Information de reference pour ce titreAccession Number: | 00006056-201402200-00052.
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Author: | Okada, Yukinori 1, 2, 3; Wu, Di 1, 2, 3, 4, 5; Trynka, Gosia 1, 2, 3; Raj, Towfique 2, 3, 6; Terao, Chikashi 7, 8; Ikari, Katsunori 9; Kochi, Yuta 10; Ohmura, Koichiro 8; Suzuki, Akari 10; Yoshida, Shinji 9; Graham, Robert R. 11; Manoharan, Arun 11; Ortmann, Ward 11; Bhangale, Tushar 11; Denny, Joshua C. 12, 13; Carroll, Robert J. 12; Eyler, Anne E. 13; Greenberg, Jeffrey D. 14; Kremer, Joel M. 15; Pappas, Dimitrios A. 16; Jiang, Lei 17; Yin, Jian 17; Ye, Lingying 17; Su, Ding-Feng 18; Yang, Jian 19, 20; Xie, Gang 21, 22, 23; Keystone, Ed 24; Westra, Harm-Jan 25; Esko, Tonu 3, 26, 27; Metspalu, Andres 26; Zhou, Xuezhong 28; Gupta, Namrata 3; Mirel, Daniel 3; Stahl, Eli A. 29; Diogo, Dorothee 1, 2, 3; Cui, Jing 1, 2, 3; Liao, Katherine 1, 2, 3; Guo, Michael H. 1, 3, 27; Myouzen, Keiko 10; Kawaguchi, Takahisa 7; Coenen, Marieke J. H. 30; van Riel, Piet L. C. M. 31; van de Laar, Mart A. F. J. 32; Guchelaar, Henk-Jan 33; Huizinga, Tom W. J. 34; Dieude, Philippe 35, 36; Mariette, Xavier 37; Bridges, Louis S. Jr 38; Zhernakova, Alexandra 25, 34; Toes, Rene E. M. 34; Tak, Paul P. 39, 40, 41; Miceli-Richard, Corinne 37; Bang, So-Young 42; Lee, Hye-Soon 42; Martin, Javier 43; Gonzalez-Gay, Miguel A. 44; Rodriguez-Rodriguez, Luis 45; Rantapaa-Dahlqvist, Solbritt 46, 47; Arlestig, Lisbeth 46, 47; Choi, Hyon K. 48, 49, 50; Kamatani, Yoichiro 51; Galan, Pilar 52; Lathrop, Mark 53; the RACI consortium +; the GARNET consortium +; Eyre, Steve 54, 55; Bowes, John 54, 55; Barton, Anne 54; de Vries, Niek 56; Moreland, Larry W. 57; Criswell, Lindsey A. 58; Karlson, Elizabeth W. 1; Taniguchi, Atsuo 9; Yamada, Ryo 59; Kubo, Michiaki 60; Liu, Jun S. 4; Bae, Sang-Cheol 42; Worthington, Jane 54, 55; Padyukov, Leonid 61; Klareskog, Lars 61; Gregersen, Peter K. 62; Raychaudhuri, Soumya 1, 2, 3, 63; Stranger, Barbara E. 64, 65; De Jager, Philip L. 2, 3, 6; Franke, Lude 25; Visscher, Peter M. 19, 20; Brown, Matthew A. 19; Yamanaka, Hisashi 9; Mimori, Tsuneyo 8; Takahashi, Atsushi 66; Xu, Huji 17; Behrens, Timothy W. 11; Siminovitch, Katherine A. 21, 22, 23; Momohara, Shigeki 9; Matsuda, Fumihiko 7, 67, 68; Yamamoto, Kazuhiko 10, 69; Plenge, Robert M. 1, 2, 3
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Institution: | (1) Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA. (2) Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA. (3) Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts 02142, USA. (4) Department of Statistics, Harvard University, Cambridge, Massachusetts 02138, USA. (5) Centre for Cancer Research, Monash Institute of Medical Research, Monash University, Clayton, Victoria 3800, Australia. (6) Program in Translational NeuroPsychiatric Genomics, Institute for the Neurosciences, Department of Neurology, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA. (7) Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan. (8) Department of Rheumatology and Clinical immunology, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan. (9) Institute of Rheumatology, Tokyo Women's Medical University, Tokyo 162-0054, Japan. (10) Laboratory for Autoimmune Diseases, Center for Integrative Medical Sciences, RIKEN, Yokohama 230-0045, Japan. (11) Immunology Biomarkers Group, Genentech, South San Francisco, California 94080, USA. (12) Department of Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA. (13) Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA. (14) New York University Hospital for Joint Diseases, New York, New York 10003, USA. (15) Department of Medicine, Albany Medical Center and The Center for Rheumatology, Albany, New York 12206, USA. (16) Division of Rheumatology, Department of Medicine, New York, Presbyterian Hospital, College of Physicians and Surgeons, Columbia University, New York, New York 10032, USA. (17) Department of Rheumatology and Immunology, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai 200003, China. (18) Department of Pharmacology, Second Military