille, France.
    Coubes, C.
    CHU Montpellier, France.
    Coutton, C.
    CHU Grenoble Alpes, France.
    Devillard, F.
    CHU Grenoble Alpes, France.
    Dieux-Coeslier, A.
    Univ Lille, France; CHU Lille, France.
    Doco-Fenzy, M.
    CHU Reims, France.
    Ewans, L. J.
    Univ New South Wales, Australia.
    Faivre, L.
    CHU Dijon, France; CHU Dijon, France; Univ Bourgogne, France.
    Fassi, E.
    Washington Univ, MO 63110 USA.
    Field, M.
    Genet Learning Disabil Serv, Australia.
    Fournier, C.
    Hop Univ Strasbourg, France.
    Francannet, C.
    CHU Clermont Fernand, France.
    Genevieve, D.
    CHU Montpellier, France.
    Giurgea, I.
    Hop Trousseau, France.
    Goldenberg, A.
    CHU Rouen, France; CHU Rouen, France; Univ Rouen, France.
    Gréen, Anna
    Region Östergötland, Diagnostikcentrum, Klinisk genetik. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Guerrot, A. M.
    CHU Rouen, France; Univ Rouen, France.
    Heron, D.
    Grp Hosp Pitie Salpetriere, France.
    Isidor, B.
    CHU Nantes, France.
    Keena, B. A.
    Childrens Hosp Philadelphia, PA 19104 USA.
    Krock, B. L.
    Childrens Hosp Philadelphia, PA 19104 USA.
    Kuentz, P.
    Univ Bourgogne, France.
    Lapi, E.
    Anna Meyer Childrens Univ Hosp, Italy.
    Le Meur, N.
    CHU Rouen, France; Univ Rouen, France.
    Lesca, G.
    Hosp Civils Lyon, France.
    Li, D.
    Childrens Hosp Philadelphia, PA 19104 USA.
    Marey, I.
    Grp Hosp Pitie Salpetriere, France.
    Mignot, C.
    Grp Hosp Pitie Salpetriere, France.
    Nava, C.
    Grp Hosp Pitie Salpetriere, France.
    Nesbitt, A.
    Childrens Hosp Philadelphia, PA 19104 USA.
    Nicolas, G.
    CHU Rouen, France; Univ Rouen, France.
    Roche-Lestienne, C.
    CHU Lille, France.
    Roscioli, T.
    Univ New South Wales, Australia.
    Satre, V.
    CHU Grenoble Alpes, Grenoble, France.
    Santani, A.
    Childrens Hosp Philadelphia, PA 19104 USA.
    Stefanova, Margarita
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk genetik.
    Steinwall Larsen, S.
    Region Östergötland, Diagnostikcentrum, Klinisk genetik.
    Saugier-Veber, P.
    CHU Rouen, France; Univ Rouen, France.
    Picker-Minh, S.
    Charite Univ Med Berlin, Germany.
    Thuillier, C.
    CHU Lille, France.
    Verloes, A.
    Hop Robert Debre, France.
    Vieville, G.
    CHU Grenoble Alpes, France.
    Wenzel, M.
    Clinical Genetics, Children’s Hospital of Philadelphia, Philadelphia, PA, USA.
    Willems, M.
    CHU Montpellier, France.
    Whalen, S.
    Grp Hosp Pitie Salpetriere, France.
    Zarate, Y. A.
    Univ Arkansas Med Sci, AR 72205 USA.
    Ziegler, A.
    CHU Angers, France.
    Manouvrier-Hanu, S.
    Univ Lille, France; CHU Lille, France.
    Kalscheuer, V. M.
    Max Planck Inst Mol Genet, Germany.
    Gerard, B.
    Hop Univ Strasbourg, France.
    Ghoumid, Jamal
    Univ Lille, France; CHU Lille, France.
    MED13L-related intellectual disability: involvement of missense variants and delineation of the phenotype2018Ingår i: Neurogenetics, ISSN 1364-6745, E-ISSN 1364-6753, Vol. 19, nr 2, s. 93-103Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Molecular anomalies in MED13L, leading to haploinsufficiency, have been reported in patients with moderate to severe intellectual disability (ID) and distinct facial features, with or without congenital heart defects. Phenotype of the patients was referred to "MED13L haploinsufficiency syndrome." Missense variants in MED13L were already previously described to cause the MED13L-related syndrome, but only in a limited number of patients. Here we report 36 patients with MED13L molecular anomaly, recruited through an international collaboration between centers of expertise for developmental anomalies. All patients presented with intellectual disability and severe language impairment. Hypotonia, ataxia, and recognizable facial gestalt were frequent findings, but not congenital heart defects. We identified seven de novo missense variations, in addition to protein-truncating variants and intragenic deletions. Missense variants clustered in two mutation hot-spots, i.e., exons 15-17 and 25-31. We found that patients carrying missense mutations had more frequently epilepsy and showed a more severe phenotype. This study ascertains missense variations in MED13L as a cause for MED13L-related intellectual disability and improves the clinical delineation of the condition.

