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PLoS One. 2015 Apr 7;10(4):e0122271. doi: 10.1371/journal.pone.0122271. eCollection 2015.

TYK2 protein-coding variants protect against rheumatoid arthritis and autoimmunity, with no evidence of major pleiotropic effects on non-autoimmune complex traits.

Author information

1
Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America; Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America; Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, United States of America; Partners HealthCare Center for Personalized Genetic Medicine, Boston, Massachusetts, United States of America.
2
Department of Biomedical Informatics, Vanderbilt University, Nashville, Tennessee, United States of America.
3
Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
4
ITGR Human Genetics Group, Genentech Inc, San Francisco, California, United States of America.
5
The Genome Institute, Washington University School of Medicine, St. Louis, Missouri, United States of America.
6
New York University Hospital for Joint Diseases, New York, New York, United States of America.
7
Arthritis Research UK Epidemiology Unit, University of Manchester, Manchester Academic Health Sciences Centre, Manchester, United Kingdom.
8
The Feinstein Institute for Medical Research, North Shore-Long Island Jewish Health System, Manhasset, New York, United States of America.
9
Columbia University, College of Physicians and Surgeons, New York, New York, United States of America.
10
The Albany Medical College and The Center for Rheumatology, Albany, New York, United States of America.
11
Radboud university medical center, Radboud Institute for Health Sciences, Department of Human Genetics, Nijmegen, The Netherlands.
12
Radboud University Medical Center, Donders Centre for Neurosciences, Department of Psychiatry and Human Genetics, Nijmegen, The Netherlands.
13
Radboud University Medical Center, Radboud Institute for Health Sciences, Nijmegen, The Netherlands.
14
Université Paris-Sud, Orsay, France; APHP-Hôpital Bicêtre, INSERM U1012, Le Kremlin Bicêtre, Paris, France.
15
Rheumatology Research Unit, Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal; Rheumatology Department, Santa Maria Hospital-CHLN, Lisbon, Portugal.
16
Amsterdam Rheumatology and Immunology Center, Department of Clinical Immunology & Rheumatology, Academic Medical Center /University of Amsterdam, Amsterdam, The Netherlands.
17
Laboratory of Immunogenetics, Department of Medical Microbiology and Infection Control, VU University Medical Center, Amsterdam, The Netherlands.
18
Amsterdam Rheumatology and Immunology Center, Department of Rheumatology, Reade, Amsterdam, The Netherlands.
19
Department of Rheumatology, Leiden University Medical Centre, Leiden, The Netherlands.
20
Division of Rheumatology and Immunology, Omaha VA and University of Nebraska Medical Center, Omaha, Nebraska, United States of America.
21
Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America; Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America; Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, United States of America.
22
Department of Biochemistry and Molecular Medicine, University of California Davis, Davis, California, United States of America.
23
Information Systems, Partners Healthcare, Charlestown, Massachusetts, United States of America.
24
Instituto de Parasitologia y Biomedicina Lopez-Neyra, CSIC, Granada, 18100, Spain.
25
Department of Rheumatology, Leiden University Medical Centre, Leiden, The Netherlands; Genetics Department, University Medical Center and Groningen University, Groningen, The Netherlands.
26
Rheumatology Unit, Department of Medicine, Karolinska Institutet and Karolinska University Hospital Solna, Stockholm, Sweden.
27
Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America; Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America; Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, United States of America; Partners HealthCare Center for Personalized Genetic Medicine, Boston, Massachusetts, United States of America; Arthritis Research UK Epidemiology Unit, University of Manchester, Manchester Academic Health Sciences Centre, Manchester, United Kingdom.
28
Department of Biomedical Informatics, Vanderbilt University, Nashville, Tennessee, United States of America; Department of Medicine, Vanderbilt University, Nashville, Tennessee, United States of America.

Abstract

Despite the success of genome-wide association studies (GWAS) in detecting a large number of loci for complex phenotypes such as rheumatoid arthritis (RA) susceptibility, the lack of information on the causal genes leaves important challenges to interpret GWAS results in the context of the disease biology. Here, we genetically fine-map the RA risk locus at 19p13 to define causal variants, and explore the pleiotropic effects of these same variants in other complex traits. First, we combined Immunochip dense genotyping (n = 23,092 case/control samples), Exomechip genotyping (n = 18,409 case/control samples) and targeted exon-sequencing (n = 2,236 case/controls samples) to demonstrate that three protein-coding variants in TYK2 (tyrosine kinase 2) independently protect against RA: P1104A (rs34536443, OR = 0.66, P = 2.3 x 10(-21)), A928V (rs35018800, OR = 0.53, P = 1.2 x 10(-9)), and I684S (rs12720356, OR = 0.86, P = 4.6 x 10(-7)). Second, we show that the same three TYK2 variants protect against systemic lupus erythematosus (SLE, Pomnibus = 6 x 10(-18)), and provide suggestive evidence that two of the TYK2 variants (P1104A and A928V) may also protect against inflammatory bowel disease (IBD; P(omnibus) = 0.005). Finally, in a phenome-wide association study (PheWAS) assessing >500 phenotypes using electronic medical records (EMR) in >29,000 subjects, we found no convincing evidence for association of P1104A and A928V with complex phenotypes other than autoimmune diseases such as RA, SLE and IBD. Together, our results demonstrate the role of TYK2 in the pathogenesis of RA, SLE and IBD, and provide supporting evidence for TYK2 as a promising drug target for the treatment of autoimmune diseases.

PMID:
25849893
PMCID:
PMC4388675
DOI:
10.1371/journal.pone.0122271
[Indexed for MEDLINE]
Free PMC Article

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