Genetic Variations in Pattern Recognition Receptor Loci Are Associated with Anti-TNF Response in Patients with Rheumatoid Arthritis

ObjectivesTo determine whether genetic variation within genes related to the Toll-like receptor, inflammasome and interferon-γ pathways contributes to the differences in treatment response to tumour necrosis factor inhibitors (anti-TNF) in patients with rheumatoid arthritis (RA).MethodsIn a retrospective case-case study, we assessed 23 functional single nucleotide polymorphisms (SNPs) in 15 genes. We included 538 anti-TNF naïve Danish RA patients from the nationwide DANBIO database. Multivariable logistic regression analyses were performed to detect associations (p-valueResultsSix of twenty successfully genotyped polymorphisms were nominally associated with EULAR treatment response. Three of these were in weak to moderate linkage disequilibrium with polymorphisms previously reported associated with anti-TNF treatment response. TLR5(rs5744174) variant allele carriers (odds ratio(OR) = 1.7(1.1–2.5),p = 0.010,q = 0.46) and TLR1(rs4833095) homozygous variant carriers (OR = 2.8(1.1–7.4),p = 0.037,q = 0.46) had higher odds for a positive treatment response. NLRP3(rs10754558) variant allele carriers (odds ratio(OR) = 0.6(0.4–1.0),p = 0.045,q = 0.46) were more likely to have a negative treatment response.The association in TLR5(rs5744174) remained significant after correction for multiple comparisons among patients negative for RF (OR = 6.2(2.4–16.3),p = 0.0002,q = 0.024). No other association withstood correction for multiple testing. Post hoc analyses showed that change in Patient Global score on a visual analogue scale (VAS) and change in pain VAS were the main factors responsible for the association.ConclusionsWe reproduced previously reported associations between genetic variation in the TLR10/1/6 gene cluster, TLR5, and NLRP3 loci and response to anti-TNF treatment in RA. Changes in VAS pain and patient global scores were the main contributors to the association found for TLR5. Furthermore, we identified other candidate genes that require replication in independent cohorts.

研究目的：旨在明确Toll样受体（Toll-like receptor, TLR）、炎症小体及γ干扰素通路相关基因的遗传变异，是否会导致类风湿关节炎（rheumatoid arthritis, RA）患者对肿瘤坏死因子抑制剂（tumour necrosis factor inhibitors, anti-TNF）的治疗应答存在差异。

研究方法：本研究采用回顾性病例-病例研究设计，对15个基因中的23个功能性单核苷酸多态性（single nucleotide polymorphism, SNPs）进行检测。研究纳入了来自全国性DANBIO数据库的538例初治抗TNF的丹麦RA患者。采用多变量logistic回归分析检测遗传变异与治疗应答的关联（P值）。

研究结果：20个成功完成基因分型的多态性位点中，有6个与欧洲抗风湿病联盟（European League Against Rheumatism, EULAR）治疗应答存在名义统计学关联。其中3个位点与既往报道的与抗TNF治疗应答相关的多态性存在弱至中等程度的连锁不平衡。携带Toll样受体5（Toll-like receptor 5, TLR5）rs5744174变异等位基因的个体（优势比（odds ratio, OR）=1.7[95%置信区间:1.1–2.5], P=0.010, q=0.46），以及Toll样受体1（Toll-like receptor 1, TLR1）rs4833095纯合变异携带者（OR=2.8[95%置信区间:1.1–7.4], P=0.037, q=0.46），获得阳性治疗应答的概率更高。携带NLR家族pyrin结构域包含3（NLR family pyrin domain containing 3, NLRP3）rs10754558变异等位基因的个体（OR=0.6[95%置信区间:0.4–1.0], P=0.045, q=0.46），获得阴性治疗应答的可能性更高。在类风湿因子（rheumatoid factor, RF）阴性的患者亚组中，经多重比较校正后，TLR5 rs5744174的关联仍具有统计学意义（OR=6.2[95%置信区间:2.4–16.3], P=0.0002, q=0.024）。其余所有关联均未通过多重检验校正。事后分析显示，患者整体评分的视觉模拟量表（visual analogue scale, VAS）变化及疼痛VAS评分变化，是驱动该关联产生的主要因素。

结论：本研究重复验证了既往报道的TLR10/1/6基因簇、TLR5及NLRP3位点的遗传变异与RA患者抗TNF治疗应答之间的关联。VAS疼痛评分与患者整体评分的变化，是TLR5相关关联的主要贡献因素。此外，本研究还鉴定出其他候选基因，需在独立队列中进行验证。