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

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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).The Pharmacogenomics Journal advance online publication, 4 October 2016; doi:10.1038/tpj.2016.66.

Original languageEnglish
JournalThe pharmacogenomics journal
Issue number1
Pages (from-to)81-86
Publication statusPublished - 2018

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    Research areas

  • Journal Article

ID: 49910849