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

项目摘要 流行病学和实验证据支持，暴露于中到高砷（As）是一个危险因素。 心血管疾病（CVD）危险因素。然而，对低砷对心血管的影响知之甚少 通过饮食接触，特别是大米。我们的目的是调查砷暴露与 代谢与临床和亚临床CVD（目的1），以及影响修改（目的2），和潜在的 在多种族动脉粥样硬化研究（梅萨）中， 来自美国6个城市的45-84岁的白色、黑人、西班牙裔和华裔美国成年人。在一项试点研究中， 梅萨（n=310），非海鲜来源的尿砷中位数（百分位数90）分别为4.9（11.7），3.8（11.3），2.2（8.5）， 2.2（6.1）微克/升的华裔美国人，西班牙裔，黑人和白人;较高的大米摄入量与 更高的尿As;和AS 3 MT（编码As（III）甲基转移酶的基因）中的候选SNP，是非特异性的。 与尿砷代谢谱显著相关。在拟议的研究中，我们将包括6，725个梅萨 基线时无CVD的受试者，平均随访12.1年，最多5次检查。 尿液样本、心血管风险因素、遗传和表观遗传数据、CVD的早期标志物和亚临床 和临床CVD结果。我们将在现场测量As形态和总As以及其他金属 尿液样本和估计非海鲜作为使用以前验证的方法。我们会评估所有的心血管疾病， 冠心病和卒中死亡率和发病率（作为临床结局）以及颈动脉内膜-中膜 厚度、冠状动脉钙化、动脉扩张性和外周动脉疾病（作为亚临床 成果）。我们将检查吸烟状况和二手烟，全基因组和代谢芯片遗传 变异、尿As代谢模式和血浆同型半胱氨酸作为一碳代谢的标志物。我们 还将评估炎症标志物（C-反应蛋白、白细胞介素（IL）-2和IL-6）、内皮功能 （可溶性细胞粘附分子），血栓形成（纤维蛋白原和纤溶酶原激活物抑制剂-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 目的1：我们将对至事件发生时间的临床结局进行考克斯比例风险模型，广义线性 基线时二元或连续亚临床结局的logit或恒等链接模型（GLM），以及边缘 纵向重复亚临床结局的线性模型。砷水平将被模拟为连续的， 分类或灵活的样条，分别。将针对潜在混杂因素逐步调整模型 包括社会人口统计学和传统CVD风险因素。将通过添加以下内容来估计效应修改 回归模型的交互作用项。对于中介分析，我们将首先估计 之间的作为和潜在的调解人使用类似的策略，在目标1，然后正式的统计调解 将进行分析。这项研究可以告知心血管的作用，或缺乏，低水平的砷 暴露，并有助于作为风险评估和心血管疾病的预防和控制在一般人群中。

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.