甲氨蝶呤注射液所致药物不良反应与叶酰多聚谷氨酸合成酶和γ-谷氨酰水解酶基因多态性的相关性

Relationships between folypolyglutamate synthetase and gamma-glutamyl hydrolase genetic polymorphisms with adverse drug reactions induced by methotrexate injection

目的考察叶酰多聚谷氨酸合成酶(FPGS)rsl544105和γ-谷氨酰水解酶(GGH)rs3758149基因多态性与甲氨蝶呤(MTX)治疗非霍奇金淋巴瘤(NHL)所致药物不良反应的相关性。方法收集81例使用大剂量MTX化疗的NHL患者血样,用直接测序法检测FPGS rsl544105和GGH rs3758149基因多态性。用美国国立癌症中心通用药物不良反应术语标准统一评价MTX化疗后的药物不良反应。用SPPS软件分析FPGS rsl544105和GGH rs3758149基因多态性与MTX药物不良反应的相关性。结果 FPGS rsl544105位点GG、GA和AA基因的分布频率分别为6.17%,39.51%和54.32%,G和A等位基因的分布频率为25.93%和74.07%。GGH rs3758149位点CC、CT和TT基因的分布频率分别为65.43%,33.33%和1.23%,C和T等位基因的分布频率为82.10%和17.90%。FPGS rs1544105野生型(GG)和突变型(GA+AA)患者发生2级以上骨髓毒性和肝毒性的比例之间差异无统计学意义(P>0.05)。GGH rs3758149野生型(CC)和突变型(CT+TT)患者发生2级以上中性粒细胞减少的比例分别为35.85%和10.71%,差异有统计学意义(P<0.05)。结论 FPGS rsl544105可能与NHL患者MTX化疗后2级以上骨髓毒性和肝毒性发生率无相关性;而GGH rs3758149基因多态性与NHL患者MTX化疗后2级以上中性粒细胞减少发生率存在相关性。

Objective To investigate the relationships between fol- ypolyglutamate synthetase （FPGS） rs1544105 and gamma -glutamyl hydrolase （GGH） rs3758149 genetic polymorphisms with adverse drug reactions of methotrexate （MTX） in patients with non - Hodgkin＇ s ma- lignant lymphoma（NHL）. Methods A total of 81 blood samples were obtained from patients with NHL using high -dose MTX. The genetic polymorphisms of FPGS rs1544105 and GGH rs3758149 were detected by gene sequencing. The adverse drug reactions were evaluated by National Cancer Institute common terminology criteria for adverse drug reactions. The relationships between genetic polymorphisms and adverse drug reac- tions of MTX were analysed by SPSS. Results For FPGS rs1544105, the frequencies of GG, GA and AA genotypes were 6. 17% , 39.51% and 54. 32% ; the frequencies of G and A alleles were 25.93% and 74. 07%. For GGH rs3758149, the frequencies of CC, CT and Tr genotypes were 65.43% , 33.33% and 1.23% ; the frequencies of C and T alleles were 82. 10% and 17.90%. The differences of rates of marrow adverse drug reaction and hepatotoxicity（ ≥grade 2） between wild geno- type（GG） and mutant genotype（ GA ＋ AA） carriers in FPGS rs1544105 were not significant （ P 〉 0. 05 ）. The rates of neutropenia （ I〉 grade 2 ）with wild genotype （C C） carriers and mutant genotype （CT ＋ TF） carriers in GGH rs3758149 were 35.85% and 10. 71% respectively, and the difference was significant （P 〈 0. 05 ）. Conclusion The genetic polymorphisms of FPGS rs1544105 may be not related to the rates of marrow adverse drug reaction and hepatotoxicity （ 1〉 grade 2）, while the genetic polymorphisms of GGH rs3758149 may contribute to the rate of neutropenia （ ≥ grade 2） induced by methotrexate in patients with NHL.