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

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA AT DAVIS · 2021 · $644,317

## Abstract

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 int...

## Key facts

- **NIH application ID:** 10216463
- **Project number:** 1R01ES032323-01A1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA AT DAVIS
- **Principal Investigator:** Mark E Hahn
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $644,317
- **Award type:** 1
- **Project period:** 2021-09-10 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10216463

## Citation

> US National Institutes of Health, RePORTER application 10216463, Gene-by-environment interactions that affect exposure-mediated congenital heart disease (1R01ES032323-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10216463. Licensed CC0.

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