We confirmed the known markers ANKRD55 (meta-analysis odds ratio [OR] 0.80; P = 2.8 × 10(-13) ) and BLK (OR 1.13; P = 7.0 × 10(-6) ) and identified new and specific markers of anti-CCP-negative RA (prolactin [PRL] [OR 1.13; P = 2.1 × 10(-6) ] and NFIA [OR 0.85; P = 2.5 × 10(-6) ]).
In individuals carrying the BLKrs13277113 GG genotype, presence of the BANK1 rs3733197 G allele increased the risk of RA (odds ratio 1.21 [95% confidence interval 1.04-1.41], P = 0.015.
A non-intronic marker at TNFAIP3, GIN1/C5orf30, STAT4, ANKRD55/IL6ST, BLK and PTPN22 showed association with RA susceptibility, irrespective of the serological status, the latter three markers remaining significantly associated with anti-CCP negative RA, after correction for multiple testing.
We replicated the genetic association with rs13277113 (p = 0.0009, OR 1.46) and rs2736340 (p = 0.0001, OR 1.63) from C8orf13-BLK (8p23.1, associated with RA and systemic lupus erythematosus), and rs763361 (p = 0.03) from CD226 (18q22.3, associated with multiple sclerosis and type 1 diabetes) in the Colombian population.
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.