Exagen Diagnostics, Inc., Albuquerque, New Mexico, USA.
Pharmacogenet Genomics. 2012 Jan;22(1):1-9. doi: 10.1097/FPC.0b013e32834d3e0b.
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.
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.
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<0.001]. Although the finding was not replicated in the Swedish cohort (OR=0.9; 95% CI: 0.64-1.37; P=0.74) a multifactor dimensionality reduction analysis superimposing the predisposing genetic attribute with patient's age, sex, and anticitrullinated peptide antibodies positivity (ACPA) revealed a pattern of interaction significant in all three cohorts (OR=2.2, 95% CI: 1.6-2.9; P<0.01). The selective advantage toward response in the presence of the predisposing genetic attribute was lost in females and ACPA-positive patients, whereas older and male ACPA-negative patients tended to exhibit a greater likelihood of response in the absence of the predisposing genetic attribute.
Gene-gene interactions together with nongenetic attributes may contribute to methotrexate efficacy in RA.
低外显率单核苷酸多态性对类风湿关节炎（RA）患者甲氨蝶呤疗效的影响在不同研究中结果并不一致。本研究旨在通过对接受甲氨蝶呤治疗的三组 RA 患者的研究，阐明甲氨蝶呤反应的结构。
采用多因子降维方法，对来自叶酸、嘌呤和嘧啶途径的基因中的单核苷酸多态性频率进行测量，以建立一个基因-基因相互作用模型。该模型纳入了 439 名在美国和荷兰接受甲氨蝶呤治疗的患者。随后，我们使用第三个来自瑞典的 530 名 RA 患者队列来验证该结果。大多数患者采用欧洲抗风湿病联盟（EULAR）标准评估甲氨蝶呤的疗效。
在 USA 和 Dutch 队列中，氨基咪唑甲酰胺核糖核苷酸转甲酰酶（C347G）、还原叶酸载体（G80A）和肌苷三磷酸焦磷酸酶（C94A）中的变异之间的非线性基因-基因相互作用模式揭示了一种遗传易感性，该易感性与甲氨蝶呤的反应显著相关（比值比（OR）=2.9，95%置信区间（CI）：1.9-4.2；P<0.001）。虽然这一发现并未在瑞典队列中得到复制（OR=0.9；95% CI：0.64-1.37；P=0.74），但多因子降维分析叠加易感性遗传特征与患者年龄、性别和抗瓜氨酸肽抗体（ACPA）阳性的结果显示，这一交互模式在三个队列中均具有统计学意义（OR=2.2，95% CI：1.6-2.9；P<0.01）。在存在易感性遗传特征的情况下，对治疗有反应的选择优势在女性和 ACPA 阳性患者中丧失，而年龄较大和男性、ACPA 阴性的患者在不存在易感性遗传特征的情况下，往往表现出更大的反应可能性。
基因-基因相互作用以及非遗传因素可能有助于 RA 患者对甲氨蝶呤的疗效。
