Yamaji Taiki, Iwasaki Motoki, Sasazuki Shizuka, Sakamoto Hiromi, Yoshida Teruhiko, Tsugane Shoichiro
Epidemiology and Prevention Division, Research Center for Cancer Prevention and Screening, National Cancer Center, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
Cancer Epidemiol Biomarkers Prev. 2009 Jan;18(1):267-74. doi: 10.1158/1055-9965.EPI-08-0702.
Genomic DNA hypomethylation has been associated with colorectal carcinogenesis. Methionine synthase A2756G (MTR A2756G) is a common nonsynonymous polymorphism in the gene that encodes methionine synthase, a key enzyme in the pathway leading to DNA methylation. Several studies, but not all, have reported relatively lower plasma homocysteine among individuals with the AG or GG genotype. Meanwhile, higher plasma homocysteine was associated with genomic DNA hypomethylation in healthy volunteers. We therefore hypothesized that minor allele carriers possess a decreased risk of colorectal adenoma, and examined this hypothesis in a case-control study of colorectal adenoma in Japan involving 723 cases and 670 controls. An unconditional logistic regression model was used to estimate odds ratios (OR) and their 95% confidence intervals (95% CI) for colorectal adenoma after adjustment for potential confounders. Despite the lack of an overall association, we observed a significant interaction between MTR A2756G and alcohol intake (P for interaction = 0.007). Compared with never drinkers with the AA genotype, never drinkers with the AG or GG genotype exhibited a significantly decreased risk (OR, 0.56; 95% CI, 0.34-0.90) whereas heavy drinkers with the same genotypes showed a substantially increased risk (OR, 1.90; 95% CI, 1.04-3.46). In addition, a marginally significant interaction was observed with folate intake (P for interaction = 0.07). The G allele may confer protection against colorectal adenoma in the presence of a considerably good folate status. Our findings add to increasing evidence that DNA methylation plays an important role even at an early stage of colorectal carcinogenesis.
基因组DNA低甲基化与结直肠癌发生有关。甲硫氨酸合酶A2756G（MTR A2756G）是编码甲硫氨酸合酶基因中的一种常见非同义多态性，甲硫氨酸合酶是导致DNA甲基化途径中的关键酶。一些研究（但并非全部）报告称，AG或GG基因型个体的血浆同型半胱氨酸水平相对较低。同时，健康志愿者中较高的血浆同型半胱氨酸与基因组DNA低甲基化有关。因此，我们假设携带次要等位基因的个体患结直肠腺瘤的风险降低，并在一项涉及723例病例和670例对照的日本结直肠腺瘤病例对照研究中检验了这一假设。使用无条件逻辑回归模型在调整潜在混杂因素后估计结直肠腺瘤的比值比（OR）及其95%置信区间（95%CI）。尽管缺乏总体关联，但我们观察到MTR A2756G与酒精摄入量之间存在显著交互作用（交互作用P = 0.007）。与AA基因型的从不饮酒者相比，AG或GG基因型的从不饮酒者患结直肠腺瘤的风险显著降低（OR，0.56；95%CI，0.34 - 0.90），而相同基因型的大量饮酒者风险大幅增加（OR，1.90；95%CI，1.04 - 3.46）。此外，观察到与叶酸摄入量存在边缘显著的交互作用（交互作用P = 0.07）。在叶酸状态相当良好的情况下，G等位基因可能对结直肠腺瘤具有保护作用。我们的研究结果进一步证明，即使在结直肠癌发生的早期阶段，DNA甲基化也起着重要作用。