Medical University, Shanghai 200433, China. (19) University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Queensland 4072, Australia. (20) Queensland Brain Institute, The University of Queensland, Brisbane, Queensland 4072, Australia. (21) Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada. (22) Toronto General Research Institute, Toronto, Ontario M5G 2M9, Canada. (23) Department of Medicine, University of Toronto, Toronto, Ontario M5S 2J7, Canada. (24) Department of Medicine, Mount Sinai Hospital and University of Toronto, Toronto M5S 2J7, Canada. (25) Department of Genetics, University Medical Center Groningen, University of Groningen, Hanzeplein 1, Groningen 9700 RB, the Netherlands. (26) Estonian Genome Center, University of Tartu, Riia 23b, Tartu 51010, Estonia. (27) Division of Endocrinology, Children's Hospital, Boston, Massachusetts 02115, USA. (28) School of Computer and Information Technology, Beijing Jiaotong University, Beijing 100044, China. (29) The Department of Psychiatry at Mount Sinai School of Medicine, New York, New York 10029, USA. (30) Department of Human Genetics, Radboud University Medical Centre, Nijmegen 6500 HB, the Netherlands. (31) Department of Rheumatology, Radboud University Medical Centre, Nijmegen 6500 HB, the Netherlands. (32) Department of Rheumatology and Clinical Immunology, Arthritis Center Twente, University Twente & Medisch Spectrum Twente, Enschede 7500 AE, the Netherlands. (33) Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden 2300 RC, the Netherlands. (34) Department of Rheumatology, Leiden University Medical Center, Leiden 2300 RC, the Netherlands. (35) Service de Rhumatologie et INSERM U699 Hopital Bichat Claude Bernard, Assistance Publique des Hopitaux de Paris, Paris 75018, France. (36) Universite Paris 7-Diderot, Paris 75013, France. (37) Institut National de la Sante et de la Recherche Medicale (INSERM) U1012, Universite Paris-Sud, Rhumatologie, Hopitaux Universitaires Paris-Sud, Assistance Publique-Hopitaux de Paris (AP-HP), Le Kremlin Bicetre 94275, France. (38) Division of Clinical Immunology and Rheumatology, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA. (39) AMC/University of Amsterdam, Amsterdam 1105 AZ, the Netherlands. (40) GlaxoSmithKline, Stevenage SG1 2NY, UK. (41) University of Cambridge, Cambridge CB2 1TN, UK. (42) Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul 133-792, South Korea. (43) Instituto de Parasitologia y Biomedicina Lopez-Neyra, CSIC, Granada 18100, Spain. (44) Department of Rheumatology, Hospital Marques de Valdecilla, IFIMAV, Santander 39008, Spain. (45) Hospital Clinico San Carlos, Madrid 28040, Spain. (46) Department of Public Health and Clinical Medicine, Umea University, Umea SE-901 87, Sweden. (47) Department of Rheumatology, Umea University, Umea SE-901 87, Sweden. (48) Channing Laboratory, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston 02115, Massachusetts, USA. (49) Section of Rheumatology, Boston University School of Medicine, Boston, Massachusetts 02118, USA. (50) Clinical Epidemiology Research and Training Unit, Boston University School of Medicine, Boston, Massachusetts 02118, USA. (51) Centre d'Etude du Polymorphisme Humain (CEPH), Paris 75010, France. (52) Universite Paris 13 Sorbonne Paris Cite, UREN (Nutritional Epidemiology Research Unit), Inserm (U557), Inra (U1125), Cnam, Bobigny 93017, France. (53) McGill University and Genome Quebec Innovation Centre, Montreal, Quebec H3A 0G1 Canada. (54) Arthritis Research UK Epidemiology Unit, Centre for Musculoskeletal Research, University of Manchester, Manchester Academic Health Science Centre, Manchester M13 9NT, UK. (55) National Institute for Health Research, Manchester Musculoskeletal Biomedical Research Unit, Central Manchester University Hospitals National Health Service Foundation Trust, Manchester Academic Health Sciences Centre, Manchester M13 9NT, UK. (56) Department of Clinical Immunology and Rheumatology & Department of Genome Analysis, Academic Medical Center/University of Amsterdam, Amsterdam 1105 AZ, the Netherlands. (57) Division