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: 9087231
• 负责人: M Daniele Fallin
• 金额: $ 35.11万
• 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 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9087231
• 关键词: Affect; American Indians; Arizona; Arsenic; Arteries; Biological Markers; Blood; 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; Prevention; Recommendation; Recruitment Activity; Resources; Risk; Risk Assessment; Risk Factors; Role; Rural Population; Sampling; South Dakota; Statistical Data Interpretation; 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; pyrosequencing; risk variant; secondary outcome; study population

 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）：水和食品中的无机砷是全球性的健康问题。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。在强心研究（SHS）中，基线尿砷浓度与CVD事件相关，支持需要研究砷相关CVD的相关机制，包括表观遗传修饰。目的：研究（1）DNA表观遗传修饰是否介导砷和CVD之间的关联，以及（2）遗传变异性是否改变了3，574名45-74岁且基线时无CVD的SHS参与者中砷相关CVD的表观遗传介导。初步研究：在SHS的一项初步研究中，砷代谢（通过尿中砷物种的相对比例测量）与全球DNA甲基化和羟甲基化相关，砷暴露与AS 3 MT的低甲基化区域相关，AS 3 MT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AS 3 MT区域的遗传变异与砷代谢的尿液测量相关。设计和设置：对亚利桑那州、俄克拉荷马州和北/南达科他州的美国印第安男性和女性进行的基于人群的前瞻性队列研究，招募于1989-1991年，并随访至2008年，作为SHS的一部分。数据收集：尿砷测量（反映长期暴露），DNA样本测量表观遗传修饰和遗传多态性，心血管疾病随访，包括冠心病，中风，外周动脉疾病和颈动脉斑块，以及广泛的数据表征心血管疾病及其危险因素。表观遗传评估：我们将使用最先进的高通量技术在基线处测量全基因组血液DNA甲基化，以鉴定可能介导砷和事件CVD终点之间的关系的特异性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。基因评估：我们将测量96个SNPs先前与砷代谢和毒性相关的强心脏家族研究，在相同的社区进行的SHS。SHS中已经提供了与CVD相关的候选基因中的SNP。统计分析：为了评估DNA表观遗传修饰是否介导砷和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）以DNA甲基化为条件的砷-CVD关联减弱。将通过一般线性模型和似然比检验评估基因-表观基因相互作用。重要性：通过调查砷表观遗传学对CVD的贡献，这项研究可以揭示砷对健康影响的新机制，识别易感人群，并为风险评估提供信息，并对以下方面产生影响： 预防和控制美国和国外饮用水和食品中的砷暴露。