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

Peter K Gregersen, Chistopher I Amos, Annette T Lee, Yue Lu, Elaine F Remmers, Daniel L Kastner, Michael F Seldin, Lindsey A Criswell, Robert M Plenge, V Michael Holers, Ted R Mikuls, Tuulikki Sokka, Larry W Moreland, S Louis Bridges Jr, Gang Xie, Ann B Begovich, Katherine A Siminovitch, Peter K Gregersen, Chistopher I Amos, Annette T Lee, Yue Lu, Elaine F Remmers, Daniel L Kastner, Michael F Seldin, Lindsey A Criswell, Robert M Plenge, V Michael Holers, Ted R Mikuls, Tuulikki Sokka, Larry W Moreland, S Louis Bridges Jr, Gang Xie, Ann B Begovich, Katherine A Siminovitch

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 x 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 x 10(-14)) for marker rs13031237 and an allelic OR = 1.21 (P = 2.60 x 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 x 10(-9)) and BLK (rs2736340; OR = 1.19; P = 5.69 x 10(-9)). c-Rel is an NF-kappaB 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 PRKCQ.

Figures

Figure 1
Figure 1
Summary of genome-wide association scan results for 2418 cases and 4504 controls. The -log10 of the trend test P values after homogeneous clustering and corrected for the residual genome wide inflation of chi square are plotted against position on each chromosome. Chromosomes are shown in alternating colors for clarity. The blue horizontal line indicates SNPs that are significant at a level (P = 5 × 10-5). The results for markers in the HLA region are truncated.
Figure 2
Figure 2
Association localization plots in the region around REL following discovery and replication phases. The p values for all samples in the GWA scan are shown as small blue diamonds, with the exception of the results for two SNPs, rs13031237 and rs13017599 (P = 9.05 × 10-9 and p = 6.01 × 10-10) in c-Rel , which are presented as red diamonds. The black diamonds show the independent results for these two SNPs in the replication samples.

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Source: PubMed

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