TRAF1–C5 as a Risk Locus for Rheumatoid Arthritis — A Genomewide Study
Robert M. Plenge, M.D., Ph.D., Mark Seielstad, Ph.D., Leonid Padyukov, M.D., Ph.D., Annette T. Lee, Ph.D., Elaine F. Remmers, Ph.D., Bo Ding, Ph.D., Anthony Liew, M.S., Houman Khalili, B.S., Alamelu Chandrasekaran, Ph.D., Leela R.L. Davies, B.S., Wentian Li, Ph.D., Adrian K.S. Tan, M.Sc., Carine Bonnard, M.Sc., Rick T.H. Ong, M.Sc., Anbupalam Thalamuthu, Ph.D., Sven Pettersson, M.D., Ph.D., Chunyu Liu, Ph.D., Chao Tian, B.S., Wei V. Chen, M.S., John P. Carulli, Ph.D., Evan M. Beckman, M.D., David Altshuler, M.D., Ph.D., Lars Alfredsson, Ph.D., Lindsey A. Criswell, M.D., M.P.H., Christopher I. Amos, Ph.D., Michael F. Seldin, M.D., Ph.D., Daniel L. Kastner, M.D., Ph.D., Lars Klareskog, M.D., Ph.D., and Peter K. Gregersen, M.D.
Background Rheumatoid arthritis has a complex mode of inheritance.Although HLA-DRB1 and PTPN22 are well-established susceptibilityloci, other genes that confer a modest level of risk have beenidentified recently. We carried out a genomewide associationanalysis to identify additional genetic loci associated withan increased risk of rheumatoid arthritis.
Methods We genotyped 317,503 single-nucleotide polymorphisms(SNPs) in a combined case–control study of 1522 case subjectswith rheumatoid arthritis and 1850 matched control subjects.The patients were seropositive for autoantibodies against cycliccitrullinated peptide (CCP). We obtained samples from two datasets, the North American Rheumatoid Arthritis Consortium (NARAC)and the Swedish Epidemiological Investigation of RheumatoidArthritis (EIRA). Results from NARAC and EIRA for 297,086 SNPsthat passed quality-control filters were combined with the useof Cochran–Mantel–Haenszel stratified analysis.SNPs showing a significant association with disease (P<1x10–8)were genotyped in an independent set of case subjects with anti–CCP-positiverheumatoid arthritis (485 from NARAC and 512 from EIRA) andin control subjects (1282 from NARAC and 495 from EIRA).
Results We observed associations between disease and variantsin the major-histocompatibility-complex locus, in PTPN22, andin a SNP (rs3761847) on chromosome 9 for all samples tested,the latter with an odds ratio of 1.32 (95% confidence interval,1.23 to 1.42; P=4x10–14). The SNP is in linkage disequilibriumwith two genes relevant to chronic inflammation: TRAF1 (encodingtumor necrosis factor receptor–associated factor 1) andC5 (encoding complement component 5).
Conclusions A common genetic variant at the TRAF1–C5 locuson chromosome 9 is associated with an increased risk of anti–CCP-positiverheumatoid arthritis.
Source Information
The authors' affiliations are listed in the Appendix. Drs. Plenge and Seielstad contributed equally to this article. Drs. Klareskog and Gregersen contributed equally to this article as principal investigators for the Swedish Epidemiological Investigation of Rheumatoid Arthritis and the North American Rheumatoid Arthritis Consortium, respectively. This article (10.1056/NEJMoa073491) was published at www.nejm.org on September 5, 2007.
Address reprint requests to Dr. Gregersen at the Feinstein Institute for Medical Research, 350 Community Dr., Manhasset, NY 11030, or at peterg{at}nshs.edu.
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