  • 82.
    Steensma, Kristy
    et al.
    Netherlands Forens Institute, Netherlands.
    Ansell, Ricky
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Biologi. Linköpings universitet, Tekniska fakulteten. Swedish National Forens Centre, SE-58194 Linkoping, Sweden.
    Clarisse, Lindy
    Netherlands Forens Institute, Netherlands.
    Connolly, Edward
    Forens Science Ireland, Ireland.
    Kloosterman, Ate D.
    Netherlands Forens Institute, Netherlands; University of Amsterdam, Netherlands.
    McKenna, Louise G.
    Forens Science Ireland, Ireland.
    van Oorschot, Roland A. H.
    Victoria Police Forens Serv Department, Australia.
    Szkuta, Bianca
    Victoria Police Forens Serv Department, Australia; Deakin University, Australia.
    Kokshoorn, Bas
    Netherlands Forens Institute, Netherlands.
    An inter-laboratory comparison study on transfer, persistence and recovery of DNA from cable ties2017Ingår i: Forensic Science International: Genetics, ISSN 1872-4973, E-ISSN 1878-0326, Vol. 31, s. 95-104Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    To address questions on the activity that led to the deposition of biological traces in a particular case, general information on the probabilities of transfer, persistence and recovery of cellular material in relevant scenarios is necessary. These figures may be derived from experimental data described in forensic literature when conditions relevant to the case were included. The experimental methodology regarding sampling, DNA extraction, DNA typing and profile interpretation that were used to generate these published data may differ from those applied in the case and thus the applicability of the literature data may be questioned. To assess the level of variability that different laboratories obtain when similar exhibits are analysed, we performed an inter-laboratory study between four partner laboratories. Five sets of 20 cable ties bound by different volunteers were distributed to the participating laboratories and sampled and processed according to the in-house protocols. Differences were found for the amount of retrieved DNA, as well as for the reportability and composition of the DNA profiles. These differences also resulted in different probabilities of transfer, persistence and recovery for each laboratory. Nevertheless, when applied to a case example, these differences resulted in similar assignments of weight of evidence given activity-level propositions.

  • 83.
    Tillmar, Andreas
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Medicinska fakulteten. National Board Forens Med, Department Forens Genet and Forens Toxicol, Artillerigatan 12, SE-58758 Linkoping, Sweden.
    Kling, Daniel
    Oslo University Hospital, Norway.
    Butler, John M.
    NIST, MD 20899 USA.
    Parson, Walther
    Medical University of Innsbruck, Austria; Penn State University, PA 16802 USA.
    Prinz, Mechthild
    John Jay Coll Criminal Justice, NY USA.
    Schneider, Peter M.
    University of Cologne, Germany.
    Egeland, Thore
    Norwegian University of Life Science, Norway.
    Gusmao, Leonor
    State University of Rio de Janeiro UERJ, Brazil.
    DNA Commission of the International Society for Forensic Genetics ( ISFG): Guidelines on the use of X-STRs in kinship analysis2017Ingår i: Forensic Science International: Genetics, ISSN 1872-4973, E-ISSN 1878-0326, Vol. 29, s. 269-275Artikel i tidskrift (Refereegranskat)
    Abstract [en]

