Musculoskeletal Research Group, Institute of Cellular Medicine, University of Newcastle, 4th Floor Catherine Cookson Building, Framlington Place, Newcastle upon Tyne NE2 4HH, UK.
Ann Rheum Dis. 2010 Jul;69(7):1315-20. doi: 10.1136/ard.2009.117309. Epub 2010 May 6.
To determine whether genetic variation within genes integral to the Toll-like receptor (TLR) and NFkappaB signalling systems, two cardinal regulators of inflammatory and immune responses, contributes towards the observed variation in response to tumour necrosis factor (TNF) blocking agents in patients with rheumatoid arthritis (RA).
Pairwise-tagging single nucleotide polymorphisms (SNPs) spanning 24 candidate genes were selected and genotyped in a large UK cohort of patients receiving anti-TNF therapy for RA. Multivariate regression analyses were performed to test association between individual genotypes, under an additive model, and treatment response at 6 months' follow-up assessed using both the absolute change in 28-joint count Disease Activity Score (DAS28) and the European League Against Rheumatism (EULAR) response criteria. Analyses were performed across subgroups comprising etanercept-, infliximab- and infliximab/adalimumab-treated patients as well as the combined anti-TNF-treated cohort. p Values <0.05 were considered statistically significant.
A total of 187 SNPs were successfully genotyped and analysed in 909 patients. Eight SNPs spanning six genes demonstrated nominal evidence of association with response (DAS28) across the anti-TNF-treated subgroups, six of which were restricted to etanercept-treated patients. Twelve SNPs spanning nine genes demonstrated nominal evidence of association with treatment response (DAS28 and/or EULAR) across the combined anti-TNF cohort. These included SNPs mapping to MyD88 (rs7744) and CHUK (rs11591741), which were associated under each model applied (etanercept-treated and combined anti-TNF cohort analysis (DAS28 and EULAR)).
Several SNPs mapping to the TLR and NFkappaB signalling systems demonstrated association with anti-TNF response as a whole and, in particular, with response to etanercept. Validation of these findings in an independent cohort is now warranted.
确定 Toll 样受体 (TLR) 和 NFkappaB 信号系统中对炎症和免疫反应起关键调节作用的基因内的遗传变异是否导致类风湿关节炎 (RA) 患者对肿瘤坏死因子 (TNF) 阻断剂反应的观察结果存在差异。
选择跨越 24 个候选基因的成对标记单核苷酸多态性 (SNP)，并对接受抗 TNF 治疗的大量英国 RA 患者进行基因分型。采用多元回归分析，在加性模型下，对个体基因型与 6 个月随访时的治疗反应之间进行关联检验，治疗反应采用 28 关节计数疾病活动评分 (DAS28) 的绝对变化和欧洲抗风湿病联盟 (EULAR) 反应标准进行评估。在依那西普、英夫利昔单抗和英夫利昔单抗/阿达木单抗治疗亚组以及联合抗 TNF 治疗队列中进行了分析。p 值<0.05 被认为具有统计学意义。
共成功对 909 例患者的 187 个 SNP 进行了基因分型和分析。跨越六个基因的 8 个 SNP 在抗 TNF 治疗亚组中与反应 (DAS28) 具有名义上的关联，其中六个 SNP 仅限于依那西普治疗的患者。跨越联合抗 TNF 队列的 9 个基因的 12 个 SNP 与治疗反应 (DAS28 和/或 EULAR) 具有名义上的关联。这些 SNP 包括定位在 MyD88(rs7744) 和 CHUK(rs11591741) 的 SNP，它们在应用的每种模型下都与反应相关 (依那西普治疗和联合抗 TNF 队列分析 (DAS28 和 EULAR))。
几个映射到 TLR 和 NFkappaB 信号系统的 SNP 与整个抗 TNF 反应相关，特别是与依那西普的反应相关。现在需要在独立队列中验证这些发现。
