Genetic Susceptibilty to Cardiovascular Effects of Arsenic Exposure

描述(由申请人提供)：砷暴露对心血管影响的遗传易感性项目摘要心血管疾病(CVD)是全球主要的死亡原因。最近的实验研究支持这一假设，即暴露导致氧化应激和血管炎症，这是动脉粥样硬化和心血管疾病发展的中心机制。对砷暴露对健康的其他影响的研究表明，砷的甲基化能力和遗传易感性对效应进行了修饰。然而，缺乏关于砷暴露对心血管疾病风险影响的遗传易感性的流行病学研究。2000年，我们在孟加拉国的阿拉哈扎尔建立了砷对健康的影响纵向研究(HeALS)，这是一项对11,746名参与者(最初的队列)进行的前瞻性队列研究。2007年，Heals又招募了8,288名参与者(扩展队列)，总共包括20,034名参与者。超过90%的队列人群暴露于低至中等水平的砷(&lt；300 5g/L)，这为我们提供了一个独特的机会，从公众健康关注的水平来评估饮用水中砷对健康的影响。作为母研究的一部分，正在确定队列参与者的心血管结果，并从原始队列中随机选择1160名参与者测量颈动脉内膜-中层厚度(IMT)。基于这些资源，我们大量的试点数据，以及显示AS暴露与心血管疾病发病率和死亡率呈正相关的队列分析，我们提出了一系列分析，以评估AS暴露对动脉粥样硬化和心血管疾病风险的遗传易感性。我们将评估AS暴露的心血管效应是否因AS甲基化相关基因(GSTM1、GSTT1、GSTO1、GSTP1、MTHFR和AS3MT基因)以及与氧化应激相关的基因(NOS3、SOD2和CyBA)和炎症/内皮功能障碍相关基因(肿瘤坏死因子、白介素6、ICAM1和VCAM1)的多态而不同。在第二个病例队列研究中，将再次测试最强的基因-AS交互作用，研究对象包括305个病例和从扩展队列中选择的另一个520名参与者。为了进一步确定砷暴露导致心血管疾病的潜在机制，我们将对300名受试者进行一项横断面研究，以评估砷暴露与血/尿氧化应激和炎症表型标记物之间的关系。这项拟议的研究将提供关于砷暴露可能导致心血管疾病的病理生理学和机制的宝贵知识，还可能导致改进对砷暴露的预防和风险评估。 公共卫生相关性：拟议的项目旨在评估饮用水中低至中等水平的无机砷是否会增加遗传易感人群中氧化应激、炎症和低AS代谢能力导致心血管疾病的风险。这项拟议的研究将有助于了解砷暴露可能导致心血管疾病的病理生理和机制。这一发现还可能改善对砷暴露对健康影响的风险评估。

DESCRIPTION (provided by applicant): Genetic Susceptibility to Cardiovascular Effects of Arsenic Exposure Project summary cardiovascular disease (CVD) is the leading cause of death worldwide. Recent experimental studies support the hypothesis that As exposure leads to oxidative stress and vascular inflammation, a central mechanism to the development of atherosclerosis and CVD. Studies of other health effects of As exposure have suggested effect-modification by As methylation capacity and genetic susceptibility. However, epidemiologic studies of genetic susceptibility to the effects of As exposure on CVD risk are lacking. In the year 2000, we established the Health Effects of Arsenic Longitudinal Study (HEALS), a prospective cohort study of 11,746 participants (original cohort), in Araihazar, Bangladesh. In 2007, HEALS recruited another 8,288 participants (expansion cohort) to include a total of 20,034 participants. More than 90% of the cohort have exposed to As exposure at low-to-moderate levels (<300 5g/L), providing us with a unique opportunity to assess health effects of As exposure from drinking water at the levels of public health interest. As part of the parent study, cardiovascular outcomes of the cohort participants are being ascertained, and carotid artery intima-medial thickness (IMT) is being measured for 1,160 participants randomly selected from the original cohort. On the basis of these resources, our substantial pilot data, as well as cohort analyses which show a positive association between As exposure and CVD incidence and mortality, we propose a series of analyses to assess the genetic susceptibility to the effects of As exposure on the risk of atherosclerosis and CVD. We will evaluate whether the cardiovascular effects of As exposure differ by polymorphisms in genes related to As methylation (GSTM1, GSTT1, GSTO1, GSTP1, MTHFR, and AS3MT genes) and genes related to oxidative stress (NOS3, SOD2, and CYBA) and inflammation/endothelial dysfunction (TNF, IL6, ICAM1, and VCAM1) using a cross-sectional study of IMT with the subcohort of 1,160 participants, and a case-cohort study of CVD risk with 692 cases and the same subcohort of 1,160 participants from the original cohort. The strongest gene- As interaction will be tested again in a second case-cohort study with 305 cases and another subcohort of 520 participants selected from the expansion cohort. To further characterize the underlying mechanisms by which As exposure causes CVD, we will conduct a cross-sectional study with 300 subjects to evaluate the associations between As exposure and serum/urinary phenotypic markers for oxidative stress and inflammation. The proposed study will provide valuable knowledge about the pathophysiology and mechanism by which As exposure may lead to CVD and may also lead to improved prevention and risk assessment of As exposure. PUBLIC HEALTH RELEVANCE: The proposed project aims to assess whether low-to-moderate level of inorganic arsenic from drinking water increases the risk of cardiovascular disease in genetic susceptible groups to oxidative stress, inflammation, and low As metabolism capacity. The proposed study will contribute to the knowledge about the pathophysiology and mechanism by which arsenic exposure may lead to cardiovascular diseases. The findings may also improve risk assessment of health effects of arsenic exposure.