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.

项目摘要/摘要 我们建议利用大西洋Killifish模型系统的独特特征，以阐明 先天性心脏病（CHD）病因学中的遗传变异和环境暴露。这 复杂的人类疾病包括一套结构和功能性缺陷，是最常见的 全球人类先天性畸形。冠心病的病因鲜为人知，但似乎 涉及遗传和环境风险因素，包括暴露于环境化学物质。这 Atlantic Killifish（tundulus heteroclitus）是一种基于人群的新型模型系统，可容纳大量 遗传多样性并表现出化学诱导的心血管疾病，表明模仿实质性 人类冠心病的各个方面。杀人居住在城市化环境中，这些环境被污染 包括多氯联苯（PCB）和多环芳烃（PAHS）在内的化学物质。城市的 非城市的人口在暴露于这些冠心病引起的冠心病的敏感性上有很大不同 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的相互作用 与CHD相关，扩大了我们成功使用定量特质基因座（QTL）方法 物种。该模型的一个特别令人信服的特征是自然选择增加了频率 其他稀有变体，这些变体会影响对这些（以及可能其他）重要类别的敏感性 污染物。我们以前的数据揭示了影响污染适应性的基因组的一些区域 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的基因和途径 控制对PCB和PAH诱导的CHD敏感性的变异。我们将测试遗传关联 通过使用QTL策略繁殖的复制家族中表型动物的全基因组基因分型 暴露于PCB和PAHS。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。此QTL映射将包括1）多个 遗传背景，2）多种CHD相关化学物质，每种都有不同的假设机制 动作和3）多个暴露水平。我们将测试是否关联了不同的CHD功能 在不同的遗传背景中具有独特或共享的变体，以及与疾病相关的变体 在结构多样的化学物质中是独特的或共享的，这些化学物质可能会导致不同的CHD 机制。我们将通过测试是否是 与污染环境和清洁环境之间的适应性变化相关，候选人的重点 使用EQTL映射的基因，并使用CRISPR-CAS9进行基因组编辑测试假设的关联 技术。这项在基于人群的脊椎动物模型中的研究将揭示基因基因的机制 确定对冠心病的易感性涉及的环境相互作用，这是一种常见的先天性疾病。