Confirmation of an IRAK3 polymorphism as a genetic marker predicting response to anti-TNF treatment in rheumatoid arthritis

Several genetic variants in Toll-like receptor (TLR) and nuclear factor (NF)-κB signalling pathways have been reported associated with responsiveness to tumour necrosis factor inhibitor (anti-TNF) treatment in rheumatoid arthritis (RA). The present study was undertaken to replicate these findings. In a retrospective case–case study including 1007 Danish anti-TNF-treated RA patients, we genotyped 7 previously reported associated single-nucleotide polymorphisms (SNPs) in these pathways. Furthermore, 5 SNPs previously reported by our group were genotyped in a subcohort ( N= 469). Primary analyses validated the IRAK3 rs11541076 variant as associated (odds ratio (OR)=1.33, 95% confidence interval (CI): 1.00–1.77, P -value=0.047) with a positive treatment response (EULAR (European League Against Rheumatism) good/moderate vs none response at 4±2 months), and found the NLRP3 rs461266 variant associated (OR=0.75, 95% CI: 0.60–0.94, P= 0.014) with a negative treatment response. Meta-analyses combining data from previous studies suggested smaller effect sizes of associations between variant alleles of CHUK rs11591741, NFKBIB rs3136645 and rs9403 and a negative treatment response. In conclusion, this study validates rs11541076 in IRAK3 , a negative regulator of TLR signalling, as a predictor of anti-TNF treatment response, and suggests true positive associations of previously reported SNPs within genes encoding activators/inhibitors of NF-κB ( CHUK , MYD88, NFKBIB , and NLRP3 ).