# Atrial Fibrillation Post-GWAS: Mechanisms to Treatment

> **NIH NIH P01** · CLEVELAND CLINIC LERNER COM-CWRU · 2022 · $2,841,649

## Abstract

OVERALL COMPONENT
PROJECT/SUMMARY ABSTRACT
Atrial fibrillation (AF), the most common cardiac arrhythmia, afflicts the U.S. and world with increasing
prevalence. AF incidence, progression to persistent AF, and AF complications, including stroke, are fed by
increasing obesity and age. Current therapies are limited by risks and limited efficacy, worse as AF
progresses, but no new pharmacologic agents have been approved for AF in >10 years. With identification of
>100 genetic loci that predispose to AF risk in genome-wide association studies (GWAS), the hope has been
that genetics would yield novel therapeutic targets. However, even for the top locus on chr. 4q25 near PITX2, a
gene involved in formation of pulmonary veins, the target of AF ablation, mechanisms linking variants to AF
remain elusive. Genetic findings have so far failed to yield clinically actionable results. To fill these gaps, we
seek to go beyond GWAS findings to identify direct genomic mechanisms underlying AF and better understand
their interactions with environment, comorbidities or cell stressors. Our long-term goal is to use genomic
findings to personalize preventive and therapeutic strategies for AF. Our overall P01 theme is to translate AF
genetic discoveries towards the bedside, focusing on genes to mechanisms, genes to drugs, and interactions
of genes with metabolism and environment. We build on strong preliminary data and coalesce unique human
atrial tissue biorepository and genomic data resources, novel cell and animal models, and complementary
expertise from our multidisciplinary team with a strong collaboration history. Our Central Hypothesis is that
genomic mechanistic discoveries in AF cellular and animal models will translate to human therapies. Our
thematic aims include: 1) Identify causal genes and functional mechanisms with a goal towards identification of
new therapeutic approaches for AF; 2) Investigate metabolic and inflammatory mechanisms, implicated by
genomics studies to be important in AF pathophysiology, to identify new therapeutic targets for AF prevention
and treatment; and 3) Identify candidate novel drugs for AF and develop a pipeline for in vitro and in vivo
functional testing of candidate therapies. Project 1 Genes to Function will determine causal genes, variants
and mechanisms underlying two AF GWAS loci. Project 2 Genes and Metabolism will study the contribution of
mitochondrial dysfunction to AF onset and progression. Early Stage Investigator Project Genes and Nutrition
builds on novel associations of AF with trimethylamine N-oxide (TMAO), produced by gut microbiota from
precursors such as choline found in eggs, meats and cheeses. Project 4 Genes to Omics-Informed Drugs will
identify mechanisms and repurposable drugs to prevent AF progression. Projects are supported by 4 Cores
providing administration, engineered heart tissue and atrial phenotyping, electrophysiology, and network and
systems biology analytics support that synergize discovery and t...

## Key facts

- **NIH application ID:** 10410643
- **Project number:** 1P01HL158502-01A1
- **Recipient organization:** CLEVELAND CLINIC LERNER COM-CWRU
- **Principal Investigator:** Mina Kay Chung
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $2,841,649
- **Award type:** 1
- **Project period:** 2022-07-01 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10410643

## Citation

> US National Institutes of Health, RePORTER application 10410643, Atrial Fibrillation Post-GWAS: Mechanisms to Treatment (1P01HL158502-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10410643. Licensed CC0.

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