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

  • 84.
    Tsoi, Lam C.
    et al.
    University of Michigan, MI 48109 USA; University of Michigan, MI 48109 USA; University of Michigan, MI 48109 USA.
    Stuart, Philip E.
    University of Michigan, MI 48109 USA.
    Tian, Chao
    23andMe Inc, CA 94041 USA.
    Gudjonsson, Johann E.
    University of Michigan, MI 48109 USA.
    Das, Sayantan
    University of Michigan, MI 48109 USA.
    Zawistowski, Matthew
    University of Michigan, MI 48109 USA.
    Ellinghaus, Eva
    Christian Albrechts University of Kiel, Germany.
    Barker, Jonathan N.
    Kings Coll London, England.
    Chandran, Vinod
    University of Toronto, Canada; University of Toronto, Canada.
    Dand, Nick
    Kings Coll London, England.
    Callis Duffin, Kristina
    University of Utah, UT 84132 USA.
    Enerbäck, Charlotta
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Hjärt- och Medicincentrum, Hudkliniken i Östergötland.
    Esko, Tonu
    University of Tartu, Estonia; Broad Institute MIT and Harvard, MA 02142 USA.
    Franke, Andre
    Christian Albrechts University of Kiel, Germany.
    Gladman, Dafna D.
    University of Toronto, Canada; University of Toronto, Canada.
    Hoffmann, Per
    University of Bonn, Germany; University of Basel, Switzerland.
    Kingo, Kulli
    University of Tartu, Estonia.
    Koks, Sulev
    University of Tartu, Estonia; University of Tartu, Estonia; Estonian University of Life Science, Estonia.
    Krueger, Gerald G.
    University of Utah, UT 84132 USA.
    Lim, Henry W.
    Henry Ford Hospital, MI 48202 USA.
    Metspalu, Andres
    University of Tartu, Estonia.
    Mrowietz, Ulrich
    University of Medical Centre Schleswig Holstein, Germany.
    Mucha, Soren
    Christian Albrechts University of Kiel, Germany.
    Rahman, Proton
    Mem University, Canada.
    Reis, Andre
    FAU Erlangen Nurnberg, Germany.
    Tejasvi, Trilokraj
    University of Michigan, MI 48109 USA; Ann Arbor Vet Affairs Hospital, MI 48105 USA.
    Trembath, Richard
    Kings Coll London, England.
    Voorhees, John J.
    University of Michigan, MI 48109 USA.
    Weidinger, Stephan
    University of Medical Centre Schleswig Holstein, Germany.
    Weichenthal, Michael
    University of Medical Centre Schleswig Holstein, Germany.
    Wen, Xiaoquan
    University of Michigan, MI 48109 USA.
    Eriksson, Nicholas
    23andMe Inc, CA 94041 USA.
    Kang, Hyun M.
    University of Michigan, MI 48109 USA.
    Hinds, David A.
    23andMe Inc, CA 94041 USA.
    Nair, Rajan P.
    University of Michigan, MI 48109 USA.
    Abecasis, Goncalo R.
    University of Michigan, MI 48109 USA.
    Elder, James T.
    University of Michigan, MI 48109 USA; Ann Arbor Vet Affairs Hospital, MI 48105 USA.
    Large scale meta-analysis characterizes genetic architecture for common psoriasis associated variants2017Ingår i: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 8, artikel-id 15382Artikel i tidskrift (Refereegranskat)
    Abstract [en]

