A candidate gene study of folate-associated one carbon metabolism genes and colorectal cancer risk.
A candidate gene study of folate-associated one carbon metabolism genes and colorectal cancer risk.
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DOI：
10.1158/1055-9965.epi-10-0151
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发表时间：
2010-07
期刊：
影响因子：
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通讯作者：
Haile RW
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文献类型：
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作者：
Levine AJ;Figueiredo JC;Lee W;Conti DV;Kennedy K;Duggan DJ;Poynter JN;Campbell PT;Newcomb P;Martinez ME;Hopper JL;Le Marchand L;Baron JA;Limburg PJ;Ulrich CM;Haile RW
叶酸相关一碳代谢（FOCM）可能在结直肠癌发生中发挥重要作用。 FOCM 基因的变异可以解释结直肠癌的一些潜在风险。这项研究利用了来自结肠癌家族登记处 (C-CFR) 的 1,805 个基于人群的结直肠癌病例和 2,878 个匹配的兄弟姐妹对照的数据。我们使用综合 tagSNP 方法在涉及叶酸和维生素 B12 代谢的 15 个基因中选择了 395 个 tagSNP。使用 Illumina GoldenGate 或 Sequenom 平台进行基因分型。使用自行填写的问卷收集危险因素和饮食数据。使用标准技术确定 MSI 状态，并从病理报告中获得肿瘤亚位点。使用条件逻辑回归（以同胞关系作为匹配因子）并假设对数加性或共显性模型，评估 SNP 与结直肠癌之间的关联。在对数加性模型中，DHFR 基因中的两个连锁 (r2=0.99) tagSNP（rs1677693 和 rs1643659）与多重测试校正后 CRC 风险显着降低相关（OR=0.87；95% CI=0.71 – 0.94；P=0.029 和 OR=0.87 95% CI=0.71 – 0.95, rs1677693 和 rs1643659 分别 P=0.034。仅在不使用多种维生素补充剂的个体中，这两个连锁 (r2=0.99) tagSNP 和 MTR 基因 (rs4659744) 中的一个 tagSNP 与 CRC 风险降低显着相关。总体而言，我们仅发现中等证据表明 15 种叶酸途径基因的遗传变异可能影响 CRC 风险，除了 在非多种维生素使用者中。这项研究表明，在补充叶酸后的人群中，使用多种维生素补充剂可能会改变叶酸途径基因与结直肠癌风险之间的关联。
Folate-associated one carbon metabolism (FOCM) may play an important role in colorectal carcinogenesis. Variation in FOCM genes may explain some of the underlying risk of colorectal cancer. This study utilized data from 1,805 population-based colorectal cancer cases and 2,878 matched sibling controls from the Colon Cancer Family Registry (C-CFR). We used a comprehensive tagSNP approach to select 395 tagSNPs in 15 genes involved in folate and vitamin B12 metabolism. Genotyping was performed using the Illumina GoldenGate or Sequenom platforms. Risk factor and dietary data were collected using self-completed questionnaires. MSI status was determined using standard techniques and tumor subsite was obtained from pathology reports. The association between SNPs and colorectal cancer was assessed using conditional logistic regression with sibships as the matching factor and assuming a log additive or co-dominant model. In the log additive model, two linked (r2=0.99) tagSNPs in the DHFR gene (rs1677693 and rs1643659) were associated with a significant decrease in CRC risk after correction for multiple testing (OR=0.87; 95% CI=0.71 – 0.94; P=0.029 and OR=0.87 95% CI=0.71 – 0.95, P=0.034 for rs1677693 and rs1643659 respectively. These two linked (r2=0.99) tagSNPs and one tagSNP in the MTR gene (rs4659744) were significantly associated with reduced CRC risk only among individuals not using multivitamin supplements. Overall, we found only moderate evidence that genetic variation in 15 folate pathway genes may affect CRC risk except in non multivitamin users. This study suggests that multivitamin supplement use may modify the association between folate pathway genes and CRC risk in a post folic acid supplemented population.