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，即作为暴露导致氧化应激和血管炎症，动脉粥样硬化和心血管疾病的发展的中心机制。对砷暴露的其他健康影响的研究表明，砷甲基化能力和遗传易感性可能会影响砷的修饰作用。然而，遗传易感性的影响，砷暴露CVD风险的流行病学研究缺乏。2000年，我们在孟加拉国Araihazar建立了砷对健康影响的纵向研究（HEALS），这是一项有11，746名参与者（原始队列）的前瞻性队列研究。2007年，HEALS招募了另外8，288名参与者（扩展队列），总共包括20，034名参与者。超过90%的队列暴露于低至中等水平（<300 5g/L）的As暴露，为我们提供了一个独特的机会，以评估从饮用水中暴露于公共健康利益的水平的As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局，并测量从原始队列中随机选择的1，160名参与者的颈动脉内膜中层厚度（IMT）。在这些资源的基础上，我们大量的试点数据，以及队列分析显示，作为暴露和CVD发病率和死亡率之间的正相关，我们提出了一系列的分析，以评估遗传易感性的影响，作为暴露的动脉粥样硬化和CVD的风险。我们将评估砷暴露对心血管的影响是否因砷甲基化相关基因多态性而不同（GSTM 1、GSTT 1、GSTO 1、GSTP 1、MTHFR和AS 3 MT基因）和氧化应激相关基因（NOS 3、SOD 2和CYBA）和炎症/内皮功能障碍（TNF，IL 6，ICAM 1和VCAM 1），使用IMT的横断面研究（包括1，160名参与者的子队列）和CVD风险的病例队列研究（包括692例病例和相同的1，来自原始队列的160名参与者。最强的基因- As相互作用将在第二个病例-队列研究中再次进行测试，其中有305例病例和另一个从扩展队列中选择的520名参与者的子队列。为了进一步表征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，以评估砷暴露与氧化应激和炎症的血清/尿液表型标志物之间的关联。拟议中的研究将提供有价值的知识的病理生理学和机制，作为暴露可能导致心血管疾病，也可能导致改善预防和风险评估作为曝光。

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.