Association between folate levels and CpG Island hypermethylation in normal colorectal mucosa.
Association between folate levels and CpG Island hypermethylation in normal colorectal mucosa.
复制标题
DOI：
10.1158/1940-6207.capr-10-0047
复制
发表时间：
2010-12
期刊：
影响因子：
--
通讯作者：
Issa JP
中科院分区：
文献类型：
--
作者：
Wallace K;Grau MV;Levine AJ;Shen L;Hamdan R;Chen X;Gui J;Haile RW;Barry EL;Ahnen D;McKeown-Eyssen G;Baron JA;Issa JP
一些基因的基因特异性启动子甲基化发生在衰老的正常组织中，并且可能诱发肿瘤发生。在本研究中，我们调查了正常结直肠粘膜中血液叶酸水平以及饮食和生活方式因素与 CpG 岛甲基化之间的关系。受试者参加了一项阿司匹林或叶酸预防大肠腺瘤的多中心化学预防试验。我们在后续结肠镜检查中收集了 389 名患者的 1000 份活检样本，其中 501 份来自右结肠样本，499 份来自直肠样本。我们使用亚硫酸氢盐焦磷酸测序测量了雌激素受体 α (ERα) 的 DNA 甲基化和分泌卷曲相关蛋白 1 (SFRP1)。我们使用广义估计方程回归分析来检查甲基化与选定变量之间的关联。对于 ERα 和 SFRP1，直肠中的甲基化百分比显着高于右结肠 (p = 0.001)。我们观察到每 10 岁，ERα 的甲基化水平增加 1.7%，SFRP1 的甲基化水平增加 2.9%（P < 0.0001）。与白人和西班牙裔相比，非裔美国人的 ERα 和 SFRP1 甲基化水平显着较低。较高的红细胞叶酸水平与较高水平的 ERα (p=0.03) 和 SFRP1 甲基化 (p=0.01) 相关。我们的结果表明，正常结直肠粘膜中的 CpG 岛甲基化与年龄增长、种族、直肠位置和红细胞叶酸水平有关。鉴于正常粘膜甲基化可能易患结直肠肿瘤的假设，这些数据对于健康成人补充叶酸的安全性具有重要意义。
Gene-specific promoter methylation of several genes occurs in aging normal tissues and may predispose to tumorigenesis. In the present study, we investigate the association among blood folate levels, and dietary and lifestyle factors with CpG island methylation in normal colorectal mucosa. Subjects were enrolled in a multi-center chemoprevention trial of aspirin or folic acid for the prevention of large bowel adenomas. We collected 1000 biopsies from 389 patients, 501 samples from the right colon and 499 from the rectum at the follow-up colonoscopy. We measured DNA methylation of estrogen receptor alpha (ERα) and secreted frizzled related protein-1 (SFRP1) using bisulfite pyrosequencing. We used Generalized Estimating Equations regression analysis to examine the association between methylation and selected variables. For both ERα and SFRP1, percent methylation was significantly higher in the rectum compared to the right colon (p = 0.001). For each 10 years of age, we observed a 1.7 % increase in methylation level for ERα and a 2.9 % increase for SFRP1 (P < 0.0001). African Americans had a significantly lower level of ERα and SFRP1 methylation compared to Caucasians and Hispanics. Higher RBC folate levels were associated with higher levels of both ERα (p=0.03) and SFRP1 methylation (p=0.01). Our results suggest that CpG island methylation in normal colorectal mucosa is related to advancing age, race, rectal location, and RBC folate levels. These data have important implications regarding the safety of supplementary folate administration in healthy adults given the hypothesis that methylation in normal mucosa may predispose to colorectal neoplasia.