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

  • 85.
    van Thuijl, Hinke F.
    et al.
    University of Calif San Francisco, CA 94143 USA; Vrije University of Amsterdam Medical Centre, Netherlands; Vrije University of Amsterdam Medical Centre, Netherlands.
    Mazor, Tali
    University of Calif San Francisco, CA 94143 USA.
    Johnson, Brett E.
    University of Calif San Francisco, CA 94143 USA.
    Fouse, Shaun D.
    University of Calif San Francisco, CA 94143 USA.
    Aihara, Koki
    University of Tokyo, Japan; University of Tokyo, Japan.
    Hong, Chibo
    University of Calif San Francisco, CA 94143 USA.
    Malmström, Annika
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Närsjukvården i centrala Östergötland, LAH Linköping.
    Hallbeck, Martin
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk patologi och klinisk genetik.
    Heimans, Jan J.
    Vrije University of Amsterdam Medical Centre, Netherlands.
    Kloezeman, Jenneke J.
    Erasmus MC, Netherlands.
    Stenmark Askmalm, Marie
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Hälsouniversitetet. Region Östergötland, Diagnostikcentrum, Klinisk patologi och klinisk genetik.
    Lamfers, Martine L. M.
    Erasmus MC, Netherlands.
    Saito, Nobuhito
    University of Tokyo, Japan.
    Aburatani, Hiroyuki
    University of Tokyo, Japan.
    Mukasa, Akitake
    University of Tokyo, Japan.
    Berger, Mitchell S.
    University of Calif San Francisco, CA 94143 USA.
    Söderkvist, Peter
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet. Region Östergötland, Diagnostikcentrum, Klinisk patologi och klinisk genetik.
    Taylor, Barry S.
    Mem Sloan Kettering Cancer Centre, NY 10021 USA; Mem Sloan Kettering Cancer Centre, NY 10021 USA.
    Molinaro, Annette M.
    University of Calif San Francisco, CA 94143 USA; University of Calif San Francisco, CA 94143 USA.
    Wesseling, Pieter
    Vrije University of Amsterdam Medical Centre, Netherlands; Radboud University of Nijmegen, Netherlands.
    Reijneveld, Jaap C.
    Vrije University of Amsterdam Medical Centre, Netherlands; University of Amsterdam, Netherlands.
    Chang, Susan M.
    University of Calif San Francisco, CA 94143 USA.
    Ylstra, Bauke
    Vrije University of Amsterdam Medical Centre, Netherlands.
    Costello, Joseph F.
    University of Calif San Francisco, CA 94143 USA.
    Evolution of DNA repair defects during malignant progression of low-grade gliomas after temozolomide treatment2015Ingår i: Acta Neuropathologica, ISSN 0001-6322, E-ISSN 1432-0533, Vol. 129, nr 4, s. 597-607Artikel i tidskrift (Refereegranskat)
    Abstract [en]

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

  • 86.
    Verma, Deepti
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    Genetic variations in the NALP3 inflammasome: a susceptibility factor for inflammatory diseases2009Licentiatavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

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

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

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

    Delarbeten
    1. Gene polymorphisms in the NALP3 inflammasome are associated with interleukin-1 production and severe inflammation: Relation to Common Inflammatory Diseases?
    Öppna denna publikation i ny flik eller fönster >>Gene polymorphisms in the NALP3 inflammasome are associated with interleukin-1 production and severe inflammation: Relation to Common Inflammatory Diseases?
    Visa övriga...
    2008 (Engelska)Ingår i: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 58, nr 3, s. 888-894Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

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

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

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

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

    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:liu:diva-19048 (URN)10.1002/art.23286 (DOI)
    Tillgänglig från: 2009-06-11 Skapad: 2009-06-09 Senast uppdaterad: 2017-12-13Bibliografiskt granskad
    2. Genetic variation in proteins of the cryopyrin inflammasome influences susceptibility and severity of rheumatoid arthritis (the Swedish TIRA project)
    Öppna denna publikation i ny flik eller fönster >>Genetic variation in proteins of the cryopyrin inflammasome influences susceptibility and severity of rheumatoid arthritis (the Swedish TIRA project)
    Visa övriga...
    2008 (Engelska)Ingår i: Rheumatology, ISSN 1462-0324, Vol. 47, nr 4, s. 415-417Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

