Atrial fibrillation (AF) increases risk of heart failure, stroke and death, and AF has been found to have a significant heritable component. Genome wide association studies (GWAS) have identified numerous single nucleotide polymorphisms (SNPs) associated with increased risk of AF. However, the causative variants, relevant genes and mechanisms by which they promote AF remain unclear. To enhance our understanding of the causative genes involved in heritable AF, we propose to evaluate the impact of SNPs identified in recent GWAS on the expression of messenger RNA, miRNA and related proteins in the target tissue of interest, human left atria, taken from a unique biorepository of over 1000 human atrial tissues from cardiac surgery patients.
Specific aims are: 1) To determine how AF phenotypes alter the human atrial transcriptome, and 2) To identify and test candidate functional genetic variants that alter atrial transcript expression.
Aim 1 studies will use state-of-the-art technology (RNA-seq, miRNA-seq) and bioinformatics to determine AF phenotype associations with gene transcripts, including lowly expressed transcripts and mRNA isoforms, and miRNAs, and co-regulated gene modules. We will test the functional effects of regulating selected genes using siRNA knockdown and cDNA transfection strategies in an atrial myocyte cell line, human ESC-derived atrial cells and in human atrial fibroblasts to determine whether altered expression of these genes affects downstream gene expression and selected biological pathways.
Aim 2 studies will identify genetic variants associated with atrial gene expression by expression quantitative trait locus (eQTL), and allelic expression imbalance analyses. Candidate variants will be validated in reporter gene transfection studies. The proposed interdisciplinary studies are a logical and important follow up to recent GWAS that will provide novel, unbiased mechanistic insights into the impact of SNPs highly associated with AF on atrial RNA expression patterns. We expect our studies to identify functional links between AF-associated genetic loci and gene expression, and to identify SNPs, genes, and pathways that are causally related to the etiology and progression of AF and that may represent new targets for AF treatment and prevention.
Atrial fibrillation (AF), associated with aging, obesity, risk for stroke, heart failure and death, afflicts millions of Americans with an incidence that is projected to triple over the next several decades. AF susceptibility is heritable, but despite successful identification of genetic variants associated with AF, the links between these findings and how they cause AF remain unclear. The proposed studies aim to make these functional connections, which will facilitate identification of new targets for AF treatment and prevention.
|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|
|Hsu, Jeffrey; Gore-Panter, Shamone; Tchou, Gregory et al. (2018) Genetic Control of Left Atrial Gene Expression Yields Insights into the Genetic Susceptibility for Atrial Fibrillation. Circ Genom Precis Med 11:e002107|
|Christophersen, Ingrid E; Magnani, Jared W; Yin, Xiaoyan et al. (2017) Fifteen Genetic Loci Associated With the Electrocardiographic P Wave. Circ Cardiovasc Genet 10:|
|Zakeri, Rosita; Van Wagoner, David R; Calkins, Hugh et al. (2017) The burden of proof: The current state of atrial fibrillation prevention and treatment trials. Heart Rhythm 14:763-782|
|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|
|Gorenek Chair, Bulent; Pelliccia Co-Chair, Antonio; Benjamin, Emelia J et al. (2017) European Heart Rhythm Association (EHRA)/European Association of Cardiovascular Prevention and Rehabilitation (EACPR) position paper on how to prevent atrial fibrillation endorsed by the Heart Rhythm Society (HRS) and Asia Pacific Heart Rhythm Society (AP Eur J Prev Cardiol 24:4-40|
|May, Anna M; Van Wagoner, David R; Mehra, Reena (2017) OSA and Cardiac Arrhythmogenesis: Mechanistic Insights. Chest 151:225-241|
|Gore-Panter, Shamone R; Rennison, Julie H; Van Wagoner, David R (2017) Genetic-Genomic Insights Into the Metabolic Determinants of Spontaneous Atrial Fibrillation. Circ Arrhythm Electrophysiol 10:|
|Cho, Jae Hyung; Youn, So Jin; Moore, JoEllyn C et al. (2017) Safety of Oral Dofetilide Reloading for Treatment of Atrial Arrhythmias. Circ Arrhythm Electrophysiol 10:|
|Calkins, Hugh; Hindricks, Gerhard; Cappato, Riccardo et al. (2017) 2017 HRS/EHRA/ECAS/APHRS/SOLAECE expert consensus statement on catheter and surgical ablation of atrial fibrillation. Heart Rhythm 14:e275-e444|
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