HRH2 启动子多态性对胃上皮细胞中 DAPK 和 CDH1 异常 DNA 甲基化的影响。
Influence of HRH2 promoter polymorphism on aberrant DNA methylation of DAPK and CDH1 in the gastric epithelium.
机构信息
Department of Gastroenterology, Kanazawa Medical University, 1-1, Daigaku, Uchinada-machi, Ishikawa, 920-0293, Japan.
出版信息
BMC Gastroenterol. 2013 Jan 2;13:1. doi: 10.1186/1471-230X-13-1.
BACKGROUND
Aberrant methylation patterns in CpG island are known to be influential in gene silencing. Histamine plays important physiological roles in the upper gastrointestinal tract and acts via the H2 receptor. We report an investigation into the effect of HRH2 promoter polymorphism (rs2607474 G > A) on the methylation of DAPK and CDH1.
METHODS
Non cancerous gastric mucosa samples were obtained from 115 subjects with gastric cancer (GC) and 412 non-cancer subjects (non-GC). Methylation status of genes was determined by MSP. The genotyping of rs2607474 was performed by PCR-SSCP.
RESULTS
Methylation of DAPK and CDH1 was observed in 296 and 246 subjects, respectively. The frequency of CDH1 methylation in the subjects with GC was significantly lower in cancer lesion than in non cancerous mucosa, whereas that of DAPK methylation was not different. The allelic distribution of rs2607474 was 401GG, 119GA and 7AA. The GG homozygote was associated with a significantly increased risk for methylation of both DAPK and CDH1 (p < 0.0001 and p = 0.0009, respectively). In the non-GC subjects or more than 60 years of age, GG homozygote was more closely associated with both DAPK and CDH1 methylation. However, this genotype did not show an increased risk for the development of methylation of both genes in patients with GC. In H. pylori negative subjects, GG homozygote showed an increased risk for the methylation of both DAPK and CDH1 (p = 0.0074 and p = 0.0016, respectively), whereas this genotype was associated with an increased risk for the development of DAPK methylation in H. pylori positive subjects (p = 0.0018). In addition, in subjects older than 60 years of age, atrophy and metaplasia scores were significantly higher in the GG homozygote (p = 0.011 and p = 0.039, respectively) and a significant correlation was observed between age and atrophy or metaplasia.
CONCLUSIONS
Our results suggest that rs2607474 GG homozygote confers a significantly increased risk for age- and inflammation-related DAPK and CDH1 methylation.
背景
CpG 岛的异常甲基化模式被认为在基因沉默中具有重要影响。组胺在胃肠道上部发挥着重要的生理作用，通过 H2 受体发挥作用。我们报告了 HRH2 启动子多态性（rs2607474 G > A）对 DAPK 和 CDH1 甲基化的影响的研究。
方法
从 115 例胃癌（GC）患者和 412 例非癌症患者（非 GC）中获得非癌性胃黏膜样本。通过 MSP 确定基因的甲基化状态。通过 PCR-SSCP 进行 rs2607474 的基因分型。
结果
分别在 296 例和 246 例患者中观察到 DAPK 和 CDH1 的甲基化。GC 患者的 CDH1 甲基化频率在癌灶中明显低于非癌性黏膜，而 DAPK 甲基化则无差异。rs2607474 的等位基因分布为 401GG、119GA 和 7AA。GG 纯合子与 DAPK 和 CDH1 的甲基化显著相关（p < 0.0001 和 p = 0.0009）。在非 GC 患者或 60 岁以上的患者中，GG 纯合子与 DAPK 和 CDH1 的甲基化更密切相关。然而，该基因型并未显示出在 GC 患者中两种基因甲基化发展的风险增加。在 H. pylori 阴性患者中，GG 纯合子与 DAPK 和 CDH1 的甲基化风险增加相关（p = 0.0074 和 p = 0.0016），而在 H. pylori 阳性患者中，该基因型与 DAPK 甲基化的发展风险增加相关（p = 0.0018）。此外，在 60 岁以上的患者中，GG 纯合子的萎缩和化生评分明显较高（p = 0.011 和 p = 0.039），年龄与萎缩或化生之间存在显著相关性。
结论
我们的研究结果表明，rs2607474 GG 纯合子显著增加了年龄和炎症相关的 DAPK 和 CDH1 甲基化的风险。
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