类风湿关节炎患者选用甲氨蝶呤前应查MTHFR基因多态性

1.目的

甲氨蝶呤在类风湿关节炎的治疗中应用最广泛，但约45%的患者因其无效或毒性在2年内中断治疗。一些研究者报道类风湿关节炎患者的MTHFR基因C677T位点多态性对甲氨蝶呤疗效上的结果相互矛盾，本研究目的是进一步了解该基因与欧洲类风湿关节炎患者的相关性。

2．方法

共有269例来自意大利和匈牙利的类风湿关节炎患者，其中73.2%的患者（197例患者）有甲氨蝶呤治疗资料，使用荧光定量PCR对C677T基因多态性（rs1801133)进行基因分型，并用基因分型相关分析和Kaplan-Meier法，对甲氨蝶呤继续服用者和终止服用者间行统计学比较。

3．结果

197例RA患者中有85例患者（43%）终止甲氨蝶呤治疗，不管在研究终点(p=0.375)还是随访期(p=0.324)，均未发现C677T基因型与甲氨蝶呤终止治疗的相关性。但仅限于单用甲氨蝶呤治疗的68例患者进行分析发现，这种相关性正好处在显著性边缘(OR 3.15, 95% CI 0.93-10.67, p=0.057)，与此一致的是，Kaplan-Meier分析显示，携带TT纯合子者在更短的时间内中断甲氨蝶呤治疗(p=0.042)。

4．结论

欧洲多中心队列研究显示，MTHFR基因的C677T多态性（TT纯合子型）与单用甲氨蝶呤中断治疗相关，肯定了以前的结果。

5．附原文

Abstract OBJECTIVES: Methotrexate (MTX) is the most widely prescribed drug for rheumatoid arthritis (RA) patients, but 45% of them discontinue therapy with in two years, either due to inefficacy or toxicity. Several authors have reported contradictory results related to C677T polymorphism in the MTHFR gene and response to MTX in RA. The purpose of this study was to further explore this genotype-response association in a European RA population. METHODS: This retrospective longitudinal study included a total of 269 RA patients from Italy and Hungary, of whom 73.2% had available data on MTX treatment (197 patients). C677T polymorphism (rs1801133) was genotyped by quantitative PCR using TaqMan assays. Genotype association analysis and Kaplan-Meier method were used for statistical comparisons between patients continuing and patients who abandoned MTX treatment. RESULTS: A total of 85 out of the 197 RA patients (43%) abandoned MTX treatment by the time of analysis. No significant genotype-MTX discontinuation association was found for the overall population, either at the end of the study (p=0.375), or during the follow-up (p=0.324). When the analysis was restricted to the 68 patients on MTX monotherapy, a borderline association (OR 3.15, 95% CI 0.93-10.67, p=0.057) was noted with the recessive genetic model. In agreement with that, a Kaplan-Meier analysis showed a significantly shorter time-to-discontinuation of MTX monotherapy for homozygous carriers of the T-allele (p=0.042). CONCLUSIONS: These results demonstrate that the C677T polymorphism in the MTHFR gene is involved in MTX monotherapy discontinuation in a multicentre European patient cohort, confirming previous results.

6．引自

Uribarri M1, Ruiz-Larrañaga O2, Arteta D1, Hernández L1, Alcaro MC3, Martínez A1, Escorza-Treviño S1, Estonba A2, Migliorini P4, Czirják L5, del Amo J1.Influence of MTHFR C677T polymorphism on methotrexate monotherapy discontinuation in rheumatoid arthritispatients: results from the GAPAID European project. Clin Exp Rheumatol. 2015 Sep-Oct;33(5):699-705. Epub 2015 Aug 27.