Curtin Karen, Bigler Jeannette, Slattery Martha L, Caan Bette, Potter John D, Ulrich Cornelia M
University of Utah Health Sciences Center, Salt Lake City, Utah, USA.
Cancer Epidemiol Biomarkers Prev. 2004 Feb;13(2):285-92. doi: 10.1158/1055-9965.epi-03-0083.
5,10-methylenetetrahydrofolate reductase (MTHFR) is a key enzyme in folate metabolism, diverting metabolites toward methylation reactions or nucleotide synthesis. Using data from an incident case-control study (1608 cases and 1972 controls) we investigated two polymorphisms in the MTHFR gene, C677T and A1298C, and their associations with risk of colon cancer. All of the combined genotypes were evaluated separately, and the 1298AA/677CC (wild-type/wild-type) group was considered the reference group. Among both men and women, the 677TT/1298AA (variant/wild-type) genotype was associated with a small reduction in risk [men: odds ratio (OR), 0.7, 95% confidence interval (CI), 0.5-1.0; women: OR, 0.8, 95% CI, 0.5-1.2]. However, the 677CC/1298CC (wild-type/variant) genotype was associated with a statistically significant lower risk among women (OR, 0.6; 95% CI, 0.4-0.9) but not men. When the polymorphisms were considered individually, for A1298C a significant risk reduction associated with the homozygous variant CC genotype was seen among women only (OR, 0.6; 95% CI, 0.5-0.9), and nonstatistically significant reduced risks were observed for the variant 677 TT genotypes among both men and women. Stratification by nutrient intakes showed inverse associations with higher intakes of folate, vitamin B(2), B(6), B(12), and methionine among women with the MTHFR 677CC/1298AA genotypes, but not those with 677TT/1298AA. We observed opposite risk trends for both MTHFR variants, depending on whether women used hormone-replacement therapy or not (P for interaction = <.01). In summary, this study supports recent findings that the MTHFR A1298C polymorphism may be a predictor of colon cancer risk and have functional relevance. The possible interaction with hormone-replacement therapy warrants additional investigation.
5,10-亚甲基四氢叶酸还原酶（MTHFR）是叶酸代谢中的关键酶，可使代谢产物转向甲基化反应或核苷酸合成。利用一项病例对照研究（1608例病例和1972例对照）的数据，我们调查了MTHFR基因中的两种多态性，即C677T和A1298C，以及它们与结肠癌风险的关联。对所有组合基因型分别进行评估，将1298AA/677CC（野生型/野生型）组作为参照组。在男性和女性中，677TT/1298AA（变异型/野生型）基因型与风险略有降低相关[男性：比值比（OR）为0.7，95%置信区间（CI）为0.5 - 1.0；女性：OR为0.8，95%CI为0.5 - 1.2]。然而，677CC/1298CC（野生型/变异型）基因型在女性中与统计学上显著较低的风险相关（OR为0.6；95%CI为0.4 - 0.9），但在男性中并非如此。当单独考虑多态性时，对于A1298C，仅在女性中观察到与纯合变异型CC基因型相关的显著风险降低（OR为0.6；95%CI为0.5 - 0.9），而在男性和女性中，变异型677TT基因型的风险降低无统计学意义。按营养素摄入量分层显示，在MTHFR 677CC/1298AA基因型的女性中，风险与较高的叶酸、维生素B(2)、B(6)、B(12)和蛋氨酸摄入量呈负相关，但在677TT/1298AA基因型的女性中并非如此。根据女性是否使用激素替代疗法，我们观察到两种MTHFR变异型的风险趋势相反（交互作用P值 = <.01）。总之，本研究支持了最近的发现，即MTHFR A1298C多态性可能是结肠癌风险的一个预测指标且具有功能相关性。与激素替代疗法的可能相互作用值得进一步研究。
