Gene-by-environment interactions that affect exposure-mediated congenital heart disease

影响暴露介导的先天性心脏病的基因与环境相互作用

• 批准号: 10655611
• 负责人: Mark E Hahn
• 金额: $ 62.37万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-10 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10655611
• 关键词: Affect; Animals; Aromatic Polycyclic Hydrocarbons; Biological Models; Breeding; CRISPR/Cas technology; Candidate Disease Gene; Cardiovascular Diseases; Cardiovascular system; Catalogs; Chemicals; Complex; Congenital Abnormality; Data; Development; Disease; Disease Outcome; Dose; Embryo; Environment; Environmental Exposure; Environmental Risk Factor; Etiology; Evaluation; Event; Exhibits; Exposure to; Family; Frequencies; Fundulus heteroclitus; Gene Expression Profile; Generations; Genes; Genetic; Genetic Variation; Genome; Genome Scan; Genomics; Genotype; Heritability; Human; Individual Differences; Killifishes; Maps; Mediating; Modeling; Molecular; Natural Selections; Natural experiment; Outcome; Pathway interactions; Pattern; Phenotype; Pollution; Polychlorinated Biphenyls; Population; Predisposition; Quantitative Genetics; Quantitative Trait Loci; Research; Resistance; Role; Severity of illness; System; Testing; Urbanization; Variant; Vertebrates; Zebrafish; adverse outcome; candidate selection; chemical association; congenital heart disorder; disease phenotype; environmental chemical; experimental study; fitness; fluoranthene; gene environment interaction; genetic approach; genetic association; genetic risk factor; genetic testing; genome editing; genome-wide; genomic data; human disease; in vivo; insight; malformation; novel; phenanthrene; pollutant; population based; rare variant; response; segregation; transcriptomics

Project Summary/Abstract We propose to exploit unique features of the Atlantic killifish model system to elucidate the interaction of genetic variation and environmental exposures in the etiology of congenital heart disease (CHD). This complex human disease encompasses a suite of structural and functional deficits and is the most common human congenital malformation worldwide. The etiology of CHD is poorly understood, but appears to involve both genetic and environmental risk factors, including exposure to environmental chemicals. The Atlantic killifish (Fundulus heteroclitus) is a novel population-based model system that harbors substantial genetic diversity and exhibits chemical-induced cardiovascular disease states that mimic substantial aspects of CHD in humans. Killifish inhabit urbanized environments that are polluted by mixtures of chemicals including polychlorinated biphenyls (PCBs) and polycyclic aromatic hydrocarbons (PAHs). Urban and non-urban populations vary profoundly in their sensitivity to CHD caused by exposure to these compounds. We propose to use this unique and powerful system to explore gene-environment interactions associated with CHD, expanding on our successful use of the Quantitative Trait Loci (QTL) approach in this species. A particularly compelling feature of this model is that natural selection has increased the frequency of otherwise rare variants that influence sensitivity to these (and potentially other) important classes of pollutants. Our previous data reveal some regions of the genome that affect fitness in polluted environments, and contribute to variation in sensitivity to CHD. The overall objective of the proposed research is to determine the genes and pathways harboring genetic variation that controls sensitivity to PCB- and PAH-induced CHD. We will test for genetic associations through genome-wide genotyping of phenotyped animals in replicate families bred using QTL strategies and exposed to PCB and PAHs. Experiments will test for genetic association with multiple specific structural and functional deficits that define the suite of CHD phenotypes. This QTL mapping will include 1) multiple genetic backgrounds, 2) multiple CHD-associated chemicals, each with different hypothesized mechanisms of action, and 3) multiple exposure levels. We will test whether the different CHD features are associated with unique or shared variants in different genetic backgrounds, and whether disease-associated variants are unique or shared among structurally diverse classes of chemicals that may cause CHD by different mechanisms. We will evaluate the relevance of CHD-associated variants by testing whether they are associated with variable fitness between polluted and clean environments, focus inference of candidate genes using eQTL mapping, and test hypothesized associations using genome editing by CRISPR-Cas9 technology. This research in a population-based vertebrate model will reveal mechanisms underlying gene- environment interactions involved in determining susceptibility to CHD, a common congenital condition.

项目概要/摘要 我们建议利用大西洋鳉鱼模型系统的独特特征来阐明 先天性心脏病（CHD）病因中的遗传变异和环境暴露。这 复杂的人类疾病包含一系列结构和功能缺陷，是最常见的疾病 全世界人类先天畸形。 CHD 的病因尚不清楚，但似乎 涉及遗传和环境风险因素，包括接触环境化学品。这 大西洋鳉鱼（Fundulusheteroclitus）是一种新型的基于群体的模型系统，拥有大量的 遗传多样性，并表现出化学诱发的心血管疾病状态，模仿大量 人类冠心病的各个方面。鳉鱼生活在被以下混合物污染的城市化环境中 化学物质包括多氯联苯 (PCB) 和多环芳烃 (PAH)。城市的 和非城市人群对因接触这些物质而引起的冠心病的敏感性存在很大差异 化合物。我们建议使用这个独特而强大的系统来探索基因与环境的相互作用 与 CHD 相关，扩展了我们在这方面成功使用的数量性状位点 (QTL) 方法 物种。该模型的一个特别引人注目的特征是自然选择增加了频率 影响对这些（以及可能的其他）重要类别的敏感性的其他罕见变异 污染物。我们之前的数据揭示了基因组中影响污染环境适应性的一些区域 环境，并导致对 CHD 敏感性的变化。 拟议研究的总体目标是确定携带遗传性的基因和途径 控制对 PCB 和 PAH 诱发的 CHD 敏感性的变异。我们将测试遗传关联 通过对使用 QTL 策略培育的重复家系中的表型动物进行全基因组基因分型， 暴露于 PCB 和 PAH。实验将测试与多种特定结构和基因的遗传关联 定义一系列先心病表型的功能缺陷。该 QTL 作图将包括 1) 多个 遗传背景，2) 多种与 CHD 相关的化学物质，每种化学物质都有不同的假设机制 行动，以及 3) 多重暴露水平。我们将测试不同的 CHD 特征是否相关 不同遗传背景中具有独特或共享的变异，以及是否与疾病相关的变异 结构不同类别的化学物质是独特的或共有的，这些化学物质可能通过不同的方式引起冠心病 机制。我们将通过测试 CHD 相关变异是否存在来评估它们的相关性 与污染环境和清洁环境之间的可变适应度相关，候选的焦点推理 使用 eQTL 作图分析基因，并使用 CRISPR-Cas9 进行基因组编辑来测试假设的关联 技术。这项基于群体的脊椎动物模型的研究将揭示基因的潜在机制 环境相互作用决定了对一种常见先天性疾病先天性疾病的易感性。