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

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

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

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

    Nyckelord
    Disease course, Genetics, Inflammasome, Rheumatoid arthritis
    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:liu:diva-14380 (URN)10.1093/rheumatology/kem372 (DOI)
    Tillgänglig från: 2007-04-20 Skapad: 2007-04-20 Senast uppdaterad: 2015-08-31Bibliografiskt granskad
  • 87.
    Vihola, Anna
    et al.
    Univ Helsinki, Finland.
    Palmio, Johanna
    Tampere Univ, Finland; Univ Hosp Tampere, Finland.
    Danielsson, Olof
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Närsjukvården i centrala Östergötland, Neurologiska kliniken i Linköping.
    Penttila, Sini
    Univ Hosp Tampere, Finland; Tampere Univ, Finland.
    Louiselle, Daniel
    Washington Univ, MO 63110 USA.
    Pittman, Sara
    Washington Univ, MO 63110 USA.
    Weihl, Conrad
    Washington Univ, MO 63110 USA.
    Udd, Bjarne
    Univ Helsinki, Finland; Univ Helsinki, Finland; Tampere Univ, Finland; Univ Hosp Tampere, Finland; Vaasa Cent Hosp, Finland.
    Novel mutation in TNPO3 causes congenital limb-girdle myopathy with slow progression2019Ingår i: NEUROLOGY-GENETICS, ISSN 2376-7839, Vol. 5, nr 3, artikel-id UNSP e337Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Objective We report a second family with autosomal dominant transportinopathy presenting with congenital or early-onset myopathy and slow progression, causing proximal and less pronounced distal muscle weakness. Methods Patients had clinical examinations, muscle MRI, EMG, and muscle biopsy studies. The MYOcap gene panel was used to identify the gene defect in the family. Muscle biopsies were used for histopathologic and protein expression studies, and TNPO3 constructs were used to study the effect of the mutations in transfected cells. Results We identified a novel heterozygous mutation, c.2757delC, in the last part of the transportin-3 (TNPO3) gene in the affected family members. The mutation causes an almost identical frameshift affecting the stop codon and elongating the C-term protein product of the TNPO3 transcript, as was previously reported in the first large Spanish-Italian LGMD1F kindred. TNPO3 protein was increased in the patient muscle and accumulated in the subsarcolemmal and perinuclear areas. At least one of the cargo proteins, the splicing factor SRRM2 was normally located in the nucleus. Transiently transfected mutant TNPO3 constructs failed to localize to cytoplasmic annulate lamellae pore complexes in cells. Conclusions We report the clinical, molecular genetic, and histopathologic features of the second transportinopathy family. The variability of the clinical phenotype together with histopathologic findings suggests that several molecular pathways may be involved in the disease pathomechanism, such as nucleocytoplasmic shuttling, protein aggregation, and defective protein turnover.

  • 88.
    von Otter, Malin
    et al.
    University of Gothenburg, Sweden.
    Bergström, Petra
    University of Gothenburg, Sweden.
    Quattrone, Aldo
    Magna Graecia University of Catanzaro, Italy; CNR, Italy.
    Valeria De Marco, Elvira
    CNR, Italy.
    Annesi, Grazia
    CNR, Italy.
    Söderkvist, Peter
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk patologi och klinisk genetik.
    Bezzina Wettinger, Stephanie
    University of Malta, Malta.
    Drozdzik, Marek
    Pomeranian Medical University, Poland.
    Bialecka, Monika
    Pomeranian Medical University, Poland.
    Nissbrandt, Hans
    University of Gothenburg, Sweden.
    Klein, Christine
    Medical University of Lubeck, Germany.
    Nilsson, Michael
    University of Gothenburg, Sweden; University of Newcastle, Australia.
    Hammarsten, Ola
    University of Gothenburg, Sweden.
    Nilsson, Staffan
    Chalmers, Sweden.
    Zetterberg, Henrik
    University of Gothenburg, Sweden; UCL Institute Neurol, England.
    Genetic associations of Nrf2-encoding NFE2L2 variants with Parkinson s disease a multicenter study2014Ingår i: BMC Medical Genetics, ISSN 1471-2350, E-ISSN 1471-2350, Vol. 15, nr 131Artikel i tidskrift (Refereegranskat)
    Abstract [en]

