全基因组关联研究发现TNF抑制剂治疗RA与7个位点的多态性有关

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Arthritis Rheum. 2010 Nov 8. [Epub ahead of print] Genome-wide association study of genetic predictors of anti-tumour necrosis factor (TNF) treatment in rheumatoid arthritis (RA) identifies associations with polymorphisms at seven loci. Plant D, Bowes J, Potter C, Hyrich KL, Morgan AW, Wilson AG, Isaacs JD, Barton A. Arthritis Research UK Epidemiology Unit, University of Manchester, Manchester, UK. Abstract OBJECTIVE: Anti-tumour necrosis factor (TNF) agents are successful therapies in rheumatoid arthritis (RA); however, inadequate response occurs in 30-40% of patients treated. Knowledge of genetic factors influencing response may facilitate personalised therapy. The purpose of this study was to identify genetic predictors of response to anti-TNF therapy in RA and to validate our findings in independent cohorts. METHODS: Genome-wide association (GWA) data was available from the Wellcome Trust Case-Control Consortium for 566 anti-TNF-treated RA patients. Multivariate linear regression analysis of change in 28 joint count disease activity score (DAS28) at 6 months was conducted at each single nucleotide polymorphism (SNP) using an additive model. Associated markers (P < 10(-3)) were genotyped in two independent replication cohorts (n = 379 and n = 341) and a combined analysis was performed. RESULTS: Of 171 successfully genotyped markers demonstrating association with treatment response in the GWA data, 7 were corroborated in the combined analysis. The strongest effect was at rs17301249 mapping to the gene EYA4 on chromosome 6: the minor allele conferred improved response to treatment (coef. -0.27, P = 5.67E-05). The minor allele of rs1532269, mapping to the PDZD2 gene, was associated with reduced treatment response (coef. 0.20, P = 7.37E-04). The remaining associated SNPs mapped to intergenic-regions on chromosomes 1, 4, 11 and 12. CONCLUSIONS: Using a genome-wide strategy, we have identified and validated association of 7 genetic loci with response to anti-TNF treatment in RA. Additional confirmation of these findings in further cohorts will be required.

全基因组关联研究发现TNF抑制剂治疗RA与7个位点的多态性有关 Plant D, et al.Arthritis Rheum. 2010 Nov 8.   目的：TNF抑制剂能有效治疗RA，但仍有30%~40%患者疗效欠佳。明确影响疗效的遗传因素可能有助于个体化治疗。本文旨在明确TNF抑制剂治疗RA疗效的遗传预测因素，并在独立队列中验证我们的发现。   方法：从威康信托基金会病例控制协会的566例使用TNF抑制剂的RA患者采集全基因组关联（GWA）数据。采用相加模型、对各单核苷酸多态性（SNP）进行6个月DAS28变化的多变量线性回归分析。相关标记物(P < 10(-3))在2个独立复制队列中进行遗传分型（n = 379和n = 341），并进行组合分析。   结果：在GWA的171个成功遗传分型、与疗效相关的标记物中，7个在组合分析中得到验证。定位于6号染色体上EYA4基因的rs17301249作用最强：次要等位基因与疗效较好有关(coef. -0.27, P = 5.67E-05)。定位于PDZD2基因的rs1532269次要等位基因与疗效欠佳相关（coef. 0.20, P = 7.37E-04）。其他相关的SNPs定位在第1、4、11和12号染色体的基因间隔区。   结论：采用全基因组策略，我们鉴定并验证了7个与TNF抑制剂治疗RA疗效相关的遗传位点。这些发现需要进一步证实。