基因多态性影响甲氨蝶呤治疗强直性脊柱炎患者的疗效和毒性

Gene polymorphisms Impact on the Efficacy and Toxicity of Methotrexate Therapy in Patients with Ankylosing Spondylitis

目的探讨相关基因多态性和非遗传因素对甲氨蝶呤治疗强直性脊柱炎的疗效和毒性的影响,为个体化用药提供依据。方法选择105例于2009年12月~2015年1月在某院风湿科就诊的强直性脊柱炎患者。采用限制性片段长度多态性聚合酶链式反应法检测6个单核苷酸基因多态性位点,包括RFC1 G80A、MDR1 C3435T、GGH C-401T、FPGS(rs1544105)G>A、MTHFR C677T和MTHFR A1298C。采用χ~2检验、非参数检验、回归分析等方法检验上述基因及非遗传因素与甲氨蝶呤疗效及毒性间的相关性。结果年龄对强直性脊柱炎功能指数、疾病活动指数(BASFIb、BASDAIb)有显著影响(P=0.027,P=0.004),年龄越大,疗效越差(r=-0.216,r=-0.276)。MTHFR A1298C与总疗效有显著相关性(P=0.017),纯合型的患者更容易发生治疗失败。MDR1 C3435T纯合型对BASFIb有影响,纯合型患者躯体功能恢复更差(P=0.046)。各基因型与不良反应间的相关性差异无统计学意义。结论 MTHFR A1298C、MDR1 C3435T及年龄显著影响疗效,需注意个体化给药。暂未发现甲氨蝶呤不良反应的风险基因。

OBJECTIVE To determine the correlation between gene polymorphisms,non-genetic factors and efficacy and toxicity of methotrexate therapy in patients with ankylosing spondylitis for individual administration. METHODS A number of 105 patients with ankylosing spondylitis were recruited,who were treated in department of rheumatology between Dec. 2009 and Jan. 2015. Genotypes of RFC1 G80 A,MDR1 C3435 T,GGH C-401 T,FPGS（ rs1544105） G A,MTHFR C677 T and MTHFR A1298 C were detected by PCRRFLP method. The correlation between genetic factors and non-genetic factors and efficacy and toxicity of methotrexate were analyzed by using chi-square test,non-parametric test and regression analysis,etc. RESULTS BASFIb、BASDAIb were impacted by age（ P =0.027,P = 0.004）. The older the patient,the lower the response（ r =-0.216,r =-0.276）. Total response was affected significantly by MTHFR A1298C（ P = 0.017）. Patients carried with MTHFR 1298 CC genotype were more likely experienced low efficacy. BASFIb was affected by MDR1 C3435 T. Patients carried with TT genotype were harder to get good response. No association was found between genetic polymorphisms and toxicity. CONCLUSION The efficacy of methotrexate is impacted by MTHFR A1298 C,MDR1 C3435 T and age. More attention should be paid to those patients for better efficacy by individual administration. No risk genotype is found to correlate with toxicity of methotrexate.