Methylenetetrahydrofolate reductase polymorphism, dietary interactions, and risk of colorectal cancer.
Methylenetetrahydrofolate reductase polymorphism, dietary interactions, and risk of colorectal cancer.
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发表时间：
1997-03
期刊：
影响因子：
11.2
通讯作者：
Jing Ma;M. Stampfer;E. Giovannucci;C. Artigas;D. J. Hunter;C. Fuchs;W. Willett;J. Selhub;C. Hennekens;R. Rozen
中科院分区：
文献类型：
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作者：
Jing Ma;M. Stampfer;E. Giovannucci;C. Artigas;D. J. Hunter;C. Fuchs;W. Willett;J. Selhub;C. Hennekens;R. Rozen
叶酸衍生物在实验性结直肠癌的发生中很重要；低叶酸摄入量，特别是大量酒精摄入量，与增加风险有关。5，10-亚甲基四氢叶酸还原酶(MTHFR)催化5，10-亚甲基四氢叶酸转化为5-甲基四氢叶酸，5-亚甲基四氢叶酸是合成蛋氨酸所必需的叶酸的主要循环形式。MTHFR中一种常见的突变(677C->；T)会降低酶的活性，导致5-甲基四氢叶酸水平降低。为了评估叶酸代谢在人类癌症发生中的作用，我们研究了MTHFR突变、血浆叶酸水平及其与结肠癌风险的相互作用。我们还研究了基因型和酒精摄入量之间的相互作用。我们在医生健康研究中使用了嵌套式病例对照设计。在确定酒精摄入量并抽取血样时，参与者的基线年龄为40-84岁。在12年的随访中，我们确定了202例结直肠癌病例，并根据年龄和吸烟状况将他们与326名非癌症对照组进行了匹配。我们对MTHFR基因多态进行了基因分型，并测量了血浆叶酸水平。与纯合正常或杂合基因相比，携带纯合突变的男性(对照组为15%)患结直肠癌的风险减半[优势比(OR)为0.49；95%可信区间(CI)为0.27-0.87]。总体而言，我们观察到，在血浆叶酸水平不足的患者中，患结直肠癌的风险略有显著增加(OR，1.78；95%CI，0.93-3.42)(MTHFR中的IT突变可能通过增加DNA合成的5，10-亚甲基四氢叶酸水平来降低结肠癌风险，但叶酸摄入量低或酒精摄入量高可能会抵消部分保护作用。
Folate derivatives are important in experimental colorectal carcinogenesis; low folate intake, particularly with substantial alcohol intake, is associated with increased risk. The enzyme 5,10-methylenetetrahydrofolate reductase (MTHFR) catalyzes the conversion of 5,10-methylenetetrahydrofolate, required for purine and thymidine syntheses, to 5-methyltetrahydrofolate, the primary circulatory form of folate necessary for methionine synthesis. A common mutation (677C-->T) in MTHFR reduces enzyme activity, leading to lower levels of 5-methyltetrahydrofolate. To evaluate the role of folate metabolism in human carcinogenesis, we examined the associations of MTHFR mutation, plasma folate levels, and their interaction with risk of colon cancer. We also examined the interaction between genotype and alcohol intake. We used a nested case-control design within the Physicians' Health Study. Participants were ages 40-84 at baseline when alcohol intake was ascertained and blood samples were drawn. During 12 years of follow-up, we identified 202 colorectal cancer cases and matched them to 326 cancer-free controls by age and smoking status. We genotyped for the MTHFR polymorphism and measured plasma folate levels. Men with the homozygous mutation (15% in controls) had half the risk of colorectal cancer [odds ratio (OR), 0.49; 95% confidence interval (CI), 0.27-0.87] compared with the homozygous normal or heterozygous genotypes. Overall, we observed a marginal significant increased risk of colorectal cancer (OR, 1.78; 95% CI, 0.93-3.42) among those whose plasma folate levels indicated deficiency (IT mutation in MTHFR reduces colon cancer risk, perhaps by increasing 5,10-methylenetetrahydrofolate levels for DNA synthesis, but that low folate intake or high alcohol consumption may negate some of the protective effect.