新疆维吾尔族和汉族急性淋巴细胞白血病患儿亚甲基四氢叶酸还原酶基因多态性分布及甲氨蝶呤个体化用药分析

Methylene tetrahydrofolate reductase gene polymorphism and methotrexate individual therapy in Xinjiang Uygur and Han children with acute lymphocytic leukemia

目的分析亚甲基四氢叶酸还原酶(MTHFR)基因C677T、A1298C位点基因型和等位基因在新疆维吾尔族和汉族急性淋巴细胞白血病(ALL)患儿中的分布情况;通过基因检测指导甲氨蝶呤个体化用药方案,降低甲氨蝶呤不良反应的发生率。方法采用荧光染色原位杂交方法,检测2016年1月至2017年9月就诊于新疆维吾尔自治区人民医院的35例维吾尔族和29例汉族ALL患儿的MTHFR C677T、A1298C基因多态性,分析两民族间基因型频率和等位基因频率是否存在差异;通过MTHFR C677T、A1298C基因型检测,调整1例发生甲氨蝶呤不良反应患儿的给药剂量。结果维吾尔族ALL患儿中,MTHFR C677T的3种基因型CC、CT和TT的分布频率分别为37.1%(13/35)、48.6%(17/35)和14.3%(5/35),等位基因C、T的分布频率分别为61.4%(43/70)、38.6%(27/70);汉族ALL患儿中,3种基因型CC、CT和TT的分布频率分别为58.6%(17/29)、20.7%(6/29)和20.7%(6/29),等位基因C、T的分布频率分别为69.0%(40/58)和31.0%(18/58)。维吾尔族ALL患儿中,MTHFR A1298C的3种基因型AA、AC和CC的分布频率分别为60.0%(21/35)、34.3%(12/35)和5.7%(2/35),等位基因A、C的分布频率分别为77.1%(54/70)、22.9%(16/70);汉族ALL患儿中,3种基因型AA、AC和CC的分布频率分别为55.2%(16/29)、44.8%(13/29)和0.0%(0/29),等位基因A、C的分布频率分别为77.6%(45/58)和22.4%(13/58)。维吾尔族和汉族ALL患儿MTHFR C677T、A1298C基因型频率和等位基因频率比较,差异均无统计学意义(均P>0.05)。发生甲氨蝶呤不良反应的1例ALL患儿的MTHFR C677T基因型为CT,A1298C基因型为AC,经过基因型指导患儿甲氨蝶呤用药后,患儿不良反应症状较前有明显改善。结论新疆维吾尔族和汉族ALL患儿MTHFR C677T、A1298C基因型及等位基因分布频率不存在显著差异,但个体间MTHFR基因多态性差异可以作为降低甲氨蝶呤严重不良反应的重要参考因素之一,化疗方案开始前对患儿进行MTHFR基因检测是必要且可行的。

Objective To observe the distribution of methylene tetrahydrofolate reductase（MTHFR） gene C677T and A1298C in Xinjiang Uygur and Han children with acute lymphocytic leukemia（ALL）; to develop methotrexate individualized therapy under the guidance of MTHFR C677T, A1298C gene polymorphism. Methods Genotypes and alleles of MTHFR C677T, A1298C were tested by the fluorescence staining in situ hybridization in 35 Uygur ALL children and 29 Han ALL children who were admitted from January 2016 to September 2017 in People′s Hospital of Xinjiang Uygur Autonomous Region; gene frequency was analyzed between nationalities. One case with severe methotrexate adverse reactions was treated by a new regimen of methotrexate chemotherapy according to the results of MTHFR C677T, A1298C gene testing. Results Among Uygur ALL children, MTHFR C667T frequencies of CC, CT, AA genotypes were 37.1%（13/35）, 48.6%（17/35） and 14.3%（5/35）; frequencies of C and T alleles were 61.4%（43/70） and 38.6%（27/70）. Among Han ALL children, frequencies of MTHFR C667T CC, CT, TT genotypes were 58.6%（17/29）, 20.7%（6/29） and 20.7%（6/29）; frequencies of C and T alleles were 69.0%（40/58） and 31.0%（18/58）. MTHFR A1298C AA, AC, CC frequencies in Uygur children were 60.0%（21/35）, 34.3%（12/35） and 5.7%（2/35）; A and C frequencies were 77.1%（54/70） and 22.9%（16/70）. MTHFR A1298C AA, AC, CC frequencies in Han children were 55.2%（16/29）, 44.8%（13/29） and 0.0%（0/29）; A and C frequencies were 77.6%（45/58） and 22.4%（13/58）. There were no significant differences of MTHFR C677T, A1298C genotypes and alleles between Uygur and Han children（all P＞0.05）. Symptoms of drug adverse reactions in the children with methotrexate chemotherapy were alleviated after adjustment of medication regimen. Conclusions Gene distributions of MTHFR C677T and A1298C have no significant differences between Uygur and Han ALL children in Xinjiang region. Individual difference of MTHFR gene can provide a reference for the prevention of methotrexate adverse reactions, and it is necessary for ALL children to have gene testing before methotrexate chemotherapy.