FPGS、GGH 和 MTHFR 基因多态性对中国急性淋巴细胞白血病患儿血清甲氨蝶呤水平的影响。
Influence of genetic polymorphisms of FPGS, GGH, and MTHFR on serum methotrexate levels in Chinese children with acute lymphoblastic leukemia.
机构信息
Department of Pharmacy, Beijing Shijitan Hospital, Capital Medical University, Beijing, China.
出版信息
Cancer Chemother Pharmacol. 2014 Aug;74(2):283-9. doi: 10.1007/s00280-014-2507-8. Epub 2014 Jun 8.
PURPOSE
To investigate the correlation between common genetic polymorphisms of folylpolyglutamate synthase (FPGS), gamma-glutamyl hydrolase (GGH), and methylenetetrahydrofolate reductase (MTHFR) and serum levels of methotrexate (MTX) in Chinese children with acute lymphoblastic leukemia (ALL).
METHODS
Ninety-one children with ALL who received high-dose MTX were recruited. The polymorphisms FPGS (rs1544105 G>A), GGH (rs3758149 C>T), and MTHFR (rs1801133 C>T) were genotyped through polymerase chain reaction-restriction fragment length polymorphism analysis. Serum MTX was measured by fluorescence polarization immunoassay. The association between targeted polymorphisms and MTX concentration-to-dose (C/D) ratios was assessed, and between targeted polymorphisms and the percent of MTX above the therapeutic threshold (40 µmol/L).
RESULTS
The minor allele frequencies of rs1544105 G (34.1%), rs3758149 T (19.2%), and rs1801133 C (48.4%) observed in our population were significantly lower than those reported for European populations (64.2, 30.8, and 69.0%, respectively). The association between the GGH rs3758149 polymorphism and MTX C/D was gender-specific; in girls, the MTX C/D at 24 h of GGH rs3758149 CC carriers (12.09 μmol/L per g/m(2)) was significantly lower than that of CT or TT carriers (16.80 μmol/L per g/m(2)). The percent of serum MTX above the therapeutic threshold in GGH rs3758149 CC carriers (18.3%) was significantly lower than that of CT and TT carriers (38.7%). The MTX C/D ratios at 24 h and the percent of MTX >40 µmol/L for the A-T-T (three variant alleles) haplotype were significantly higher than those for other haplotypes combined (P < 0.05).
CONCLUSIONS
These data indicate that FPGS rs1544105, GGH rs3758149, and MTHFR rs1801133 polymorphisms contribute to the variability of MTX pharmacokinetics, and their genotyping may be useful to reduce toxicities associated with MTX therapy.
目的
研究中国急性淋巴细胞白血病（ALL）患儿中叶酸多聚谷氨酸合酶（FPGS）、γ-谷氨酰水解酶（GGH）和亚甲基四氢叶酸还原酶（MTHFR）的常见遗传多态性与甲氨蝶呤（MTX）血清水平之间的相关性。
方法
招募了 91 名接受高剂量 MTX 治疗的 ALL 患儿。通过聚合酶链反应-限制性片段长度多态性分析检测 FPGS(rs1544105 G>A)、GGH(rs3758149 C>T)和 MTHFR(rs1801133 C>T)的多态性。通过荧光偏振免疫测定法测定血清 MTX 浓度。评估了目标多态性与 MTX 浓度-剂量（C/D）比值之间的关系，以及与 MTX 超过治疗阈值（40 μmol/L）的百分比之间的关系。
结果
我们人群中 rs1544105 G（34.1%）、rs3758149 T（19.2%）和 rs1801133 C（48.4%）的次要等位基因频率明显低于欧洲人群的报道（64.2%、30.8%和 69.0%）。GGH rs3758149 多态性与 MTX C/D 的相关性具有性别特异性；在女孩中，GGH rs3758149 CC 携带者（24 小时 MTX C/D 为 12.09 μmol/L/g/m²）明显低于 CT 或 TT 携带者（16.80 μmol/L/g/m²）。GGH rs3758149 CC 携带者（18.3%）的血清 MTX 超过治疗阈值的百分比明显低于 CT 和 TT 携带者（38.7%）。24 小时 MTX C/D 比值和 MTX>C40μmol/L 的 A-T-T（三个变异等位基因）单倍型的百分比明显高于其他单倍型的总和（P<0.05）。
结论
这些数据表明 FPGS rs1544105、GGH rs3758149 和 MTHFR rs1801133 多态性导致 MTX 药代动力学的变异性，其基因分型可能有助于降低与 MTX 治疗相关的毒性。
Zotero 插件