环境内分泌干扰物与雌激素信号通路关键基因的交互作用在高血压发生中的作用及机制

Hypertension is a complex human disease caused by interactions among genes and environments. Environmental endocrine disrupting chemicals (EDCs) are the most worldwide concerned “environmental pollution problems”. The latest epidemiological and laboratory studies have shown that EDCs are a new environmental risk factor for hypertension. Moreover, owing to their effects on individual sensitivity to EDCs’ exposure, the variations of key genes in estrogen signaling pathway may have the interactions with EDCs to jointly induce hypertension. A two stage case-control study will be carried out to analyze the role and relevance of EDCs exposure level, the single nucleotide polymorphism (SNP) of the key genes in estrogen signaling pathway and their interactions in hypertension of Chinese Han population. Furthermore, methods of classification and regression tree (CART) and artificial neural network (ANN) will be applied to build high-risk predictive model of hypertension. In addition, various techniques including luciferase reporter assay, electrophoretic mobility shift assay, chromatin immunoprecipitation and Western Blot will be performed to study the function of positive associated SNPs thoroughly. The researches will elucidate the role and the possible mechanism of hypertension induced by EDCs and provide important scientific basis for EDCs control and governance. The selected SNPs that associated with the increased morbidity risk of hypertension can be utilized as genetic markers in clinical practice, such as hypertension screens, predictions of prognosis and design for drug targeting.

高血压是遗传、环境因素交互作用的结果。环境内分泌干扰物（EDCs）是目前世界范围内最受关注的“环境问题”。最新的流行病学调查和实验室研究结果显示，EDCs是诱发高血压的新的环境危险因素，且与雌激素信号通路关键基因的遗传变异存在复杂的交互作用，共同诱导高血压的发生。本项目拟采用“两阶段病例-对照”关联性研究策略，系统分析EDCs暴露水平、雌激素信号通路关键基因的遗传变异及彼此交互作用与中国汉族人群高血压发生的关系，采用分类回归树和人工神经网络构建高血压高危个体风险预测模型，并应用荧光素酶报告基因、凝胶迁移率阻滞实验、染色质免疫沉淀、Western Blot等技术深入探讨与高血压易感性相关的阳性关联SNPs的生物学机制。本研究为进一步阐明EDCs致高血压的作用机制及EDCs的控制治理提供重要科学依据，筛选得到的高血压关联SNPs亦可作为遗传标记物，用于高风险个体的筛查和药物靶向治疗。

高血压是遗传、环境因素交互作用的结果。本项目将现场流行病学调查与实验室研究工作相结合，采用病例-对照的关联性研究策略，深入探讨了典型环境内分泌干扰物——双酚A及其替代物（双酚S和双酚F）的暴露、雌激素信号通路关键基因的多态性及其交互作用与高血压患病风险的关联性。研究发现双酚A的暴露（尿双酚A浓度）与高血压患病风险存在正向关联，且关联具有性别特异性（在男性中更为显著）；雌激素信号通路关键基因ESR1 rs2234693、MMP2 rs243865和rs243866、ESR1和MMP2基因的单体型均与高血压患病风险存在显著关联；在相加交互模型中，与仅BPA暴露组相比，BPA暴露在ESR1 rs2234693、MMP2 rs243865和rs243866的显性基因型中对高血压患病风险的效应值均有不同程度的增加。研究结果表明环境内分泌干扰物双酚A的暴露可能增加高血压的患病风险，且与特定基因型存在交互作用。这为中国汉族人群高血压的综合防治以及双酚A的控制治理提供了一种新的路径和理论支持。