MTHFR基因多态性及单体型与大剂量甲氨蝶呤化疗毒性反应的相关性研究

Association between the methylenetetrahydrofolate reductase gene polymorphisms and haplotype with toxicity response of high dose methotrexate chemotherapy

目的探讨亚甲基四氢叶酸还原酶（MTHFR）基因多态性及其单体型与急性淋巴细胞白血病患儿大剂量甲氨蝶呤（HDMTX）化疗毒性反应的相关性。方法采用聚合酶链反应一限制性片段长度多态性方法对HDMTX化疗后出现毒性反应（n=61）和无毒性反应的患儿（n=36）MTHFR基因677C〉T、1298A〉C单核苷酸多态性（SNP）进行基因分型和单体型分析，并应用病例对照分析方法进行相关性研究。结果MTHFR677C〉T不同基因型在两组患儿中的分布频率差异无统计学意义（x2=4．609，P=0．100）。1298A〉C不同基因型在两组患儿中的分布频率差异有统计学意义（x2=10．192，P=0．006），1298C等位基因（AC＋CC基因型）携带者出现毒性反应的风险降低（OR=0．245，95％CI：0．099～0．607，P=0．002）。677C〉T与1298A〉C存在着强连锁不平衡（D’=0．895），CC单体型携带者出现毒性反应的风险降低（OR=O．338，95％C1：0．155～0．738，P=0．005），而TA单体型携带者出现毒性反应的风险增加（OR=1．907，95％C!：1．045～3．482，P=0．035）。结论MTHFR1298C等位基因及CC单体型可能是HDMTX毒性反应的保护因素，TA单体型可能是危险因素。

Objective To investigate the association between single nucleotide polymorphisms （SNP） and its haplotypes of methylenetetrahydrofolate reductase （MTHFR） gene with high dose methotrexate （HDMTX）-induced toxicity in children with acute lymphoblastic leukemia （ALL）. Methods HDMTX-treated children with ALL （1.2 to 14-years old） were selected from inpatient and followed for a retrospective study. The toxicity response of HDMTX chemotherapy was evaluated using WHO common toxicity criteria. Sixty-one patients with therapy-related toxicity and 36 patients without therapy-related toxicity were genotyped for 2 SNP （677C〉T and 1298A〉C） of the MTHFR gene by polymerase chain reaction-restriction fragment length polymorphism. Frequency of haplotypes and linkage disequilibrium of MTHFR gene were analyzed by SHEsis program. Results The distribution of MTHFR gene 677C〉T polymorphism did not appeare different between groups with or without toxicity response （Z2=4.609, P=0.100） , but the 1298A〉C polymorphism was significantly different （~2_ I 0.192, P = 0.006）. Individuals who carried C allele （AC ＋ CC genotype） had a decreased risk of toxicity response compared to AA genotype （0R=0.245,95%CI： 0.099-0.607, P=0.002）. 677C〉T and 1298A〉C polymorphisms showed strong linkage disequilibrium （D＇ = 0.895 ）. The CC haplotype was significantly associated with decreased risk of toxicity response （OR= 0.338,95%CI： 0.155-0.738, P=0.005）, while the TA haplotype was significantly associated with the increased risk of toxicity response （0R=1.907, 95% CI： 1.045-3.482, P=0.035）. Conclusion MTHFR gene 1298C allele and CC haplotype might serve as protective factors while TA haplotype as a risk factor for the susceptibility to toxicity response of HDMTX chemotherapy in children with ALL.