REL, encoding a member of the NF-κB family of transcription factors, is a newly defined risk locus for rheumatoid arthritis

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Abstract

We conducted a genome-wide association study of rheumatoid arthritis in 2,418 cases and 4,504 controls from North America and identified an association at the REL locus, encoding c-Rel, on chromosome 2p13 (rs13031237, P = 6.01 × 10−10). Replication in independent case-control datasets comprising 2,604 cases and 2,882 controls confirmed this association, yielding an allelic OR = 1.25 (P = 3.08 × 10−14) for marker rs13031237 and an allelic OR = 1.21 (P = 2.60 × 10−11) for marker rs13017599 in the combined dataset. The combined dataset also provides definitive support for associations at both CTLA4 (rs231735; OR = 0.85; P = 6.25 × 10−9) and BLK (rs2736340; OR = 1.19; P = 5.69 × 10−9). c-Rel is an NF-κB family member with distinct functional properties in hematopoietic cells, and its association with rheumatoid arthritis suggests disease pathways that involve other recently identified rheumatoid arthritis susceptibility genes including CD40, TRAF1, TNFAIP3 and PRKCQ1,2.

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Figure 1: Summary of genome-wide association results for 2,418 cases and 4,504 controls.
Figure 2: Association localization plots in the region around REL following discovery and replication phases.

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Acknowledgements

This work was supported by grants from the US National Institutes of Health NO1-AR-2-2263 (P.K.G.), RO1 AR44422 (P.K.G.) and by the Eileen Ludwig Greenland Center for Rheumatoid Arthritis and the Muriel Fusfeld Foundation. The work was also supported in part by the Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases and by grants from the Canadian Institutes for Health Research (MOP79321) and Ontario Research Fund (RE01061) and a Canada Research Chair to K.A.S.

Author information

P.K.G. organized and designed the study, supervised genotyping of US samples, contributed to statistical analysis and is the primary author of the manuscript. C.I.A. coordinated the design of the study, carried out and supervised all of the statistical analyses, and contributed to the writing of the manuscript. A.T.L. performed GWAS on all US samples and organized samples for distribution to carry out replication studies. E.L. carried out statistical analysis. E.F.R. contributed to study design, carried out replication genotyping and participated in preparation of the manuscript. D.L.K. contributed to study design and participated in review of the manuscript. M.F.S. contributed to study design and data analysis and participated in manuscript preparation. L.A.C. contributed to study design, contributed subjects for study and participated in manuscript preparation. R.M.P. contributed to study design and participated in manuscript preparation. V.M.H., T.R.M., T.S., S.L.B. and L.W.M. contributed subject populations for study and contributed to manuscript preparation. G.X. carried out genotyping and sample preparation of Canadian samples. A.B.B. contributed samples for study, carried out replication genotyping and participated in manuscript preparation. K.A.S. participated in study design and organization, supervised all genotyping of Canadian samples and participated in preparation of the manuscript.

Correspondence to Peter K Gregersen or Katherine A Siminovitch.

Supplementary information

Supplementary Text and Figures

Supplementary Tables 1,3,4,5 (PDF 110 kb)

Supplementary Table 2

Association results for SNPs with P < 0.01 (XLS 826 kb)

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