Chen J, Giovannucci E, Kelsey K, Rimm E B, Stampfer M J, Colditz G A, Spiegelman D, Willett W C, Hunter D J
Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts 02115, USA.
Cancer Res. 1996 Nov 1;56(21):4862-4.
We examined the relationship of a common polymorphism (667C-->T) of the methylenetetrahydrofolate reductase (MTHFR) gene with the risk of colorectal cancer in a case-control study conducted in the Health Professionals Follow-up Study. MTHFR genotypes were ascertained from blood samples among 144 men previously diagnosed with colorectal cancer and 627 controls. The adjusted odds ratio (OR) for the MTHFR variant homozygous (val/val) genotype was 0.57 [95% confidence interval (CI), 0.30-1.06]. High dietary intake of methionine (OR, 0.27; 95% CI, 0.06-1.20) and low consumption of alcohol (OR, 0.11; 95% CI, 0.01-0.85) were associated with reduced incidence of colorectal cancer. Alcohol intake was a stronger risk factor among men with the val/val genotype (P, trend = 0.01), and consumption of five or more alcoholic drinks per week abolished the reduced risk of colorectal cancer among val/val individuals (P, interaction = 0.02). The inverse association of methionine with colorectal cancer risk was slightly stronger among individuals with the MTHFR val/val genotype. These data suggest that dietary methyl supply is particularly critical among MTHFR val/val individuals. When dietary methyl supply is high, MTHFR val/val individuals may be at reduced risk of colorectal cancer probably because higher levels of 5,10-methylenetetrahydrofolate may prevent imbalances of nucleotide pools during DNA synthesis. In contrast, when 5-methyltetrahydrofolate is depleted by alcohol consumption, val/val individuals may be less able to compensate, leading to potentially oncogenic alterations in DNA methylation.
在健康专业人员随访研究中开展的一项病例对照研究里，我们探究了亚甲基四氢叶酸还原酶（MTHFR）基因常见多态性（667C→T）与结直肠癌风险之间的关系。从144名先前被诊断为结直肠癌的男性和627名对照者的血样中确定MTHFR基因型。MTHFR变异纯合子（val/val）基因型的校正比值比（OR）为0.57 [95%置信区间（CI），0.30 - 1.06]。高膳食蛋氨酸摄入量（OR，0.27；95% CI，0.06 - 1.20）和低酒精消费量（OR，0.11；95% CI，0.01 - 0.85）与结直肠癌发病率降低相关。酒精摄入量在val/val基因型男性中是更强的风险因素（P，趋势 = 0.01），并且每周饮用五杯或更多酒精饮料会消除val/val个体中结直肠癌风险的降低（P，交互作用 = 0.02）。蛋氨酸与结直肠癌风险的负相关在MTHFR val/val基因型个体中略强。这些数据表明，膳食甲基供应在MTHFR val/val个体中尤为关键。当膳食甲基供应充足时，MTHFR val/val个体患结直肠癌的风险可能降低，这可能是因为较高水平的5,10 - 亚甲基四氢叶酸可防止DNA合成过程中核苷酸池的失衡。相反，当5 - 甲基四氢叶酸因酒精消费而耗尽时，val/val个体可能较难进行补偿，从而导致DNA甲基化中潜在的致癌性改变。