of Rheumatology and Clinical Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA. (58) Rosalind Russell Medical Research Center for Arthritis, Division of Rheumatology, Department of Medicine, University of California San Francisco, San Francisco, California 94117, USA. (59) Unit of Statistical Genetics, Center for Genomic Medicine Graduate School of Medicine Kyoto University, Kyoto 606-8507, Japan. (60) Laboratory for Genotyping Development, Center for Integrative Medical Sciences, RIKEN, Yokohama 230-0045, Japan. (61) Rheumatology Unit, Department of Medicine (Solna), Karolinska Institutet, Stockholm SE-171 76, Sweden. (62) The Feinstein Institute for Medical Research, North Shore-Long Island Jewish Health System, Manhasset, New York 11030, USA. (63) NIHR Manchester Musculoskeletal Biomedical, Research Unit, Central Manchester NHS Foundation Trust, Manchester Academic Health Sciences Centre, Manchester M13 9NT, UK. (64) Section of Genetic Medicine, University of Chicago, Chicago, Illinois 60637, USA. (65) Institute for Genomics and Systems Biology, University of Chicago, Chicago, Illinois 60637, USA. (66) Laboratory for Statistical Analysis, Center for Integrative Medical Sciences, RIKEN, Yokohama 230-0045, Japan. (67) Core Research for Evolutional Science and Technology (CREST) program, Japan Science and Technology Agency, Kawaguchi, Saitama 332-0012, Japan. (68) Institut National de la Sante et de la Recherche Medicale (INSERM) Unite U852, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan. (69) Department of Allergy and Rheumatology, Graduate School of Medicine, the University of Tokyo, Tokyo 113-0033, Japan.
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Title: | Genetics of rheumatoid arthritis contributes to biology and drug discovery.[Letter]
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Source: | Nature. 506(7488):376-381, February 20, 2014.
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Abstract: | : A major challenge in human genetics is to devise a systematic strategy to integrate disease-associated variants with diverse genomic and biological data sets to provide insight into disease pathogenesis and guide drug discovery for complex traits such as rheumatoid arthritis (RA) 1. Here we performed a genome-wide association study meta-analysis in a total of >100,000 subjects of European and Asian ancestries (29,880 RA cases and 73,758 controls), by evaluating ~10 million single-nucleotide polymorphisms. We discovered 42 novel RA risk loci at a genome-wide level of significance, bringing the total to 101 (refs 2, 3, 4). We devised an in silico pipeline using established bioinformatics methods based on functional annotation 5, cis-acting expression quantitative trait loci 6 and pathway analyses 7,8,9-as well as novel methods based on genetic overlap with human primary immunodeficiency, haematological cancer somatic mutations and knockout mouse phenotypes-to identify 98 biological candidate genes at these 101 risk loci. We demonstrate that these genes are the targets of approved therapies for RA, and further suggest that drugs approved for other indications may be repurposed for the treatment of RA. Together, this comprehensive genetic study sheds light on fundamental genes, pathways and cell types that contribute to RA pathogenesis, and provides empirical evidence that the genetics of RA can provide important information for drug discovery.
(C) 2014 Nature Publishing Group
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Language: | English.
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Document Type: | LETTER.
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Journal Subset: | Life & Biomedical Sciences. Science.
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ISSN: | 0028-0836
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NLM Journal Code: | 0410462, nsc
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DOI Number: | https://dx.doi.org/10.1038/natur...- ouverture dans une nouvelle fenêtre
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