Genetic determinants of methotrexate toxicity in rheumatoid arthritis patients: a study of polymorphisms affecting methotrexate transport and folate metabolism
Genetic determinants of methotrexate toxicity in rheumatoid arthritis patients: a study of polymorphisms affecting methotrexate transport and folate metabolism
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DOI：
10.1007/s00228-008-0521-7
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发表时间：
2008-11-01
影响因子：
2.9
通讯作者：
Dolzan, Vita
中科院分区：
文献类型：
--
作者：
Grabar, Petra Bohanec;Logar, Dusan;Dolzan, Vita
目的甲氨蝶呤（MTX）是一种用于治疗类风湿关节炎（RA）的缓解病情的抗风湿药物。还原型叶酸携带者的遗传多态性（RFC 1 A80 G），P-糖蛋白（MDR 1 G2677 T>A/C和C3435 T），5，10-亚甲基四氢叶酸还原酶（MTHFR C677 T和A1298 C），胸苷酸合成酶（TS 2R -> 3R），甲硫氨酸合酶（MS A2756 G）和甲硫氨酸合成酶还原酶（MTRR A66G）方法采用基因分型方法对213例RA患者进行基因分型，并对213例RA患者的基因多态性进行分析。观察到56例（26.3%）患者因不良反应和/或毒性而停止MTX治疗。RFC 1 A80 G和MDR 1 C3435 T多态性增加MTX总体毒性的风险MTHFR A1298 C基因多态性对MTX的毒性有保护作用（P= 0.039，OR=3.574，95%CI =1.065-11.993和P=0.032，OR=7.801，95%CI = 1.194-50.960）结论叶酸代谢途径和MTX转运蛋白基因多态性可能影响MTX治疗的毒副反应，但不影响疗效。
Objective Methotrexate (MTX) is a disease-modifying antirheumatic drug used in the treatment of rheumatoid arthritis ( RA). Genetic polymorphisms of reduced folate carrier (RFC1 A80G), P-glycoprotein (MDR1 G2677T>A/C and C3435T), 5,10-methylenetetrahydrofolate reductase ( MTHFR C677T and A1298C), thymidylate synthase (TS 2R -> 3R), methionine synthase ( MS A2756G) and methionine synthase reductase ( MTRR A66G) modify MTX transport and metabolic effects and may influence the treatment response.Methods A genotyping approach was used to determine the studied polymorphisms in 213 RA patients.Results We observed that 56 (26.3%) patients discontinued MTX treatment due to poor response and/or toxicity. RFC1 A80G and MDR1 C3435T polymorphisms increased the risk for overall MTX toxicity (P= 0.039, OR=3.574, 95% CI=1.065-11.993 and P=0.032, OR=7.801, 95% CI= 1.194-50.960 respectively), while MTHFR A1298C polymorphism had a protective effect on overall MTX toxicity (P=0.027, OR=0.170, 95% CI=0.035-0.820).Conclusion Our results suggest that genetic polymorphisms in the folate metabolic pathway and MTX transporters modify the toxicity but not the efficacy of MTX treatment..