Patterns of interaction between genetic and nongenetic attributes and methotrexate efficacy in rheumatoid arthritis
Patterns of interaction between genetic and nongenetic attributes and methotrexate efficacy in rheumatoid arthritis
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DOI：
10.1097/fpc.0b013e32834d3e0b
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发表时间：
2012-01-01
影响因子：
2.6
通讯作者：
Guchelaar, Henk-Jan
中科院分区：
文献类型：
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作者：
Dervieux, Thierry;Wessels, Judith A. M.;Guchelaar, Henk-Jan
目的低外显率单核苷酸多态性对甲氨蝶呤治疗类风湿性关节炎（RA）疗效的影响在不同研究中并不一致。我们试图阐明在接受甲氨蝶呤治疗的三组RA患者中甲氨蝶呤反应的结构。方法对美国和荷兰439例接受甲氨蝶呤治疗的患者的叶酸、嘌呤和嘧啶途径基因的单核苷酸多态性频率进行测量，建立基因-基因相互作用的多因素降维模型。来自瑞典的530名RA患者的第三个队列被用来重复研究结果。大多数患者使用欧洲抗风湿病联盟标准评估甲氨蝶呤的疗效。结果氨咪唑羧酰胺核糖核苷酸转化酶（C347G）、叶酸还原载体（G80A）和肌苷-三磷酸焦磷酸酶（C94A）变异之间基因-基因相互作用的非线性模式显示，在美国和荷兰队列中，易感遗传属性与甲氨蝶呤反应显著相关[优势比(OR)=2.9, 95%可信区间（CI）： 1.9-4.2；P
Objective The contribution of low-penetrance single nucleotide polymorphisms to methotrexate efficacy in rheumatoid arthritis (RA) is inconsistent between studies. We sought to elucidate architecture of methotrexate response in three cohorts of patients with RA treated with methotrexate.Methods Single nucleotide polymorphism frequencies in genes from folate, purine, and pyrimidine pathways were measured to develop a model of gene-gene interactions using multifactor dimensionality reduction in 439 patients who received methotrexate in the USA and The Netherlands. A third cohort of 530 patients with RA from Sweden was used to replicate the findings. Methotrexate efficacy was assessed using the European League Against Rheumatism criteria in the majority of patients.Results Nonlinear patterns of gene-gene interactions between variants in aminoimidazole carboxamide ribonucleotide transformylase (C347G), reduced-folate carrier (G80A) and inosine-triphosphate pyrophosphatase (C94A) revealed a predisposing genetic attribute significantly associated with methotrexate response in the USA and Dutch cohorts [odds ratio (OR)=2.9, 95% confidence interval (CI): 1.9-4.2; P