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: 10216463
• 负责人: Mark E Hahn
• 金额: $ 64.43万
• 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/10216463
• 关键词: Affect; Animals; Aromatic Hydrocarbons; Aromatic Polycyclic Hydrocarbons; Biological Models; 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 Risk; Genetic Variation; Genome; Genome Scan; Genomics; Genotype; Heritability; Human; Individual Differences; Killifishes; 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; Structure; System; Testing; Variant; Vertebrates; Zebrafish; adverse outcome; base; congenital heart disorder; disease phenotype; environmental chemical; experimental study; fitness; fluoranthene; gene environment interaction; genetic approach; genetic association; genetic testing; genetic variant; genome editing; genome-wide; genomic data; human disease; in vivo; insight; malformation; novel; phenanthrene; pollutant; population based; rare variant; response; transcriptomics; urban setting

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.

项目总结/摘要 我们建议利用大西洋鳉鱼模型系统的独特功能来阐明 先天性心脏病（CHD）病因中的遗传变异和环境暴露。这 复杂的人类疾病包括一系列结构和功能缺陷， 人类先天性畸形冠心病的病因尚不清楚，但似乎 涉及遗传和环境风险因素，包括接触环境化学品。的 大西洋鳉（Fundulus heteroclitus）是一种新的基于种群的模式系统， 遗传多样性，并表现出化学诱导的心血管疾病状态， 人类CHD的各个方面。刀鱼栖息在城市化的环境中， 化学品包括多氯联苯（PCB）和多环芳烃（PAH）。城市 和非城市人口在他们对冠心病的敏感性方面存在很大差异， 化合物.我们建议使用这个独特而强大的系统来探索基因-环境相互作用 与CHD相关，扩展了我们成功使用的数量性状基因座（QTL）方法， 物种这个模型的一个特别引人注目的特征是，自然选择增加了 其他罕见的变异，影响敏感性，这些（和潜在的其他）重要类别的 污染物我们以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，并有助于对CHD的敏感性的变化。 拟议研究的总体目标是确定基因和途径， 控制对PCB和PAH诱导的CHD敏感性的变异。我们将测试基因关联 通过在使用QTL策略繁殖的复制家族中对表型动物进行全基因组基因分型， 暴露于PCB和PAH。实验将测试与多个特定结构和 定义CHD表型套件的功能缺陷。该QTL作图将包括1）多个 遗传背景，2）多种CHD相关化学物质，每种化学物质具有不同的假设机制 3）多个暴露水平。我们将测试不同的CHD特征是否相关 在不同的遗传背景中具有独特或共有的变异，以及是否与疾病相关的变异 是独特的或共享的结构不同类别的化学品，可能会导致冠心病的不同 机制等我们将通过检测CHD相关变异体是否 与污染和清洁环境之间的可变适应度相关，候选人的焦点推断 使用eQTL作图的基因，并使用CRISPR-Cas9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- 环境相互作用参与决定CHD的易感性，CHD是一种常见的先天性疾病。