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


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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  1. Coenen, M.J. & Gregersen, P.K. Rheumatoid arthritis: a view of the current genetic landscape. Genes Immun. 10, 101–111 (2009).

    Article  CAS  Google Scholar 

  2. Raychaudhuri, S. et al. Common variants at CD40 and other loci confer risk of rheumatoid arthritis. Nat. Genet. 40, 1216–1223 (2008).

    Article  CAS  Google Scholar 

  3. Barton, A. et al. Rheumatoid arthritis susceptibility loci at chromosomes 10p15, 12q13 and 22q13. Nat. Genet. 40, 1156–1159 (2008).

    Article  CAS  Google Scholar 

  4. Arnett, F.C. et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum. 31, 315–324 (1988).

    Article  CAS  Google Scholar 

  5. Schellekens, G.A. et al. The diagnostic properties of rheumatoid arthritis antibodies recognizing a cyclic citrullinated peptide. Arthritis Rheum. 43, 155–163 (2000).

    Article  CAS  Google Scholar 

  6. Ding, B. et al. Different patterns of associations with anti-citrullinated protein antibody-positive and anti-citrullinated protein antibody-negative rheumatoid arthritis in the extended major histocompatibility complex region. Arthritis Rheum. 60, 30–38 (2009).

    Article  CAS  Google Scholar 

  7. Lee, H.S. et al. Genetic risk factors for rheumatoid arthritis differ in Caucasian and Korean populations. Arthritis Rheum. 60, 364–371 (2009).

    Article  CAS  Google Scholar 

  8. Plenge, R.M. et al. TRAF1–C5 as a risk locus for rheumatoid arthritis—a genomewide study. N. Engl. J. Med. 357, 1199–1209 (2007).

    Article  CAS  Google Scholar 

  9. Trynka, G. et al. Coeliac disease associated risk variants in TNFAIP3 and REL implicate altered NF-κB signalling. Gut advance online publication, doi:10.1136/gut.2008.169052 (24 February 2009).

  10. Pennisi, E. Genetics. 17q21.31: not your average genomic address. Science 322, 842–845 (2008).

    Article  CAS  Google Scholar 

  11. Hom, G. et al. Association of systemic lupus erythematosus with C8orf13-BLK and ITGAM-ITGAX. N. Engl. J. Med. 358, 900–909 (2008).

    Article  CAS  Google Scholar 

  12. Harley, J.B. et al. Genome-wide association scan in women with systemic lupus erythematosus identifies susceptibility variants in ITGAM, PXK, KIAA1542 and other loci. Nat. Genet. 40, 204–210 (2008).

    Article  CAS  Google Scholar 

  13. Hayden, M.S., West, A.P. & Ghosh, S. NF-κB and the immune response. Oncogene 25, 6758–6780 (2006).

    Article  CAS  Google Scholar 

  14. Mise-Omata, S. et al. A proximal κB site in the IL-23 p19 promoter is responsible for RelA- and c-Rel-dependent transcription. J. Immunol. 179, 6596–6603 (2007).

    Article  CAS  Google Scholar 

  15. Grumont, R. et al. c-Rel regulates interleukin 12 p70 expression in CD8(+) dendritic cells by specifically inducing p35 gene transcription. J. Exp. Med. 194, 1021–1032 (2001).

    Article  CAS  Google Scholar 

  16. Mason, N.J., Liou, H.C. & Hunter, C.A. T cell-intrinsic expression of c-Rel regulates Th1 cell responses essential for resistance to Toxoplasma gondii. J. Immunol. 172, 3704–3711 (2004).

    Article  CAS  Google Scholar 

  17. Bunting, K. et al. Genome-wide analysis of gene expression in T cells to identify targets of the NF-κB transcription factor c-Rel. J. Immunol. 178, 7097–7109 (2007).

    Article  CAS  Google Scholar 

  18. Owyang, A.M. et al. c-Rel is required for the protection of B cells from antigen receptor-mediated, but not Fas-mediated, apoptosis. J. Immunol. 167, 4948–4956 (2001).

    Article  CAS  Google Scholar 

  19. Lu, K.T., Sinquett, F.L., Dryer, R.L., Song, C. & Covey, L.R. c-Rel plays a key role in deficient activation of B cells from a non-X-linked hyper-IgM patient. Blood 108, 3769–3776 (2006).

    Article  CAS  Google Scholar 

  20. Zhou, H.J. et al. Nuclear CD40 interacts with c-Rel and enhances proliferation in aggressive B-cell lymphoma. Blood 110, 2121–2127 (2007).

    Article  CAS  Google Scholar 

  21. Plenge, R.M. et al. Two independent alleles at 6q23 associated with risk of rheumatoid arthritis. Nat. Genet. 39, 1477–1482 (2007).

    Article  CAS  Google Scholar 

  22. Toubi, E. & Shoenfeld, Y. The role of CD40–CD154 interactions in autoimmunity and the benefit of disrupting this pathway. Autoimmunity 37, 457–464 (2004).

    Article  CAS  Google Scholar 

  23. Boumpas, D.T. et al. A short course of BG9588 (anti-CD40 ligand antibody) improves serologic activity and decreases hematuria in patients with proliferative lupus glomerulonephritis. Arthritis Rheum. 48, 719–727 (2003).

    Article  CAS  Google Scholar 

  24. Criswell, L.A. et al. Analysis of families in the multiple autoimmune disease genetics consortium (MADGC) collection: the PTPN22 620W allele associates with multiple autoimmune phenotypes. Am. J. Hum. Genet. 76, 561–571 (2005).

    Article  CAS  Google Scholar 

  25. Sokka, T. & Pincus, T. An Early Rheumatoid Arthritis Treatment Evaluation Registry (ERATER) in the United States. Clin. Exp. Rheumatol. 23, S178–S181 (2005).

    CAS  PubMed  Google Scholar 

  26. Wang, Y. et al. Common 5p15.33 and 6p21.33 variants influence lung cancer risk. Nat. Genet. 40, 1407–1409 (2008).

    Article  CAS  Google Scholar 

  27. Wolfe, F., Michaud, K., Gefeller, O. & Choi, H.K. Predicting mortality in patients with rheumatoid arthritis. Arthritis Rheum. 48, 1530–1542 (2003).

    Article  Google Scholar 

  28. Fries, J.F. et al. HLA-DRB1 genotype associations in 793 white patients from a rheumatoid arthritis inception cohort: frequency, severity, and treatment bias. Arthritis Rheum. 46, 2320–2329 (2002).

    Article  CAS  Google Scholar 

  29. Weisman, M. et al. Analysis at one year of an inception cohort of early rheumatoid arthritis (RA): the SONORA study. Arthritis Rheum. 48, S119 (2003).

    Article  Google Scholar 

  30. Mitchell, M.K., Gregersen, P.K., Johnson, S., Parsons, R. & Vlahov, D. The New York Cancer Project: rationale, organization, design, and baseline characteristics. J. Urban Health 81, 301–310 (2004).

    Article  Google Scholar 

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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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Authors and Affiliations



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.

Corresponding authors

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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Gregersen, P., Amos, C., Lee, A. et al. REL, encoding a member of the NF-κB family of transcription factors, is a newly defined risk locus for rheumatoid arthritis. Nat Genet 41, 820–823 (2009).

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