Dataset Information

Diminished PRRX1 Expression Is Associated With Increased Risk of Atrial Fibrillation and Shortening of the Cardiac Action Potential.

ABSTRACT: BACKGROUND:Atrial fibrillation (AF) affects over 33 million individuals worldwide. Genome-wide association studies have identified at least 30 AF loci, but the mechanisms through which individual variants lead to altered disease risk have remained unclear for the majority of these loci. At the 1q24 locus, we hypothesized that the transcription factor PRRX1 could be a strong candidate gene as it is expressed in the pulmonary veins, a source of AF in many individuals. We sought to identify the molecular mechanism, whereby variation at 1q24 may lead to AF susceptibility. METHODS AND RESULTS:We sequenced a ?158 kb region encompassing PRRX1 in 962 individuals with and without AF. We identified a broad region of association with AF at the 1q24 locus. Using in silico prediction and functional validation, we identified an enhancer that interacts with the promoter of PRRX1 in cells of cardiac lineage. Within this enhancer, we identified a single-nucleotide polymorphism, rs577676, which alters enhancer activity in a mouse atrial cell line and in embryonic zebrafish and differentially regulates PRRX1 expression in human left atria. We found that suppression of PRRX1 in human embryonic stem cell-derived cardiomyocytes and embryonic zebrafish resulted in shortening of the atrial action potential duration, a hallmark of AF. CONCLUSIONS:We have identified a functional genetic variant that alters PRRX1 expression, ultimately resulting in electrophysiological alterations in atrial myocytes that may promote AF.

SUBMITTER: Tucker NR

PROVIDER: S-EPMC5679717 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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Publications

Diminished <i>PRRX1</i> Expression Is Associated With Increased Risk of Atrial Fibrillation and Shortening of the Cardiac Action Potential.

Tucker Nathan R NR Dolmatova Elena V EV Lin Honghuang H Cooper Rebecca R RR Ye Jiangchuan J Hucker William J WJ Jameson Heather S HS Parsons Victoria A VA Weng Lu-Chen LC Mills Robert W RW Sinner Moritz F MF Imakaev Maxim M Leyton-Mange Jordan J Vlahakes Gus G Benjamin Emelia J EJ Lunetta Kathryn L KL Lubitz Steven A SA Mirny Leonid L Milan David J DJ Ellinor Patrick T PT

Circulation. Cardiovascular genetics 20171001 5

<h4>Background</h4>Atrial fibrillation (AF) affects over 33 million individuals worldwide. Genome-wide association studies have identified at least 30 AF loci, but the mechanisms through which individual variants lead to altered disease risk have remained unclear for the majority of these loci. At the 1q24 locus, we hypothesized that the transcription factor <i>PRRX1</i> could be a strong candidate gene as it is expressed in the pulmonary veins, a source of AF in many individuals. We sought to i ...[more]

PMID: 28974514

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Project description:AimsHuman atrial electrophysiology exhibits high inter-subject variability in both sinus rhythm (SR) and chronic atrial fibrillation (cAF) patients. Variability is however rarely investigated in experimental and theoretical electrophysiological studies, thus hampering the understanding of its underlying causes but also its implications in explaining differences in the response to disease and treatment. In our study, we aim at investigating the ability of populations of human atrial cell models to capture the inter-subject variability in action potential (AP) recorded in 363 patients both under SR and cAF conditions.Methods and resultsHuman AP recordings in atrial trabeculae (n = 469) from SR and cAF patients were used to calibrate populations of computational SR and cAF atrial AP models. Three populations of over 2000 sampled models were generated, based on three different human atrial AP models. Experimental calibration selected populations of AP models yielding AP with morphology and duration in range with experimental recordings. Populations using the three original models can mimic variability in experimental AP in both SR and cAF, with median conductance values in SR for most ionic currents deviating less than 30% from their original peak values. All cAF populations show similar variations in G(K1), G(Kur) and G(to), consistent with AF-related remodeling as reported in experiments. In all SR and cAF model populations, inter-subject variability in I(K1) and I(NaK) underlies variability in APD90, variability in I(Kur), I(CaL) and I(NaK) modulates variability in APD50 and combined variability in Ito and I(Kur) determines variability in APD20. The large variability in human atrial AP triangulation is mostly determined by I(K1) and either I(NaK) or I(NaCa) depending on the model.ConclusionExperimentally-calibrated human atrial AP models populations mimic AP variability in SR and cAF patient recordings, and identify potential ionic determinants of inter-subject variability in human atrial AP duration and morphology in SR versus cAF.

Dataset Information

Diminished PRRX1 Expression Is Associated With Increased Risk of Atrial Fibrillation and Shortening of the Cardiac Action Potential.

Publications

Diminished <i>PRRX1</i> Expression Is Associated With Increased Risk of Atrial Fibrillation and Shortening of the Cardiac Action Potential.

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