rs2004640

rs2004640, a SNP in the IRF5 gene in chromosomal region 7q32.1, is one of several SNPs associated with systemic lupus erythematosus (SLE). This association has been observed in multiple populations (Caucasian, Asian, and African-Americans). The association was first noted in two relatively large studies of Caucasian patients.PMID 15657875, PMID 16642019 In ~600 Korean SLE patients, the odds ratio for the rs2004640(T) risk allele was 1.44 (CI: 1.34-1.55, overall p=1.85x10e-23). The rs2004640-T/rs2280714-T haplotype involved in both the alternative splice donor site and the elevated expression of the IRF5 protein also had a highly significant association with SLE (pooled p=2.11x 10e-16). Reconfirmed for African-Americans Reconfirmed in ~370 female Caucasian patients Reconfirmed in ~380 UK SLE families Pooled data from two populations (Japanese and Korean) were combined to determine that the rs2004640(T) allele frequency was significantly increased in SLE patients (p = 8.3 x 10 -5 ). A variant located 64 bp upstream of the first untranslated exon (exon 1A), consisting of a 5 bp insertion/deletion CGGGG (rs77571059), may be the causative SNP in this region that is most responsible for increasing SLE risk. In a Korean population, rs2004640 was associated with both the anti-CCP Ab-positive (odds ratio 1.47, CI: 1.15-1.88, pcorr = 0.01) and SE-positive group (odds ratio 1.54, CI: 1.14-2.09, pcorr = 0.03) forms of rheumatoid arthritis. Combined analysis pooling 3 independent cohorts yielded an association with an odds ratio of 1.21, CI: 1.07-1.38, pooled p = 0.0031 in a dominant model. rs2004640(T;T) is associated with susceptibility to systemic sclerosis in a study of ~800 French Caucasian patients, with an odds ratio of 1.58 (CI: 1.18 - 2.11, p trend 0.002). A meta-analysis comprising 5 case-control studies, totaling 6,582 rheumatoid arthritis cases and 5,375 controls, concluded that several IRF5 gene SNPs were indeed (still) significantly associated with the disease. The rs2004640(G) allele was associated with a slight protective effect (odds ratio 0.9, CI: 0.85-0.96, p = 0.002). Of 3 IRF5 SNPs studied, the rs2280714(A) SNP (and not this one) had the strongest association (odds ratio 1.42, CI: 1.15-1.75) in Japanese SLE patients. Association with multiple sclerosis (along with several other SNPs) was observed after combining data from Swedish and Spanish case/control studies and a Finnish trio study.