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: 8860791
• 负责人: M Daniele Fallin
• 金额: $ 56.35万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 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/8860791
• 关键词: Affect; American Indians; Arizona; Arsenic; Arteries; Biological Markers; Blood; Blood Vessels; Candidate Disease Gene; Cardiovascular Diseases; Cardiovascular system; Carotid Artery Plaques; Clinical; Code; Cohort Studies; Communities; Coronary heart disease; CpG dinucleotide; DNA; DNA Methylation; Data; Data Collection; Death Records; Development; Diabetes Mellitus; Disease; Enzymes; Epidemic; Epidemiology; Epigenetic Process; Family Study; Food; Genes; Genetic; Genetic Markers; Genetic Polymorphism; Genome; Genotype; Health; Heart; Histone Acetylation; Hospitalization; Linear Models; Maps; Measures; Mediating; Mediation; Mediator of activation protein; Metabolism; Methylation; Methyltransferase; Modification; North Dakota; Obesity; Oklahoma; Outcome; Participant; Peripheral; Peripheral arterial disease; Pilot Projects; Population; Population Study; Prevention; Recommendation; Recruitment Activity; Relative (related person); Resources; Risk; Risk Assessment; Risk Factors; Role; Rural Population; Sampling; South Dakota; Stroke; Suburban Population; System; Testing; Time; Toxic effect; Urine; Water; Woman; attenuation; base; bisulfite; cardiovascular disorder risk; cardiovascular risk factor; design; drinking water; follow-up; genetic variant; genome-wide; global health; high throughput technology; histone methylation; insight; meetings; men; novel; population based; prospective; public health relevance; pyrosequencing; risk variant; secondary outcome

 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（由申请人提供）：水和食物中的无机砷是全球健康问题。越来越多的流行病学和实验证据支持低中度无机砷暴露作为心血管疾病 (CVD) 危险因素的作用。在强心脏研究 (SHS) 中，基线尿砷浓度与 CVD 事件相关，支持研究砷相关 CVD 的相关机制的必要性，包括表观遗传修饰。目的：在 3,574 名 45-74 岁且基线时无 CVD 的 SHS 参与者中，调查 (1) DNA 表观遗传修饰是否介导砷与 CVD 之间的关联，以及 (2) 遗传变异是否改变砷相关 CVD 的表观遗传介导。初步研究：在 SHS 的一项试点研究中，砷代谢（通过尿液中砷物质的相对比例来衡量）与整体 DNA 甲基化和羟甲基化相关，砷暴露与 AS3MT 的低甲基化区域相关，AS3MT 是编码参与砷代谢的主要甲基转移酶的基因。在连锁和精细定位研究中，基因组 AS3MT 区域的遗传变异与砷代谢的尿液测量结果相关。设计和背景：作为 SHS 的一部分，对来自亚利桑那州、俄克拉荷马州和北/南达科他州的美国印第安人男性和女性进行了基于人群的前瞻性队列研究，该研究于 1989 年至 1991 年招募并跟踪至 2008 年。数据收集：尿砷测量（反映长期暴露）、用于测量表观遗传修饰和遗传多态性的 DNA 样本、包括冠心病、中风、外周动脉疾病和颈动脉斑块在内的 CVD 随访，以及表征 CVD 及其危险因素的大量数据。表观遗传评估：我们将使用最先进的高通量技术在基线上测量全基因组血液 DNA 甲基化，以确定可能介导砷和事件 CVD 终点之间关系的特定 DNA 甲基化，并使用亚硫酸氢盐焦磷酸测序验证最有希望的区域。遗传评估：我们将测量先前在强心脏家族研究中与砷代谢和毒性相关的 96 个 SNP，该研究在与 SHS 相同的社区进行。 SHS 中已经提供了与 CVD 相关的候选基因中的 S​​NP。统计分析：为了评估 DNA 表观遗传修饰是否介导砷与 CVD 之间的关联，需要满足以下条件：(1) 砷与 CVD 相关（已证实），(2) 砷与 DNA 甲基化相关，(3) DNA 甲基化与 CVD 相关，以砷暴露为条件，以及 (4) 砷与 CVD 关联的减弱 以 DNA 甲基化为条件。基因-表观基因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：通过调查砷表观遗传学对 CVD 的影响，这项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品中砷暴露的预防和控制。