Sode J, Vogel U, Bank S, Andersen P S, Hetland M L, Locht H, Heegaard N H H, Andersen V
Department of Autoimmunology and Biomarkers, Statens Serum Institut, Copenhagen, Denmark.
Department of Rheumatology, Frederiksberg Hospital, Frederiksberg, Denmark.
Pharmacogenomics J. 2018 Jan;18(1):81-86. doi: 10.1038/tpj.2016.66. Epub 2016 Oct 4.
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).
已有报道称，Toll样受体（TLR）和核因子（NF）-κB信号通路中的多个基因变异与类风湿关节炎（RA）患者对肿瘤坏死因子抑制剂（抗TNF）治疗的反应性相关。本研究旨在重复这些发现。在一项纳入1007例接受抗TNF治疗的丹麦RA患者的回顾性病例对照研究中，我们对这些信号通路中7个先前报道的相关单核苷酸多态性（SNP）进行了基因分型。此外，我们对一个亚组（N = 469）中的5个先前本研究团队报道的SNP进行了基因分型。初步分析验证了IRAK3基因的rs11541076变异与阳性治疗反应（欧洲抗风湿病联盟（EULAR）在4±2个月时评估为良好/中等反应与无反应）相关（比值比（OR）=1.33，95%置信区间（CI）：1.00 - 1.77，P值=0.047），并发现NLRP3基因的rs461266变异与阴性治疗反应相关（OR = 0.75，95% CI：0.60 - 0.94，P = 0.014）。合并先前研究数据的荟萃分析表明，CHUK基因的rs11591741、NFKBIB基因的rs3136645和rs9403的变异等位基因与阴性治疗反应之间的关联效应大小较小。总之，本研究验证了TLR信号的负调节因子IRAK3基因中的rs11541076可作为抗TNF治疗反应的预测指标，并提示了先前报道的编码NF-κB激活剂/抑制剂的基因（CHUK、MYD88、NFKBIB和NLRP3）内SNP存在真正的阳性关联。
