Atrial fibrillation (AF) is an important and increasing public health problem. Most cases occur in the elderly and so the incidence of the problem is rising; the number of Americans affected with AF is expected to surge to ~16 million by 2050. Other clinical features include hypertension and underlying heart disease while many relatively young patients have no apparent risk factors and are designated as ?lone? or early-onset AF (EOAF). The AF epidemic is further complicated by the lack of effective therapies. The limited success of treatments stems in part from an incomplete understanding of the pathophysiology of AF and failure to target therapy to the underlying mechanisms. Traditionally, AF was considered to be a sporadic, non-genetic disorder but we and others have shown that EOAF has a substantial genetic basis. Positional cloning and candidate gene approaches have linked mutations in cardiac ion channels, and signaling molecules with EOAF. While these studies have provided important insights into underlying mechanisms, most of the rare variation in susceptibility to EOAF remains unknown. Given recent advances in next generation sequencing (NGS), discovery of novel genes in other cardiovascular phenotypes and our preliminary data, the overarching goal of this proposal is to use NGS to identify novel AF genes and decipher the underlying genetic mechanisms of EOAF. Our clinical-DNA registries have systematically enrolled over 60 families from diverse ethnic background with early-onset familial AF. We propose to use this large and well-characterized cohort to address two specific aims:
Aim 1 will conduct a multi-tiered stepwise approach to identify rare genetic variants linked with EOAF. First whole exome sequencing (WES) will be performed in our existing 60 EOAF families, who do not harbor candidate gene variants, to identify rare variants predicated on rarity, ethnicity, co-segregation with AF, predicted pathogenicity and bioinformatics filtering. Second, the most promising variants will replicated in AFGen Consortium TOPMed Cohort in which over 3,500 probands with EOAF and 3,500 controls have undergone whole genome sequencing (WGS).
This aim builds on our published study in which we identified five novel candidate AF genes using a WES approach and the recent successful completion of WGS in EOAF probands in the TOPMed Cohort.
Aim 2 will determine the underlying genetic mechanisms of EOAF by functionally characterizing high priority rare variants using in vitro electrophysiology and in vivo functional assays in zebrafish to enable disease-association.
This aim builds upon our prior work where we have functionally characterized a rare AF-linked variant in the Ca channel gene identified by WES and identified rare developmental genes that modulate cardiac conduction in zebrafish. These studies will not only identify novel AF genes and provide insights into underlying genetic mechanisms of EOAF but will also uncover novel therapeutic approaches for AF. They also represent the first step in the development of sub-type specific mechanism-based therapies for this common and morbid condition.

Public Health Relevance

Atrial fibrillation, the most common sustained cardiac arrhythmia worldwide, affects approximately 2% of the US population and increases the risk of stroke, heart failure, myocardial infarction, dementia and death. Therapies for AF are sub-optimal in part because our poor understanding of the underlying mechanisms of the disorder. Here, we propose to study the early-onset form of the disease in order to not only identify novel genes and mechanisms but will also uncover new treatments for AF.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL138737-03
Application #
9735434
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Shi, Yang
Project Start
2017-09-01
Project End
2021-07-31
Budget Start
2019-08-01
Budget End
2020-07-31
Support Year
3
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Illinois at Chicago
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
098987217
City
Chicago
State
IL
Country
United States
Zip Code
60612
Choi, Seung Hoan; Weng, Lu-Chen; Roselli, Carolina et al. (2018) Association Between Titin Loss-of-Function Variants and Early-Onset Atrial Fibrillation. JAMA 320:2354-2364
Thorolfsdottir, Rosa B; Sveinbjornsson, Gardar; Sulem, Patrick et al. (2018) Coding variants in RPL3L and MYZAP increase risk of atrial fibrillation. Commun Biol 1:68
McCauley, Mark D; Darbar, Dawood (2018) Race and Socioeconomic Status Regulate Lifetime Risk of Atrial Fibrillation. Circ Arrhythm Electrophysiol 11:e006584
Argenziano, Mariana; Lambers, Erin; Hong, Liang et al. (2018) Electrophysiologic Characterization of Calcium Handling in Human Induced Pluripotent Stem Cell-Derived Atrial Cardiomyocytes. Stem Cell Reports 10:1867-1878
Chalazan, Brandon; Dickerman, Deanna; Sridhar, Arvind et al. (2018) Relation of Body Mass Index to Symptom Burden in Patients withAtrial Fibrillation. Am J Cardiol 122:235-241
Darbar, Dawood; McCauley, Mark (2017) The Pharmacogenomics of a Mutation 'Hotspot' for the Short QT Syndrome. JACC Clin Electrophysiol 3:744-746
Patel, Neel J; Wells, Quinn S; Huang, Shi et al. (2017) Relation of Obstructive Sleep Apnea and a Common Variant at Chromosome 4q25 to Atrial Fibrillation. Am J Cardiol 119:1387-1391
Christophersen, Ingrid E; Rienstra, Michiel; Roselli, Carolina et al. (2017) Large-scale analyses of common and rare variants identify 12 new loci associated with atrial fibrillation. Nat Genet 49:946-952
Thorolfsdottir, Rosa B; Sveinbjornsson, Gardar; Sulem, Patrick et al. (2017) A Missense Variant in PLEC Increases RiskĀ of Atrial Fibrillation. J Am Coll Cardiol 70:2157-2168
Huang, Henry; Darbar, Dawood (2017) Genetic heterogeneity of atrial fibrillation susceptibility loci across racial or ethnic groups. Eur Heart J 38:2595-2598

Showing the most recent 10 out of 12 publications