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

J Sode, U Vogel, S Bank, P S Andersen, M L Hetland, H Locht, N H H Heegaard, V Andersen

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Abstract

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).

Original languageEnglish
JournalThe Pharmacogenomics Journal
Volume18
Issue number1
Pages (from-to)81-86
ISSN1470-269X
DOIs
Publication statusPublished - Jan 2018

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Keywords

  • Alleles
  • Antirheumatic Agents/therapeutic use
  • Arthritis, Rheumatoid/drug therapy
  • Case-Control Studies
  • Female
  • Genetic Markers/genetics
  • Genotype
  • Humans
  • Interleukin-1 Receptor-Associated Kinases/genetics
  • Male
  • Middle Aged
  • Polymorphism, Single Nucleotide/genetics
  • Retrospective Studies
  • Tumor Necrosis Factor-alpha/antagonists & inhibitors

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