Combined effects of three independent SNPs greatly increase the risk estimate for RA at 6q23

Abstract

The most consistent finding derived from the WTCCC GWAS for rheumatoid arthritis (RA) was association to a SNP at 6q23. We performed a fine-mapping of the region in order to search the 6q23 region for additional disease variants. 3962 RA patients and 3531 healthy controls were included in the study. We found 18 SNPs associated with RA. The SNP showing the strongest association was rs6920220 [P = 2.6 × 10−6, OR (95% CI) 1.22 (1.13–1.33)]. The next most strongly associated SNP was rs13207033 [P = 0.0001, OR (95% CI) 0.86 (0.8–0.93)] which was perfectly correlated with rs10499194, a SNP previously associated with RA in a US/European series. Additionally, we found a number of new potential RA markers, including rs5029937, located in the intron 2 of TNFAIP3. Of the 18 associated SNPs, three polymorphisms, rs6920220, rs13207033 and rs5029937, remained significant after conditional logistic regression analysis. The combination of the carriage of both risk alleles of rs6920220 and rs5029937 together with the absence of the protective allele of rs13207033 was strongly associated with RA when compared with carriage of none [OR of 1.86 (95% CI) (1.51–2.29)]. This equates to an effect size of 1.50 (95% CI 1.21–1.85) compared with controls and is higher than that obtained for any SNP individually. This is the first study to show that the confirmed loci from the GWA studies, that confer only a modest effect size, could harbour a significantly greater effect once the effect of additional risk variants are accounted for.

A failure of TNFAIP3 negative regulation maintains sustained NF-κB activation in Sjögren’s syndrome

“…Given its key function in the fine-tuning of NF-jB signalling, it should be expected that defects in TNFAIP3 expression or function could lead to chronic inflammation and tissue damage. Recent findings have revealed a crucial link between polymorphisms in the human TNFAIP3 locus and a wide spectrum of human autoimmune and inflammatory diseases (Eldor et al 2006;Nenci et al 2007;Graham et al 2008;Musone et al 2008;Orozco et al 2009). …”

Molecular Mechanisms of Rheumatoid Arthritis Revealed by Categorizing Subtypes of Fibroblast-Like Synoviocytes

“…Recently, it was reported that the expression level of A20 in RA-FLSs was lower than that in OA-FLSs (Elsby et al, 2010). Although the difference was not significant, this finding could provide in vitro evidence of altered A20 transcription by 6q23 intergenic SNPs associated with RA (Dieguez-Gonzalez et al, 2009;Orozco et al, 2009). Thus, we speculated that the down-regulation of NF-B inhibitors might be a possible mechanism for enhanced activation of NF-B in high-responder FLSs.…”

Investigation of Candidate Gene Polymorphisms in an Immune Response as Markers for the Risk of Developing Rheumatoid Arthritis and Producing Autoantibodies

“…Как и в подавляющем боль-шинстве исследований, ассоциативная взаимосвязь с по-лиморфизмами имеет разнонаправленный вектор: ми-норные аллели полиморфизмов rs675520 и rs6920220 -положительно, а rs10499194 -отрицательно ассоциирова-ны с РА. Необходимо отметить, что в GWAS и других крупномасштабных исследованиях пик ассоциативной связи приходится на межгенный регион хромосомы 6q23, между генами OLIG3 и TNFAIP3 (известен также как А20) [33][34][35][36][37]. Данный участок хромосомы не содержит после-довательностей, кодирующих какие-либо известные к на-стоящему времени белки.…”