Low-level Arsenic Exposure and Cardiovascular Disease in Multi-Ethnic Adults (MESA As)

项目总结 流行病学和实验证据支持，暴露于中到高砷(AS)是一种 心血管疾病(CVD)危险因素。然而，人们对低AS对心血管的影响知之甚少。 通过饮食接触，特别是大米。我们的目标是调查AS暴露和AS之间的未来联系。 临床和亚临床心血管疾病的代谢(目标1)，以及效果调整(目标2)，以及潜力 动脉粥样硬化(MESA)多种族研究中这些关联的介体(目标3)，一项队列研究 来自美国6个城市的45-84岁的白人、黑人、西班牙裔和华裔美国成年人。在一项先导研究中 MESA(n=310)，非海产品尿的中位数(90百分位)分别为4.9(11.7)，3.8(11.3)，2.2(8.5)， 对于华裔美国人、西班牙裔美国人、黑人和白人来说，2.2(6.1)微克/L；较高的大米摄入量与 高尿AS；和AS3MT(编码AS(III)甲基转移酶基因)的候选SNP不是 与尿液显著相关的代谢特征。在拟议的研究中，我们将包括6725个台地 基线时无心血管疾病的参与者，平均跟踪时间为12.1年，最多5次检查。 尿样、心血管危险因素、遗传和表观遗传学数据、心血管疾病的早期标志物和亚临床 临床心脑血管疾病的结果是可用的。我们将在现货中测量As的种类和总量以及其他金属 尿样和使用先前验证的方法估计非海鲜。我们将评估所有的心血管疾病， 冠心病和卒中死亡率和发病率(作为临床结果)和颈动脉内膜中层 厚度、冠状动脉钙化、动脉扩张性和外周动脉疾病(亚临床 结果)。我们将检查吸烟状况和二手烟，全基因组和代谢芯片基因 变异，尿液作为代谢模式，血浆同型半胱氨酸作为一碳代谢的标志。我们 还将评估炎症标志物(C-反应蛋白、白介素2和白介素6)、内皮功能 (可溶性细胞黏附分子)、血栓形成(纤维蛋白原和纤溶酶原激活物抑制物-1)、 电生理学(QT间期)、高血压、糖尿病和表观遗传修饰(DNA甲基化)。在……里面 目的1我们将进行临床结果发生时间的COX比例风险模型，广义线性 具有Logit或身份链接的模型(GLM)，用于基线和边际条件下的二元或连续亚临床结果 具有纵向重复亚临床结果的线性模型。砷的水平将被模拟为连续的， 分别为分类样条线或柔性样条线。将逐步调整模型以适应潜在的混杂因素 包括社会人口学和传统的心血管疾病危险因素。效果修改将通过添加 回归模型的交互作用项。对于调解分析，我们将首先估计关联 使用与目标1类似的策略，在AS和潜在调解人之间，然后是正式的统计调解 将应用分析。这项研究可以提供关于低水平AS的心血管作用或其缺乏的信息 并有助于在普通人群中进行AS风险评估和心血管疾病的预防和控制。

PROJECT SUMMARY Epidemiologic and experimental evidence supports that exposure to moderate-to-high arsenic (As) is a cardiovascular disease (CVD) risk factor. Little is known, however, on the cardiovascular effects of low As exposure through diet, particularly rice. We aim to investigate the prospective association of As exposure and metabolism with clinical and subclinical CVD (Aim 1), as well as effect modification (Aim 2), and potential mediators (Aim 3) of these associations in the Multi-Ethnic Study of Atherosclerosis (MESA), a cohort study of White, Black, Hispanic, and Chinese-American adults 45-84 years of age from 6 US cities. In a pilot study in MESA (n=310), median (percentile 90) urine As not derived from seafood was 4.9 (11.7), 3.8 (11.3), 2.2 (8.5), 2.2 (6.1) µg/L for Chinese Americans, Hispanics, Blacks and Whites; higher rice intake was associated with higher urine As; and a candidate SNP in AS3MT (gene encoding As(III) methyltransferase), was non- significantly associated with urine As metabolism profile. In the proposed study, we will include 6,725 MESA participants free of CVD at baseline who have been followed for a mean of 12.1 years with up to 5 exams. Urine samples, cardiovascular risk factors, genetic and epigenetic data, early markers of CVD, and subclinical and clinical CVD outcomes are available. We will measure As species and total As and other metals in spot urine samples and estimate non seafood As using a previously validated method. We will evaluate all CVD, coronary heart disease and stroke mortality and incidence (as clinical outcomes) and carotid intima-media thickness, coronary artery calcification, arterial distensibility and peripheral arterial disease (as subclinical outcomes). We will examine smoking status and secondhand smoke, genome-wide and Metabochip genetic variants, urine As metabolism patterns, and plasma homocysteine as a marker of one-carbon metabolism. We will also evaluate markers of inflammation (C-reactive protein, interleukin(IL)-2, and IL-6), endothelial function (soluble cell adhesion molecules), thrombosis (fibrinogen and plasminogen activator inhibitor-1, electrophysiology (QT interval), hypertension, diabetes, and epigenetic modifications (DNA methylation). In Aim 1 we will conduct Cox proportional hazards models for time to event clinical outcomes, generalized linear models (GLM) with logit or identity link for binary or continuous subclinical outcomes at baseline, and marginal linear models with repeated subclinical outcomes longitudinally. Arsenic levels will be modeled as continuous, categorical or flexible splines, separately. Models will be progressively adjusted for potential confounders including sociodemographic and traditional CVD risk factors. Effect modification will be estimated by adding interaction terms to the regression models. For mediation analyses, we will first estimate the association between As and the potential mediators using similar strategies as in Aim 1, then formal statistical mediation analysis will be applied. This study can inform on the cardiovascular role, or lack thereof, of low-level As exposure and contribute to As risk assessment and to CVD prevention and control in general populations.