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首页> 外文期刊>Pharmacogenetics and genomics >Patterns of interaction between genetic and nongenetic attributes and methotrexate efficacy in rheumatoid arthritis.
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Patterns of interaction between genetic and nongenetic attributes and methotrexate efficacy in rheumatoid arthritis.

机译：类风湿关节炎的遗传和非遗传属性与甲氨蝶呤功效之间相互作用的模式。

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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<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. CONCLUSION: Gene-gene interactions together with nongenetic attributes may contribute to methotrexate efficacy in RA.
机译：目的：低渗透性单核苷酸多态性对类风湿关节炎（RA）甲氨蝶呤疗效的影响在研究之间是不一致的。我们试图阐明三组甲氨蝶呤治疗的RA患者甲氨蝶呤反应的结构。方法：在美国和荷兰，对439例接受甲氨蝶呤治疗的患者进行了叶酸，嘌呤和嘧啶途径基因的单核苷酸多态性频率测量，以建立基因-基因相互作用模型。来自瑞典的530名RA患者的第三批研究被用于复制研究结果。使用欧洲抗风湿联盟标准对大多数患者进行甲氨蝶呤疗效评估。结果：在美国和荷兰，氨基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）的变体之间的基因-基因相互作用的非线性模式揭示了与甲氨蝶呤反应显着相关的诱因遗传属性队列[比值比（OR）= 2.9，95％置信区间（CI）：1.9-4.2; P ＜0.001]。尽管这一发现并未在瑞典队列中重复（OR = 0.9; 95％CI：0.64-1.37; P = 0.74），但多因素降维分析将易感的遗传属性与患者的年龄，性别和抗瓜氨酸肽抗体阳性（ACPA）叠加在一起）揭示了在所有三个队列中均显着的相互作用模式（OR = 2.2，95％CI：1.6-2.9; P <0.01）。女性和ACPA阳性患者在存在易感基因属性的情况下对反应的选择优势丧失了，而老年和男性ACPA阴性患者在缺乏易感基因属性的情况下往往表现出更大的反应可能性。结论：基因-基因相互作用以及非遗传属性可能有助于甲氨蝶呤在RA中的疗效。

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