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

  • 89.
    Ward, Liam
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för barns och kvinnors hälsa. Linköpings universitet, Medicinska fakulteten.
    Olausson, Patrik
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för samhällsmedicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Sinnescentrum, Smärt och rehabiliteringscentrum.
    Li, Wei
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för barns och kvinnors hälsa. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Barn- och kvinnocentrum, Kvinnokliniken i Linköping.
    Yuan, Ximing
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Hjärt- och Medicincentrum, Arbets- och miljömedicin.
    Proteomics and multivariate modelling reveal sex-specific alterations in distinct regions of human carotid atheroma2018Ingår i: Biology of Sex Differences, ISSN 2042-6410, Vol. 9, artikel-id 54Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BackgroundAtherosclerotic lesions are comprised of distinct regions with different proteomic profiles. Men and women develop differences in lesion phenotype, with lesions from women generally being more stable and less prone to rupture. We aimed to investigate the differences in proteomic profiles between sexes, including distinct lesion regions, to identify altered proteins that contribute to these differences observed clinically.MethodsCarotid endarterectomy samples (ten men/ten women) were obtained, and intraplaque biopsies from three distinct regions (internal control, fatty streak and plaque) were analysed by tandem-mass spectrometry. Multivariate statistical modelling, using orthogonal partial least square-discriminant analysis, was used to discriminate the proteomes between men and women.ResultsMultivariate discriminant modelling revealed proteins from 16 functional groups that displayed sex-specific associations. Additional statistics revealed ten proteins that display region-specific alterations when comparing sexes, including proteins related to inflammatory response, response to reactive oxygen species, complement activation, transport and blood coagulation. Transport protein afamin and blood coagulation proteins antithrombin-III and coagulation factor XII were significantly increased in plaque region from women. Inflammatory response proteins lysozyme C and phospholipase A2 membrane-associated were significantly increased in plaque region from men. Limitations with this study are the small sample size, limited patient information and lack of complementary histology to control for cell type differences between sexes.ConclusionsThis pilot study, for the first time, utilises a multivariate proteomic approach to investigate sexual dimorphism in human atherosclerotic tissue, and provides an essential proteomic platform for further investigations to help understand sexual dimorphism and plaque vulnerability in atherosclerosis.

  • 90.
    Willander, Kerstin
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Hematologiska kliniken US.
    Jakobsen Falk, Ingrid
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning.
    Chaireti, Roza
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Närsjukvården i centrala Östergötland, Medicinska akutkliniken.
    Paul, Esbjörn
    Division of Hematology, Department of Medicine, Karolinska Institutet, Huddinge, Stockholm, Sweden.
    Monica, Hermanson
    Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.
    Gréen, Henrik
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Hälsouniversitetet. Department of Forensic Genetics and Forensic Toxicology, National Board of Forensic Medicine, Linköping, Sweden.
    Lotfi, Kourosh
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk farmakologi.
    Söderkvist, Peter
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk patologi och klinisk genetik.
    Mutations in the isocitrate dehydrogenase 1/2 genes and IDH1 SNP 105C>T have a prognostic value in acute myeloid leukemia2014Ingår i: Biomarker Research, ISSN 2050-7771, Vol. 2, nr 18Artikel i tidskrift (Refereegranskat)
    Abstract [en]

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

  • 91.
    Willems, Els
    et al.
    KU Leuven, Department of Biosystems, Laboratory of Livestock Physiology, Kasteelpark Arenberg 30 box 2456, 3001 Leuven, Belgium.
    Guerrero-Bosagna, Carlos
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Biologi. Linköpings universitet, Tekniska fakulteten.
    Decuypere, Eddy
    KU Leuven, Department of Biosystems, Laboratory of Livestock Physiology, Kasteelpark Arenberg 30 box 2456, 3001 Leuven, Belgium.
    Janssens, Steven
    KU Leuven, Department of Biosystems, Research Group Livestock Genetics, Kasteelpark Arenberg 30 box 2456, 3001 Leuven, Belgium.
    Buyse, Johan
    KU Leuven, Department of Biosystems, Laboratory of Livestock Physiology, Kasteelpark Arenberg 30 box 2456, 3001 Leuven, Belgium.
    Buys, Nadine
    KU Leuven, Department of Biosystems, Research Group Livestock Genetics, Kasteelpark Arenberg 30 box 2456, 3001 Leuven, Belgium.
    Jensen, Per
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Biologi. Linköpings universitet, Tekniska fakulteten.
    Everaert, Nadia
    4University of Liège, Gembloux Agro-Bio Tech, Precision Livestock and Nutrition Unit, Passage des Déportés 2, 5030 Gembloux, Belgium.
    Differential Expression of Genes and DNA Methylation associated with Prenatal Protein Undernutrition by Albumen Removal in an avian model2016Ingår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6Artikel i tidskrift (Refereegranskat)
    Abstract [en]

