Polymorphisms in the methylenetetrahydrofolate reductase gene are associated with susceptibility to acute leukemia in adults
Polymorphisms in the methylenetetrahydrofolate reductase gene are associated with susceptibility to acute leukemia in adults
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DOI：
10.1073/pnas.96.22.12810
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发表时间：
1999-10-26
影响因子：
11.1
通讯作者：
Morgan, G
中科院分区：
文献类型：
--
作者：
Skibola, CF;Smith, MT;Morgan, G
5，10-亚甲基四氢叶酸还原酶(MTHFR)催化5，10-亚甲基四氢叶酸还原为甲硫氨酸合成的主要甲基供体5-甲基四氢叶酸(5-甲基四氢叶酸)。MTHFR基因中常见的677个C-->；T多态导致耐热性和MTHFR活性降低，从而减少甲基四氢呋喃和增加亚甲基四氢呋喃。最近，亚甲基四氢叶酸还原酶(MTHFR)(1298A->；C)的另一个多态也被发现，它也导致酶活性降低。我们测试了这些变异等位基因的携带者是否对成人急性白血病有保护作用。我们分析了英国308名成人急性白血病患者和491名年龄和性别匹配的对照组的病例对照研究中的DNA。采用聚合酶链式反应-限制性片段长度多态性分析方法检测MTHFR变异等位基因。在71例急性淋巴细胞白血病(ALL)患者中，MTHFR 677TT基因型与114例对照组相比明显降低，发病风险降低4.3倍[优势比(OR=0.23；95%CI=0.06-0.81])。我们观察到，携带MTHFR 1298AC多态的个体患ALL的风险降低3倍(OR=0.33；95%CI=0.15-0.73)，携带MTHFR 1298cc变异等位基因的个体患ALL的风险降低14倍(OR=0.07；95%CI=0.00-1.77)。在急性髓系白血病中，237例患者和377例对照组的MTHFR 677和1298基因频率差异无统计学意义。携带MTHFR 677TT、1298AC和1298cc等位基因的个体患成人ALL的风险较低，但不存在急性髓系白血病，提示叶酸缺乏可能在ALL的发生发展中起关键作用。
Reduction of 5,10-methylenetetrahydrafolate (methyleneTHF), a donor far methylating dUMP to dTMP in DNA synthesis, to 5-methyltetrahydrofolate (methylTHF), the primary methyl donor for methionine synthesis, is catalyzed by 5,10-methylenetetrahydrofolate reductase (MTHFR). A common 677 C --> T polymorphism in the MTHFR gene results in thermolability and reduced MTHFR activity that decreases the pool of methylTHF and increases the pool of methyleneTHF. Recently, another polymorphism in MTHFR (1298 A --> C) has been identified that also results in diminished enzyme activity. We tested whether carriers of these variant alleles are protected from adult acute leukemia. We analyzed DNA from a case-control study in the United Kingdom of 308 adult acute leukemia patients and 491 age- and sex-matched controls. MTHFR variant alleles were determined by a PCR-restriction fragment length polymorphism assay. The MTHFR 677TT genotype was lower among 71 acute lymphocytic: leukemia (ALL) cases compared with 114 controls, conferring a 4.3-fold decrease in risk of ALL [odds ratio (OR = 0.23; 95% Cl = 0.06-0.81]. We observed a 3-fold reduction in risk of ALL in individuals with the MTHFR 1298AC polymorphism (OR = 0.33; 95% CI = 0.15-0.73) and a 14-fold decreased risk of ALL in those with the MTHFR 1298CC Variant allele (OR = 0.07; 95% Cl = 0.00-1.77). In acute myeloid leukemia, no significant difference in MTHFR 677 and 1298 genotype frequencies was observed between 237 cases and 377 controls. Individuals with the MTHFR 677TT, 1298AC and 1298CC genotypes have a decreased risk of adult ALL, but not acute myeloid leukemia, which suggests that folate inadequacy may play a key role in the development of ALL.