Methionine Synthase A2756G Polymorphism Interacts with Alcohol and Folate Intake to Influence the Risk of Colorectal Adenoma
Methionine Synthase A2756G Polymorphism Interacts with Alcohol and Folate Intake to Influence the Risk of Colorectal Adenoma
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DOI：
10.1158/1055-9965.epi-08-0702
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发表时间：
2009-01-01
影响因子：
3.8
通讯作者：
Tsugane, Shoichiro
中科院分区：
文献类型：
--
作者：
Yamaji, Taiki;Iwasaki, Motoki;Tsugane, Shoichiro
基因组DNA低甲基化与结直肠癌的发生有关。蛋氨酸合成酶A2756G （MTR A2756G）是编码蛋氨酸合成酶的基因中常见的非同义多态性，蛋氨酸合成酶是导致DNA甲基化途径的关键酶。一些研究（但不是全部）报道了AG或GG基因型个体的血浆同型半胱氨酸相对较低。同时，在健康志愿者中，较高的血浆同型半胱氨酸与基因组DNA低甲基化有关。因此，我们假设少量等位基因携带者患结直肠腺瘤的风险降低，并在日本的一项涉及723例和670例对照的结直肠腺瘤病例对照研究中检验了这一假设。在调整潜在混杂因素后，使用无条件逻辑回归模型估计结直肠腺瘤的优势比（OR）及其95%置信区间（95% CI）。尽管缺乏整体关联，但我们观察到MTR A2756G与酒精摄入量之间存在显著的相互作用（相互作用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的风险显著降低（or, 0.56; 95% CI, 0.34-0.90），而相同基因型的重度饮酒者的风险显著增加（or, 1.90; 95% CI, 1.04-3.46）。此外，与叶酸摄入量之间存在显著的交互作用（交互作用P = 0.07）。在叶酸水平相当好的情况下，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，DNA甲基化在结直肠癌发生的早期阶段也起着重要作用。（癌症流行病学杂志，2009;18(1):267-74）
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 ail 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. (Cancer Epidemiol Biomarkers Prev 2009;18(1):267-74)