Common variants at CD40 and other loci confer risk of rheumatoid arthritis

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To identify rheumatoid arthritis risk loci in European populations, we conducted a meta-analysis of two published genome-wide association (GWA) studies totaling 3,393 cases and 12,462 controls1,2. We genotyped 31 top-ranked SNPs not previously associated with rheumatoid arthritis in an independent replication of 3,929 autoantibody-positive rheumatoid arthritis cases and 5,807 matched controls from eight separate collections. We identified a common variant at the CD40 gene locus (rs4810485, P = 0.0032 replication, P = 8.2 × 10−9 overall, OR = 0.87). Along with other associations near TRAF1 (refs. 2,3) and TNFAIP3 (refs. 4,5), this implies a central role for the CD40 signaling pathway in rheumatoid arthritis pathogenesis. We also identified association at the CCL21 gene locus (rs2812378, P = 0.00097 replication, P = 2.8 × 10−7 overall), a gene involved in lymphocyte trafficking. Finally, we identified evidence of association at four additional gene loci: MMEL1-TNFRSF14 (rs3890745, P = 0.0035 replication, P = 1.1 × 10−7 overall), CDK6 (rs42041, P = 0.010 replication, P = 4.0 × 10−6 overall), PRKCQ (rs4750316, P = 0.0078 replication, P = 4.4 × 10−6 overall), and KIF5A-PIP4K2C (rs1678542, P = 0.0026 replication, P = 8.8 × 10−8 overall).

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Figure 1: Enrichment of SNPs with z scores >2 in replication samples.
Figure 2: CD40 region and association with rheumatoid arthritis.
Figure 3: CCL21 region and association with rheumatoid arthritis.


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We thank the WTCCC for making access to genotype data available online, and for providing autoantibody status of the WTCCC rheumatoid arthritis cases. We thank S. Myers and J. Marchini for help with IMPUTE. S.R. is supported by a T32 NIH training grant (AR007530-23), a K08 grant from the NIH (KAR055688A), and through the BWH Rheumatology Fellowship program, directed by S. Helfgott. R.M.P. is supported by a K08 grant from the NIH (AI55314-3), a private donation from the Fox Trot Fund, the William Randolph Hearst Fund of Harvard University, and holds a Career Award for Medical Scientists from the Burroughs Wellcome Fund. M.J.D. is supported by a UO1 NIH grant (UO1 HG004171). The BRASS Registry is supported by a grant from Millennium Pharmaceuticals and Biogen-Idec. The Broad Institute Center for Genotyping and Analysis is supported by grant U54 RR020278 from the National Center for Research Resources. The NARAC is supported by NIH grants RO1-AR44422 and NO1-AR-2-2263 (P.K.G.). This work was also supported in part by the Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health. The EIRA study is supported by grants from the Swedish Medical Research Council, the Swedish Council for Working Life and Social Research, King Gustaf V's 80-year Foundation, the Swedish Rheumatic Foundation, the Stockholm County Council, the insurance company Arbetsmarknadens Försäkringsaktiebolag, and the County of Sörmland Research and Development Center. Genotyping of the EIRA cohort was supported by the Agency for Science Technology and Research (Singapore). Genotyping of the GCI and LUMC samples was funded by Celera. D.A. is a Burroughs Wellcome Fund Clinical Scholar in Translational Research, and a Distinguished Clinical Scholar of the Doris Duke Charitable Foundation. B.D.K. was supported by the NIH Clinical Research Training Program, a public-private partnership between the Foundation for the National Institutes of Health and Pfizer Inc. E.W.K. is supported by NIH grants R01 AR49880, CA87969, P60 AR047782, K24 AR0524-01 and BIRCWH K12 HD051959 (supported by US National Institute of Mental Health, National Institute of Allergy and Infectious Diseases, National Institute of Child Health and Human Development and the Office of the Director). K.H.C. is the recipient of an Arthritis Foundation/American College of Rheumatology Arthritis Investigator Award and a Katherine Swan Ginsburg Memorial Award. L.A.C. is a Kirkland Scholar Awardee and her work on this project was supported by K24 AR02175, R01 AI065841 and 5 M01 RR-00079. P.P.T. and N.d.V. were supported by European Community's FP6 funding (Autocure). We acknowledge the help of C. Ellen van der Schoot for healthy control samples for GENRA and the help of B.A.C. Dijkmans, D. van Schaardenburg, A.S. Peña, P.L. Klarenbeek, Z. Zhang, M.T. Nurmohammed, W.F. Lems, R.R.J. van de Stadt, W.H. Bos, J. Ursum, M.G.M. Bartelds, D.M. Gerlag, M.G.H. van der Sande, C.A. Wijbrandts and M.M.J. Herenius in gathering GENRA subject samples and data. We thank Y. Li, S. Schrodi, and J. Sninsky (Celera); and B. Voight and C. Cotsapas (Broad Institute) for comments on the manuscript.

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S.R., M.J.D. and R.M.P. designed the study, conducted the statistical analysis, interpreted the primary data, and wrote the initial manuscript. E.F.R. and B.D.K. generated Sequenom genotype data on the replication samples from North America (at NIAMS); N.P.B., R.H., L.G., S.W. and C.G. generated Sequenom genotype data on the replication samples from North America and NHS (at the Broad Institute); A.T.L. and P.K.G. generated the NARAC genome-wide association genotype data; A.B.B., M.C., K.G.A. and J.J.C. generated genotype data on GCI and LUMC samples (at Celera); F.A.S.K., R.E.M.T., A.H.M.M., and T.W.J.H. contributed LUMC samples; G.J.W., P.P.T., J.B.A.C., I.E.V.D.H.-B. and N.d.V. contributed GENRA samples; K.H.C., J. Cui and E.W.K. contributed NHS samples and interpretation of the study data; L.K., L.P., B.D. and L.A. contributed EIRA samples and helped interpret the data; J.W. is principle investigator of the rheumatoid arthritis WTCCC study and contributed to the study design; N.A.S. and M.E.W. are principle investigators of BRASS, and J. Coblyn contributed BRASS subject samples. P.K.G. is principle investigator of NARAC, provided replication samples and guidance on the study design, and helped to interpret the data. D.A. provided guidance on study design, interpretation of data and initial draft of manuscript. B.M.N. contributed statistical analysis. M.S. generated the genome-wide genotype data on EIRA. L.A.C., C.I.A., M.F.S., D.L.K., E.F.R., A.T.L., R.M.P. and P.K.G. are all members of NARAC and have contributed to the study design. All authors contributed to writing the final manuscript.

Correspondence to Robert M Plenge.

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