Arsenic and the Human Genome: susceptibility and response to exposure

砷与人类基因组：暴露的易感性和反应

• 批准号: 9557490
• 负责人: Brandon Lee Pierce
• 金额: $ 67.38万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-15 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9557490
• 关键词: Aging; Arsenic; Arsenicals; Bangladesh; Bangladeshi; Behavior; Biological; Biological Markers; Cardiovascular Diseases; Chromosomal Loss; DNA Methylation; Data; Disease; Environment; Environmental Health; Epidemiology; Epigenetic Process; Exposure to; Food Contamination; Genes; Genetic; Genetic Predisposition to Disease; Genetic study; Genome; Genomics; Goals; Health; Heritability; Human; Human Genome; Immunoglobulin Variable Region; Individual; Inherited; Intervention; Knowledge; Length; Longevity; Lung diseases; Malignant Neoplasms; Measurement; Metabolism; Non-Malignant; Outcome; Participant; Pharmacology; Point Mutation; Predisposition; Research; Resources; Risk; Role; Rural; Subgroup; Technology; Testing; Toxic effect; Variant; Work; cancer type; cohort; contaminated drinking water; data resource; drinking water; epidemiology study; gene environment interaction; genetic information; genome wide association study; genome-wide; genomic data; global health; high risk; mitochondrial DNA mutation; novel marker; response; skin lesion; telomere

PROJECT SUMMARY Arsenic contamination of food and drinking water is a serious global health issue in the U.S. and worldwide. Arsenical skin lesions are a common and early sign of arsenic toxicity, but exposure to arsenic is also associated with risk for various types of cancer, cardiovascular disease, non-malignant respiratory disease, and shortened life span. A major focus of epidemiological research on arsenic exposure has been understanding genetic susceptibility to arsenic toxicity. Genetic studies have discovered roles for both inherited variation (e.g., AS3MT variants) as well as dynamic features of the genome (i.e., telomere length) in susceptibility to arsenic toxicity and response to exposure. Additional research is needed to fully understand these gene-environment relationships. The last decade of research on genetic susceptibility to disease in humans has clearly demonstrated that large studies with genome-wide measurement are highly likely to deliver discoveries that are re-producible. Thus, we propose creating a large genomic data resource in the context of an epidemiological study of arsenic exposure in rural Bangladesh. We will use this resource to identify the features of the human genome that reflect susceptibility or response to arsenic exposure. Our first goal is to extend our ongoing work on the genetics of arsenic metabolism efficiency (AME) and GxE (gene-by- environment interaction) to identify inherited variants that influence arsenic metabolism or arsenic toxicity. Under this goal, we will investigate the biological mechanisms of arsenic-related variants and evaluate the utility genetic information for exposure reduction. Achieving this goal will entail activities such as genome-wide association and heritability studies of AME and arsenical skin lesion risk, genome-wide searches for GxE, estimating the effects of SNPs on arsenic-related health outcomes, and evaluating the impact of returning genetic results to participants on exposure-related behaviors. Our second goal is to extend or our work on arsenic and telomere length to identify additional dynamic features of the genome that reflect biological response to arsenic or susceptibility to arsenic toxicity. Achieving this goal will entail testing numerous genomic features for association with arsenic exposure and arsenical skin lesion status, including somatic chromosomal losses and point mutations, DNA methylation, epigenetic aging, and mitochondrial DNA mutation and copy number. If successful, this project will provide novel biomarkers of susceptibility and toxicity as well as biomarkers of the biological effects of arsenic exposure. The biomarkers identified will provide information useful for (1) identifying subgroups of highly susceptible individuals, (2) understanding biological mechanisms underlying susceptibility and toxicity, and (3) motivating susceptible individuals to reduce their exposure. Furthermore, we will continue developing technologies for targeted measurement of copy number variable regions for large scale epidemiological and environmental health research. This work has the potential to have transformative impact not only on knowledge, but also on both global and local environmental health.

项目总结 食品和饮用水中的砷污染在美国和世界范围内是一个严重的全球健康问题。 砷皮肤损害是砷中毒的常见和早期迹象，但暴露在砷中也是 与各种癌症、心血管疾病、非恶性呼吸道疾病、 并缩短了寿命。关于砷暴露的流行病学研究的一个主要焦点是 了解砷中毒的遗传易感性。基因研究已经发现了两者的作用 遗传变异(例如AS3MT变异体)以及基因组的动态特征(即端粒长度) 对砷毒性的敏感性和对暴露的反应。还需要进一步的研究才能充分了解 这些基因与环境的关系。过去十年关于疾病遗传易感性的研究 人类已经清楚地证明，用全基因组测量的大型研究极有可能提供 可重复生产的发现。因此，我们建议在以下背景下创建一个大型基因组数据资源 孟加拉国农村地区砷暴露的流行病学研究。我们将使用此资源来确定 反映对砷暴露的敏感性或反应的人类基因组的特征。我们的第一个目标是 扩展我们正在进行的砷代谢效率(AME)和GxE(逐个基因)遗传学方面的工作 环境交互作用)，以确定影响砷代谢或砷毒性的遗传变异。 在这一目标下，我们将研究与砷相关的变异的生物学机制，并评估 减少暴露的有用遗传信息。要实现这一目标，需要开展全基因组等活动 AME与砷中毒皮损风险的相关性和遗传力研究，全基因组搜索GxE， 评估SNPs对砷相关健康结局的影响，并评估返乡的影响 对参与者暴露相关行为的遗传结果。我们的第二个目标是扩大或扩大我们的工作 砷和端粒长度用于识别反映生物学特性的基因组的其他动态特征 对砷的反应或对砷中毒的敏感性。要实现这一目标，需要进行大量的测试 与砷暴露和砷皮肤损害状态相关的基因组特征，包括体细胞 染色体丢失和点突变、DNA甲基化、表观遗传老化和线粒体DNA突变 和复印号。如果成功，该项目还将提供新的敏感性和毒性生物标记物。 作为砷暴露生物效应的生物标志物。已确定的生物标志物将提供信息 有助于(1)确定高感个体的亚群，(2)了解生物学机制 潜在的敏感性和毒性，以及(3)激励易感人群减少暴露。 此外，我们将继续开发针对拷贝数变量的有针对性的测量技术 开展大规模流行病学和环境健康研究的区域。这项工作有可能具有 不仅对知识产生变革性的影响，而且对全球和当地的环境健康产生变革性的影响。