Nathan R Tucker1, Elena V Dolmatova1, Honghuang Lin1, Rebecca R Cooper1, Jiangchuan Ye1, William J Hucker1, Heather S Jameson1, Victoria A Parsons1, Lu-Chen Weng1, Robert W Mills1, Moritz F Sinner1, Maxim Imakaev1, Jordan Leyton-Mange1, Gus Vlahakes1, Emelia J Benjamin1, Kathryn L Lunetta1, Steven A Lubitz1, Leonid Mirny1, David J Milan1, Patrick T Ellinor2. 1. From the Cardiovascular Research Center (N.R.T., E.V.D., R.R.C., J.Y., W.J.H., H.S.J., V.A.P., L.-C.W., R.W.M., J.L.-M., S.A.L., D.J.M., P.T.E.) and Department of Surgery (G.V.), Massachusetts General Hospital, Boston; National Heart, Lung and Blood Institute's and Boston University's Framingham Heart, MA (H.L., E.J.B., K.L.L.); Computational Biomedicine Section (H.L.), Cardiology Section (E.J.B.), and Preventive Medicine Section (E.J.B.), Department of Medicine, Boston University School of Medicine, MA; Department of Medicine I, University Hospital Munich, Campus Grosshadern, Ludwig-Maximilians-University, Germany (M.F.S.); Institute for Medical Engineering and Sciences, Massachusetts Institute of Technology, Cambridge (M.I., L.M.); Department of Epidemiology (E.J.B.) and Department of Biostatistics (K.L.L.), Boston University School of Public Health, MA; and Program in Medical and Populations Genetics, Broad Institute, Cambridge, MA (S.A.L., D.J.M., P.T.E.). 2. From the Cardiovascular Research Center (N.R.T., E.V.D., R.R.C., J.Y., W.J.H., H.S.J., V.A.P., L.-C.W., R.W.M., J.L.-M., S.A.L., D.J.M., P.T.E.) and Department of Surgery (G.V.), Massachusetts General Hospital, Boston; National Heart, Lung and Blood Institute's and Boston University's Framingham Heart, MA (H.L., E.J.B., K.L.L.); Computational Biomedicine Section (H.L.), Cardiology Section (E.J.B.), and Preventive Medicine Section (E.J.B.), Department of Medicine, Boston University School of Medicine, MA; Department of Medicine I, University Hospital Munich, Campus Grosshadern, Ludwig-Maximilians-University, Germany (M.F.S.); Institute for Medical Engineering and Sciences, Massachusetts Institute of Technology, Cambridge (M.I., L.M.); Department of Epidemiology (E.J.B.) and Department of Biostatistics (K.L.L.), Boston University School of Public Health, MA; and Program in Medical and Populations Genetics, Broad Institute, Cambridge, MA (S.A.L., D.J.M., P.T.E.). ellinor@mgh.harvard.edu.
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.
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.
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