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Two independent alleles at 6q23 associated with risk of rheumatoid arthritis

Abstract

To identify susceptibility alleles associated with rheumatoid arthritis, we genotyped 397 individuals with rheumatoid arthritis for 116,204 SNPs and carried out an association analysis in comparison to publicly available genotype data for 1,211 related individuals from the Framingham Heart Study1. After evaluating and adjusting for technical and population biases, we identified a SNP at 6q23 (rs10499194, 150 kb from TNFAIP3 and OLIG3) that was reproducibly associated with rheumatoid arthritis both in the genome-wide association (GWA) scan and in 5,541 additional case-control samples (P = 10−3, GWA scan; P < 10−6, replication; P = 10−9, combined). In a concurrent study, the Wellcome Trust Case Control Consortium (WTCCC) has reported strong association of rheumatoid arthritis susceptibility to a different SNP located 3.8 kb from rs10499194 (rs6920220; P = 5 × 10−6 in WTCCC)2. We show that these two SNP associations are statistically independent, are each reproducible in the comparison of our data and WTCCC data, and define risk and protective haplotypes for rheumatoid arthritis at 6q23.

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Figure 1: Q-Q plots of GWA analyses in unrelated individuals: influence of missing genotype data and population stratification.
Figure 2: Case-control association results and linkage disequilibrium (LD) structure at 6q23.
Figure 3: Haplotype analysis in our replication samples and in the WTCCC study of 2,000 individuals with rheumatoid arthritis and 3,000 controls.

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Acknowledgements

The Framingham Heart Study is conducted and supported by the National Heart, Lung, and Blood Institute (NHLBI) in collaboration with Boston University. This manuscript was not prepared in collaboration with investigators of the Framingham Heart Study and does not necessarily reflect the opinions or views of the Framingham Heart Study, Boston University or NHLBI. We appreciate the comments provided by B. Voight and J. Hirschhorn during the preparation of the manuscript. We appreciate the release of genome-wide association results by the WTCCC, which was of great value to our analysis. The BRASS Registry is supported by a grant from Millennium Pharmaceuticals and Biogen-Idec. R.M.P. is supported by a K08 grant from the US National Institutes of Health (AI55314-3). The NARAC is supported by US National Institutes of Health 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. D.A. is a Burroughs Wellcome Fund Clinical Scholar in Translational Research and a Distinguished Clinical Scholar of the Doris Duke Charitable Foundation.

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Clinical samples were collected and prepared by R.M.P., E.W.K., N.M., D.M.L., E.F.R., A.T.L., L.P., L.A., J.C., M.E.W., L.K., P.K.G. and N.A.S. Genotyping was contributed by R.M.P., L.D., N.P.B., B.B., M.D., M.P., R.B., W.W., C.H., D.A.H., S.B.G., M.F.S., E.I., R.R. and A.N.P. Statistical analysis was carried out and interpreted by R.M.P., C.C., L.D., A.L.P., P.I.W.D., J.M., I.P., R.R.G., R.G., S.P., M.J.D. and D.A. The manuscript was written by R.M.P., C.C., M.J.D. and D.A.

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Correspondence to Robert M Plenge.

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Competing interests

R.R., A.N.P. and E.I. were employed by Millennium Pharmaceuticals at the time the study was conducted.

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Plenge, R., Cotsapas, C., Davies, L. et al. Two independent alleles at 6q23 associated with risk of rheumatoid arthritis. Nat Genet 39, 1477–1482 (2007). https://doi.org/10.1038/ng.2007.27

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