环境内分泌干扰物双酚A暴露和DNA甲基化相关基因与2型糖尿病发生的前瞻性研究

Exposure to bisphenol A (BPA) could cause type 2 diabetes via DNA methylation, but evidence from population-based studies are needed. DNA methyltransferase (DNMT) and methyl-CpG binding domain protein (MBD) are key regulars of DNA methylation. Therefore, the expression of genes coding for DNMT and MBD can be a marker of DNA methylation. Moreover, single nucleotide polymorphisms (SNPs) of DNMT and MBD genes may interact with BPA exposure and contribute to the occurrence of type 2 diabetes. On basis of the Dongfeng-Tongji Cohort, we plan to perform a nested case-control study, and measure serum BPA concentrations among 1039 pairs of diabetes cases and controls at baseline, from which the whole blood-derived mRNA expression levels of 5 DNMT and MBD genes will also be measured among 100 pairs that are randomly selected. Along with available genetic data, we will prospectively analyze the main effects and interaction of personal exposure to BPA and SNPs in candidate genes on type 2 diabetes, and establish a diabetes prediction model including BPA exposure and positive SNPs. We will also examine the difference of gene expression levels between cases and controls, and explore the involvement of DNA methylation in the association between BPA exposure and incident type 2 diabetes via analyzing the relationship of personal exposure to BPA, fasting blood glucose levels, and expression levels of candidate genes. Our results will provide scientific evidence for investigating the role of DNA methylation in type 2 diabetes caused by BPA exposure, and for screening high-risk individuals and accurate prevention of type 2 diabetes.

双酚A暴露可通过DNA甲基化诱发2型糖尿病，但缺乏人群研究证据。甲基转移酶（DNMT）和甲基-CpG结合域蛋白（MBD）是调控DNA甲基化的关键因素，编码DNMT和MBD的基因可作为DNA甲基化的标志物，并可能与双酚A暴露存在交互作用。本项目采用巢式病例对照研究，结合课题组全基因组位点分型数据，分别测定东风-同济队列基线1039对和其中100对糖尿病病例对照血清双酚A水平和全血中5个DNMT和MBD基因表达水平，前瞻性分析个体双酚A暴露、候选基因多态性位点、双酚A暴露-基因交互作用对2型糖尿病的影响，并建立引入双酚A暴露和候选基因多态性位点的风险预测模型；比较病例组和对照组候选基因表达是否存在差异，分析个体双酚A暴露、候选基因表达水平、2型糖尿病之间关系。本项目将为探讨DNA甲基化在双酚A暴露致2型糖尿病发生的中介效应，以及2型糖尿病高危人群筛选和个体精准预防提供科学依据。

本项目通过年龄、性别1:1匹配的巢式病例对照研究设计，前瞻性地分析环境内分泌干扰物双酚A、DNA甲基化相关基因与2型糖尿病发生风险的主效应和交互作用。研究结果表明，双酚A与2型糖尿病发生风险呈现U型非线性关联；以包括甲基化相关基因部分位点在内的88个SNP建立的遗传风险评分与研究对象基线空腹血糖水平显著相关；同时具有较高血清双酚A水平和遗传风险评分的研究对象发生2型糖尿病的风险显著升高，但并未发现双酚A与遗传风险评分存在交互作用。双酚A和遗传风险评分能够显著改善基于传统危险因素建立的2型糖尿病发生风险预测模型的预测效力。以上发现可为研究双酚A暴露的健康效应、识别2型糖尿病高危人群以及疾病的精准预防提供新的线索。