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Cardiovascular Genetics and Metabolics: Exploring Underlying Mechanisms for Personalizing Treatment Strategies in Atrial Fibrillation

thesis
posted on 10.03.2022, 16:29 by Brandon Chalazan
Background: Over the last two decades, genome wide association studies (GWAS) have identified over 100 atrial fibrillation (AF) susceptible loci and family based studies have uncovered multiple mutations in cardiac ion channels, structural proteins, transcription factors and signalling molecules. Although genetic approaches for AF have provided important insights into the underlying pathophysiology, the pathophysiological mechanisms and response to therapy are poorly understood especially in diverse populations.

Objective: To better understand the underlying genetic, molecular and electrophysiological mechanisms for AF.

Methods: We recruited several hundred multi-ethnic patients with familial and early-onset AF into a clinical and genetic biorepository. Targeted genotyping of AF risk single nucleotide polymorphisms (SNP) and sequencing candidate genes was performed. We also performed comprehensive molecular, transcriptomic and electrophysiologic analyses of retinoic acid (RA) guided human induced pluripotent stem cell (hiPSC) atrial cardiomyocytes (CM). We further characterized the electrophysiological phenotype of gain-of-function (GOF) AF-linked SCN5A mutations, elucidated the underlying cellular mechanisms and assessed mechanism-based therapies using patient-specific atrial hiPSC-CMs.

Results: We showed that probands of African and Hispanic descent with early-onset AF were more likely to have a first-degree relative with AF, supporting a genetic predisposition across diverse populations. Our studies also identified a common SNP at the chromosome (chr) 4q25 locus to be strongly associated with AF. Sequencing candidate genes for AF identified a small proportion of early-onset AF probands who contained a disease-causing mutation with the majority located in the gene (TTN) that encodes for Titin. We also further demonstrate in our studies a mechanism by which RA generates an atrial electrophysiological signature through the downstream regulation of calcium channel gene expression by COUP-TFII. Using patient-specific atrial hiPSC-CMs, we established a mechanistic link between triggered AF and enhanced late sodium current from an AF-causing SCN5A GOF mutation.

Conclusion: A substantial proportion of AF cannot be explained by traditional AF risk factors and strongly implicates an interaction between the environment and genetics. Collectively, our results support genetic testing in patients with well-defined familial AF and early-onset AF. It also supports using atrial hiPSC-CMs to model AF-causing mutations with the goal of identifying the underlying cellular mechanisms and uncovering new mechanism-based therapy to enable a personalized treatment approach in AF.

Funding

AHA 17MCPRP33420153

History

First Supervisor

Prof. Aidan Bradford

Second Supervisor

Prof. Dawood Darbar

Comments

Submitted for the Award of Doctor of Philosophy to the Royal College of Surgeons in Ireland, 2020

Published Citation

Chalazan B,. Cardiovascular Genetics and Metabolics: Exploring Underlying Mechanisms for Personalizing Treatment Strategies in Atrial Fibrillation [PHD Thesis] Dublin: Royal College of Surgeons in Ireland; 2020

Degree Name

Doctor of Philosophy (PhD)

Date of award

30/11/2020

Programme

  • Doctor of Philosophy (PhD)