Arsenic, Epigenetics and Incident Cardiovascular Disease in American Indians

美洲印第安人的砷、表观遗传学和心血管疾病事件

• 批准号: 9416700
• 负责人: M Daniele Fallin
• 金额: $ 18.01万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-06-15 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9416700
• 关键词: Arsenic; Epigenetics; Incident; Cardiovascular; Disease

 DESCRIPTION (provided by applicant): Inorganic arsenic in water and food are global health problems. Increasing epidemiologic and experimental evidence supports the role of low-moderate inorganic arsenic exposure as a cardiovascular disease (CVD) risk factor. In the Strong Heart Study (SHS), baseline urine arsenic concentrations were associated with incident CVD, supporting the need to investigate relevant mechanisms for arsenic related CVD, including epigenetic modifications. Objective: To investigate (1) if DNA epigenetic modifications mediate the association between arsenic and CVD and (2) if genetic variability modifies epigenetic mediation of arsenic related CVD in 3,574 SHS participants 45-74 years old and free of CVD at baseline. Preliminary studies: In a pilot study in the SHS, arsenic metabolism, measured by the relative proportion of arsenic species in urine, was associated with global DNA methylation and hydroxymethylation and arsenic exposure was associated with a hypomethylated region of AS3MT, the gene that codes a major methyltransferase involved in arsenic metabolism. In linkage and fine-mapping studies, genetic variants in the AS3MT region of the genome were associated with urine measures of arsenic metabolism. Design and setting: Population-based prospective cohort study of American Indian men and women from Arizona, Oklahoma and North/South Dakota recruited in 1989-1991 and followed through 2008 as part of the SHS. Data collection: Urine arsenic measures (reflecting long-term exposure), DNA samples to measure epigenetic modifications and genetic polymorphisms, CVD follow-up including coronary heart disease, stroke, peripheral artery disease and carotid plaque, and extensive data characterizing CVD and its risk factors are available. Epigenetic assessment: We will measure genome- wide blood DNA methylation at baseline using state-of-the-art high throughput technology to identify specific DNA methylation that may mediate the relationship between arsenic and incident CVD endpoints and validate the most promising regions using bisulfite pyrosequencing. Genetic assessment: We will measure 96 SNPs previously related to arsenic metabolism and toxicity in the Strong Heart Family Study, conducted in the same communities as the SHS. SNPs in candidate genes related to CVD are already available in the SHS. Statistical analysis: To evaluate if DNA epigenetic modifications mediate the association between arsenic and CVD, the following conditions will need to be met: (1) arsenic is associated with CVD (already confirmed), (2) arsenic is associated with DNA methylation, (3) DNA methylation is associated with CVD, conditional on arsenic exposure, and (4) attenuation of the arsenic-CVD association conditional on DNA methylation. Gene- epigene interactions will be assessed via general linear models and likelihood ratio tests. Significance: By investigating the contribution of arsenic epigenetics to CVD, this study can reveal novel mechanisms for arsenic health effects, identify susceptible populations, and inform risk assessment, with implications for the prevention and control of arsenic exposure in drinking water and food in the US and abroad.

 描述（由适用提供）：水和食物中的无机砷是全球健康问题。增长的流行病学和实验证据支持低压无机砷暴露作为心血管疾病（CVD）危险因素的作用。在强大的心脏研究（SHS）中，基线尿液砷浓度与入射CVD相关，这支持需要研究砷相关CVD的相关机制，包括表观遗传学修饰。目的：研究（1）如果DNA表观遗传修饰介导了砷和CVD之间的关联，并且（2）如果遗传变异性改变了3,574 shs参与者45-74岁的3,574 shs参与者的砷相关CVD的表观遗传介导，而基线则是CVD。初步研究：在SHS的一项试点研究中，通过尿液中砷物种的相对比例测量的砷代谢与全球DNA甲基化和羟基甲基化和砷暴露有关，与AS3MT的低甲基化区域相关，该基因与主要的甲基化酶相关的基因相关。在链接和精细图研究中，基因组AS3MT区域的遗传变异与砷代谢的尿液测量有关。设计和环境：基于人群的前瞻性队列研究，对来自亚利桑那州，俄克拉荷马州和北达科他州的美洲印第安人和妇女进行了1989年至1991年的招募，随后是SHS的一部分。数据收集：尿液砷测量（反映长期暴露），测量表观遗传修饰和遗传多态性的DNA样本，包括冠状动脉疾病，中风，周围动脉疾病和Carotid Plaque，包括冠状动脉疾病的CVD随访以及广泛的数据表征CVD及其风险因素。表观遗传评估：我们将使用最先进的高通量技术在基线下在基线下测量基因组宽的血液DNA甲基化，以鉴定特定的DNA甲基化，从而可以使用Bisulfite pyrosequencing来介导砷和入射CVD CVD端点之间的关系并验证最有希望的区域。遗传评估：我们将在强大的心脏家庭研究中测量与砷代谢和毒性相关的96个SNP，该研究与SHS相同的社区进行了。与CVD有关的候选基因中的SNP已在SHS中可用。统计分析：要评估DNA表观遗传学修饰是否介导了砷和CVD之间的关联，需要满足以下条件：（1）砷与CVD（已确认）有关，（2）砷与DNA甲基化相关，（3）DNA甲基化与CVD相关，与CVD相关，均与arsenic consential contiential contiential conty arsenic contiens（4）与（4）（4）与（4）与（4）（4）与（4）与（4）相关（4）（4）与（4）与（4）相关（4）（4）与（4）相关（4）与（4）相关。在DNA甲基化的条件下。基因遗传相互作用将通过一般线性模型和似然比检验进行评估。意义：通过研究砷表观遗传学对CVD的贡献，本研究可以揭示砷健康影响的新机制，识别易感人群并为风险评估提供信息，对 美国和国外饮用水和食物中砷暴露的预防和控制。