Yin Guang, Kono Suminori, Toyomura Kengo, Hagiwara Tomoko, Nagano Jun, Mizoue Tetsuya, Mibu Ryuichi, Tanaka Masao, Kakeji Yoshihiro, Maehara Yoshihiko, Okamura Takeshi, Ikejiri Koji, Futami Kitaroh, Yasunami Yohichi, Maekawa Takafumi, Takenaka Kenji, Ichimiya Hitoshi, Imaizumi Nobutoshi
Department of Preventive Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582.
Cancer Sci. 2004 Nov;95(11):908-13. doi: 10.1111/j.1349-7006.2004.tb02201.x.
Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme regulating folate metabolism, which affects DNA synthesis and methylation. This study investigated the relation of MTHFR C677T and A1298C polymorphisms to colorectal cancer in a case-control study in Fukuoka, Japan. The subjects comprised 685 incident cases of histologically confirmed colorectal adenocarcinomas and 778 community controls selected randomly in the study area. The genotype was determined by the PCR-RFLP method using genomic DNA extracted from buffy coat. Alcohol use was ascertained by in-person interview. Statistical adjustment was made for gender, age class, area, and alcohol use. The MTHFR 677TT genotype was associated with a statistically significant decrease in the risk with an adjusted odds ratio of 0.69 (95% confidence interval 0.51-0.93) compared with the 677CC and 677CT combined, and the decrease was most evident in individuals with no alcohol consumption. While the A1298C polymorphism showed no measurable association with the overall risk of colorectal cancer, the 1298CC genotype was associated with a statistically significant increase in the risk when alcohol consumption was high, and was also associated with an approximately 2-fold increase in the risk of each of proximal and distal colon cancer. The findings add to evidence that individuals with the MTHFR 677TT genotype have a decreased risk of colorectal cancer in the absence of folate depletion, suggesting a protective role of folate by ensuring a sufficient thymidylate pool for DNA synthesis. Because very few individuals had the 1298CC genotype, the findings regarding the A1298C polymorphism need careful interpretation and confirmation in larger studies.
亚甲基四氢叶酸还原酶（MTHFR）是调节叶酸代谢的关键酶，影响DNA合成和甲基化。本研究在日本福冈的一项病例对照研究中，调查了MTHFR C677T和A1298C多态性与结直肠癌的关系。研究对象包括685例经组织学确诊的结直肠腺癌新发病例和在研究区域随机选取的778名社区对照。采用从血沉棕黄层提取的基因组DNA，通过聚合酶链反应-限制性片段长度多态性（PCR-RFLP）方法确定基因型。通过面对面访谈确定饮酒情况。对性别、年龄组、地区和饮酒情况进行了统计调整。与677CC和677CT合并基因型相比，MTHFR 677TT基因型与风险的统计学显著降低相关，调整后的优势比为0.69（95%置信区间0.51-0.93），且这种降低在不饮酒的个体中最为明显。虽然A1298C多态性与结直肠癌的总体风险没有可测量的关联，但1298CC基因型在饮酒量高时与风险的统计学显著增加相关，并且与近端和远端结肠癌的风险各自增加约2倍也相关。这些发现进一步证明，在没有叶酸缺乏的情况下，MTHFR 677TT基因型个体患结直肠癌的风险降低，表明叶酸通过确保有足够的胸苷酸池用于DNA合成发挥保护作用。由于很少有人具有1298CC基因型，关于A1298C多态性的发现需要在更大规模的研究中进行仔细解读和确认。
