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: 9984720
• 负责人: Brandon Lee Pierce
• 金额: $ 7.85万
• 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/9984720
• 关键词: Aging; Arsenic; Arsenicals; Bangladesh; Bangladeshi; Behavior; Biological; Biological Markers; Cardiovascular Diseases; Chromosomal Loss; Consumption; 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.

项目摘要 在美国和世界范围内，食物和饮用水的砷污染是全球严重的健康问题。 砷皮肤病变是砷毒性的常见和早期迹象，但暴露于砷也是 与各种类型的癌症，心血管疾病，非恶性呼吸道疾病的风险有关， 并缩短了寿命。关于砷暴露的流行病学研究的重点是 了解对砷毒性的遗传敏感性。遗传研究发现了这两者的作用 遗传变异（例如AS3MT变体）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。需要进行其他研究以充分理解 这些基因环境关系。关于遗传易感性疾病易感性的最后十年 人类清楚地表明，全基因组测量的大型研究很可能会提供 可重新实现的发现。因此，我们建议在以下情况下创建大型基因组数据资源 孟加拉国农村砷暴露的流行病学研究。我们将使用此资源来确定 人类基因组的特征反映了对砷暴露的敏感性或反应。我们的第一个目标是 扩展我们对砷代谢效率（AME）和GXE的遗传学的持续工作（基因 环境相互作用）确定影响砷代谢或砷毒性的遗传变体。 在这个目标下，我们将研究与砷相关变体的生物学机制，并评估 实用性遗传信息以减少暴露。实现这一目标将需要诸如全基因组等活动 对AME和砷皮肤病变风险的关联和遗传性研究，全基因组搜索GXE， 估计SNP对砷相关的健康结果的影响，并评估返回的影响 与暴露相关行为的参与者的遗传结果。我们的第二个目标是扩展或我们的工作 砷和端粒长度以识别反映生物学的基因组的其他动态特征 对砷或对砷毒性的敏感性的反应。实现这一目标将需要进行许多测试 与砷暴露和砷皮肤病变状态相关的基因组特征，包括躯体 染色体损失和点突变，DNA甲基化，表观遗传衰老和线粒体DNA突变 和复制号。如果成功，该项目也将提供新颖的生物标志物，具有易感性和毒性 作为砷暴露的生物学作用的生物标志物。确定的生物标志物将提供信息 对于（1）识别高度易感个体的亚组，（2）了解生物学机制 基本的敏感性和毒性，以及（3）激励易感人群减少其暴露。 此外，我们将继续开发针对拷贝数变量的目标测量技术 大规模流行病学和环境健康研究的地区。这项工作有可能拥有 不仅对知识的影响，而且对全球和地方环境健康都有影响。