Xu Wang-Hong, Shrubsole Martha J, Xiang Yong-Bing, Cai Qiuyin, Zhao Gen-ming, Ruan Zhi-xian, Cheng Jia-rong, Zheng Wei, Shu Xiao Ou
Department of Epidemiology, Shanghai Cancer Institute, PR China.
Cancer Epidemiol Biomarkers Prev. 2007 Feb;16(2):281-7. doi: 10.1158/1055-9965.EPI-06-0798.
Folate plays an important role in carcinogenesis. The enzyme 5,10-methylenetetrahydrofolate reductase (MTHFR), encoded by the MTHFR gene, is involved in this process. We investigated both the independent and joint effects of dietary folate and other methyl-related nutrients, as well as three polymorphisms of MTHFR (677C>T, 1298A>C, and 1793G>A), on endometrial cancer risk in a population-based case-control study. Between 1997 and 2003, 1,204 newly diagnosed endometrial cancer cases and 1,212 controls were recruited among women between the ages of 30 and 69 years in urban Shanghai, China. Information on dietary intake of folate and other methyl-related nutrients, including vitamin B2 (riboflavin), vitamin B6, vitamin B12, and methionine, was derived from a validated food frequency questionnaire. Genotyping was completed on 1,041 cases and 1,030 controls for MTHFR 677C>T (rs1801133), 1298A>C (rs1801131), and 1793 G>A (rs2274967) [corrected] Haplotype estimation of the three single-nucleotide polymorphisms was performed using PHASE software. Odds ratios (OR) and 95% confidence intervals (95% CI) were calculated to evaluate associations of nutrients, MTHFR genotypes, and haplotypes with endometrial cancer risk. A significant inverse association between dietary folate intake and endometrial cancer risk was observed among all subjects and non-B vitamin supplement users. The greatest reduction in endometrial cancer risk was observed among non-users of supplements in the highest quartile of dietary folate intake (OR, 0.5; 95% CI, 0.4-0.7) as compared with those in the lowest quartile. Dietary intake of folate cofactors (methionine, vitamin B2, vitamin B6, and vitamin B12) was not related to risk of endometrial cancer. No association was observed between endometrial cancer and the MTHFR 677C>T, 1298 A>C, and 1793G>A polymorphisms or derived haplotypes. Among non-users of supplements, however, the 1298C and 1793A alleles were associated with a lower risk of endometrial cancer among women with high dietary folate intake but related to a higher risk among those with low dietary folate intake (P(interaction) = 0.08 and 0.03, respectively). Further analysis showed that the lowest risk (OR, 0.6; 95% CI, 0.4-1.1) was among women with the 1298C allele and the highest intake of both folate and riboflavin (P(interaction) = 0.04). A similar association was observed for the 1793A allele (P(interaction) = 0.03). Our findings suggest that folate intake may decrease the risk of endometrial cancer and modify the effect of MTHFR polymorphisms on risk.
叶酸在致癌过程中起着重要作用。由MTHFR基因编码的5,10-亚甲基四氢叶酸还原酶（MTHFR）参与了这一过程。在一项基于人群的病例对照研究中，我们调查了膳食叶酸和其他甲基相关营养素以及MTHFR的三种多态性（677C>T、1298A>C和1793G>A）对子宫内膜癌风险的独立和联合影响。1997年至2003年期间，在中国上海市区30至69岁的女性中招募了1204例新诊断的子宫内膜癌病例和1212名对照。叶酸和其他甲基相关营养素（包括维生素B2（核黄素）、维生素B6、维生素B12和蛋氨酸）的膳食摄入量信息来自一份经过验证的食物频率问卷。对1041例病例和1030名对照进行了MTHFR 677C>T（rs1801133）、1298A>C（rs1801131）和1793G>A（rs2274967）[已校正]的基因分型。使用PHASE软件对这三种单核苷酸多态性进行单倍型估计。计算比值比（OR）和95%置信区间（95%CI）以评估营养素、MTHFR基因型和单倍型与子宫内膜癌风险的关联。在所有受试者和非B族维生素补充剂使用者中，观察到膳食叶酸摄入量与子宫内膜癌风险之间存在显著的负相关。与膳食叶酸摄入量最低四分位数的人群相比，膳食叶酸摄入量最高四分位数的非补充剂使用者中，子宫内膜癌风险降低最为显著（OR，0.5；95%CI，0.4 - 0.7）。叶酸辅助因子（蛋氨酸、维生素B2、维生素B6和维生素B12）的膳食摄入量与子宫内膜癌风险无关。未观察到子宫内膜癌与MTHFR 677C>T、1298A>C和1793G>A多态性或衍生单倍型之间存在关联。然而，在非补充剂使用者中，1298C和1793A等位基因与膳食叶酸摄入量高的女性患子宫内膜癌的风险较低相关，但与膳食叶酸摄入量低的女性患子宫内膜癌的风险较高相关（交互作用P值分别为0.08和0.03）。进一步分析表明，风险最低（OR，0.6；95%CI，0.4 - 1.1）的是携带1298C等位基因且叶酸和核黄素摄入量均最高（交互作用P值 = 0.04）的女性。对于1793A等位基因也观察到了类似的关联（交互作用P值 = 0.03）。我们的研究结果表明，叶酸摄入量可能会降低子宫内膜癌的风险，并改变MTHFR多态性对风险的影响。
