Genetic variants at CD28, PRDM1 and CD2/CD58 are associated with rheumatoid arthritis risk

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To discover new rheumatoid arthritis (RA) risk loci, we systematically examined 370 SNPs from 179 independent loci with P < 0.001 in a published meta-analysis of RA genome-wide association studies (GWAS) of 3,393 cases and 12,462 controls1. We used Gene Relationships Across Implicated Loci (GRAIL)2, a computational method that applies statistical text mining to PubMed abstracts, to score these 179 loci for functional relationships to genes in 16 established RA disease loci1,3,4,5,6,7,8,9,10,11. We identified 22 loci with a significant degree of functional connectivity. We genotyped 22 representative SNPs in an independent set of 7,957 cases and 11,958 matched controls. Three were convincingly validated: CD2-CD58 (rs11586238, P = 1 × 10−6 replication, P = 1 × 10−9 overall), CD28 (rs1980422, P = 5 × 10−6 replication, P = 1 × 10−9 overall) and PRDM1 (rs548234, P = 1 × 10−5 replication, P = 2 × 10−8 overall). An additional four were replicated (P < 0.0023): TAGAP (rs394581, P = 0.0002 replication, P = 4 × 10−7 overall), PTPRC (rs10919563, P = 0.0003 replication, P = 7 × 10−7 overall), TRAF6-RAG1 (rs540386, P = 0.0008 replication, P = 4 × 10−6 overall) and FCGR2A (rs12746613, P = 0.0022 replication, P = 2 × 10−5 overall). Many of these loci are also associated to other immunologic diseases.

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Figure 1: Using Gene Relationships Across Implicated Loci (GRAIL) to prioritize candidate RA SNPs.
Figure 2: GRAIL identified interconnectivity among genes in RA loci.
Figure 3: GRAIL identifies new RA risk loci that replicate when genotyped in independent case-control samples.


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S.R. is supported by a US National Institutes of Health (NIH) Career Development Award (1K08AR055688-01A1) and an American College of Rheumatology Bridge Grant. 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, the American College of Rheumatology 'Within Our Reach' campaign and holds a Career Award for Medical Scientists from the Burroughs Wellcome Fund. M.J.D. is supported by NIH grants through the U01 (HG004171, DK62432) and R01 (DK083756-1, DK64869) mechanisms. The Broad Institute Center for Genotyping and Analysis is supported by grant U54 RR020278 from the National Center for Research Resources. The Brigham and Women's Hospital Rheumatoid Arthritis Sequential Study (BRASS) Registry is supported by a grant from Millennium Pharmaceuticals and Biogen-Idec. The North American Rheumatoid Arthritis Consortium (NARAC) is supported by the NIH (NO1-AR-2-2263 and RO1 AR44422). This research was also supported in part by the Intramural Research Program of the National Institute of Arthritis, Musculoskeletal and Skin Diseases of the NIH. This research was also supported in part by grants to KAS from the Canadian Institutes for Health Research (MOP79321 and IIN - 84042) and the Ontario Research Fund (RE01061) and by a Canada Research Chair. We acknowledge the help of C.E. van der Schoot for healthy control samples for the Genetics Network Rheumatology Amsterdam (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 patient samples and data. We thank the Myocardial Infarction Genetics Consortium (MIGen) study for the use of genotype data from their healthy controls in our study. The MIGen study was funded by the US NIH and National Heart, Lung, and Blood Institute's SNP Typing for Association with Multiple Phenotypes from Existing Epidemiologic Data (STAMPEED) genomics research program R01HL087676 and a grant from the National Center for Research Resources. We thank the Johanna Seddon Progression of AMD Study, AMD Registry Study, Family Study of AMD, The US Twin Study of AMD and the Age-Related Eye Disease Study (AREDS) for use of genotype data from their healthy controls in our study. We thank D. Hafler and the Multiple Sclerosis collaborative for use of genotype data from their healthy controls recruited at Brigham and Women's Hospital.

Author information

S.R., M.J.D., D.A. and R.M.P. designed the study, conducted the statistical analysis, interpreted the primary data and wrote the initial manuscript. All authors contributed to the final manuscript. B.P.T., E.F.R., S.E., A.H., C.G., J.J.C., G.X., E.A.S., R.C., N.P.B. and M.S. were involved directly in genotyping samples or extracting genotypes for this study. The BRASS genetic study was coordinated by E.A.S., P.L.d.J., J.C., S.R. and R.M.P. under the direction of M.E.W. and N.A.S. The CANADA genetic study was coordinated by C.I.A., X.L. and G.X. under the direction of K.A.S. The Epidemiological Investigation of Rheumatoid Arthritis (EIRA) genetic study was coordinated by L.A., B.D., L.P. and M.S. under the direction of L.K. The Genomics Collaborative Initiative (GCI) genetic study was coordinated by K.G.A., J.J.C., M.C. and Y.L. under the direction of A.B.B. The GENRA genetic study was coordinated by J.B.A.C., P.P.T., I.E.v.d.H.-B. and G.J.W. under the direction of N.d.V. The Leiden University Medical Center (LUMC) genetic study was coordinated by T.W.J.H., F.A.S.K., Y.L. and A.H.M.v.d.H.-v.M. under the direction of R.E.M.T. The NARAC genetic study was coordinated by E.F.R., C.I.A., M.C., L.A.C., D.L.K., A.T.L. and M.F.S. under the direction of P.K.G. The NHS genetic study was coordinated by K.H.C. and J.C. under the direction of E.W.K. The UK Rheumatoid Arthritis Genetics (UKRAG) genetic study was coordinated by S.E., B.I.R.A.C., A.B., J.B., P.E., E.F., P.H., A.H., L.J.H., X.K., P.M., A.W.M., D.M.R., S.S., W.T., A.G.W., P.W. and Y.E.A.R. under the direction of J.W.

Correspondence to Soumya Raychaudhuri or Robert M Plenge.

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A full list of members is provided in the Supplementary Note.

A full list of members is provided in the Supplementary Note.

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Supplementary Note, Supplementary Figures 1 and 2 and Supplementary Tables 1–5. (PDF 780 kb)

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