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

  • 92.
    Wu, Wendy Yi-Ying
    et al.
    Umea Univ, Sweden.
    Johansson, Gunnar
    Umea Univ, Sweden.
    Wibom, Carl
    Umea Univ, Sweden.
    Brannstrom, Thomas
    Umea Univ, Sweden.
    Malmström, Annika
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Närsjukvården i centrala Östergötland, LAH Linköping.
    Henriksson, Roger
    Umea Univ, Sweden.
    Golovleva, Irina
    Umea Univ, Sweden.
    Bondy, Melissa L.
    Stanford Univ, CA 94305 USA; Baylor Coll Med, TX 77030 USA.
    Andersson, Ulrika
    Umea Univ, Sweden.
    Dahlin, Anna M.
    Umea Univ, Sweden.
    Melin, Beatrice
    Umea Univ, Sweden.
    The Genetic Architecture of Gliomagenesis-Genetic Risk Variants Linked to Specific Molecular Subtypes2019Ingår i: CANCERS, Vol. 11, nr 12, artikel-id 2001Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    Genome-wide association studies have identified 25 germline genetic loci that increase the risk of glioma. The somatic tumor molecular alterations, including IDH-mutation status and 1p/19q co-deletion, have been included into the WHO 2016 classification system for glioma. To investigate how the germline genetic risk variants correlate with the somatic molecular subtypes put forward by WHO, we performed a meta-analysis that combined findings from 330 Swedish cases and 876 controls with two other recent studies. In total, 5,103 cases and 10,915 controls were included. Three categories of associations were found. First, variants in TERT and TP53 were associated with increased risk of all glioma subtypes. Second, variants in CDKN2B-AS1, EGFR, and RTEL1 were associated with IDH-wildtype glioma. Third, variants in CCDC26 (the 8q24 locus), C2orf80 (close to IDH), LRIG1, PHLDB1, ETFA, MAML2 and ZBTB16 were associated with IDH-mutant glioma. We therefore propose three etiopathological pathways in gliomagenesis based on germline variants for future guidance of diagnosis and potential functional targets for therapies. Future prospective clinical trials of patients with suspicion of glioma diagnoses, using the genetic variants as biomarkers, are necessary to disentangle how strongly they can predict glioma diagnosis.

  • 93.
    Yamamoto, Toshiyuki
    et al.
    Tokyo Womens Medical University, Japan .
    Wilsdon, Anna
    Nottingham City Hospital, UK.
    Joss, Shelagh
    Southern General Hospital, Glasgow, UK.
    Isidor, Bertrand
    Centre Hospital University of Nantes 7, France Institute Thorax, France .
    Erlandsson, Anna
    Sahlgrenska University Hospital, Gothenburg, Sweden.
    Suri, Mohnish
    Nottingham City Hospital, UK.
    Sangu, Noriko
    Tokyo Womens Medical University, Japan .
    Shimada, Shino
    Tokyo Womens Medical University, Japan .
    Shimojima, Keiko
    Tokyo Womens Medical University, Japan .
    Le Caignec, Cedric
    Centre Hospital University of Nantes 7, France Institute Thorax, France .
    Samuelsson, Lena
    Sahlgrenska University Hospital, Gothenburg, Sweden.
    Stefanova, Margarita
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk patologi och klinisk genetik. Sahlgrenska University Hospital, Gothenburg, Sweden.
    An emerging phenotype of Xq22 microdeletions in females with severe intellectual disability, hypotonia and behavioral abnormalities2014Ingår i: Journal of Human Genetics, ISSN 1434-5161, E-ISSN 1435-232X, Vol. 59, nr 6, s. 300-306Artikel i tidskrift (Refereegranskat)
    Abstract [en]

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

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