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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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.
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