Abstract 18865: Identification of a Functional SNP Regulating PRRX1 at the 1q24 Locus for Atrial Fibrillation

Medientyp: E-Artikel
Titel: Abstract 18865: Identification of a Functional SNP Regulating PRRX1 at the 1q24 Locus for Atrial Fibrillation
Beteiligte: Dolmatova, Elena; Tucker, Nathan R; Lin, Honghuang; Cooper, Rebecca R; Ye, Jiangchuan; Sinner, Moritz F; Imakaev, Maxim; Lubitz, Steven A; Leyton-Mange, Jordan; Vlahakes, Gus; Benjamin, Emelia J; Lunetta, Kathryn L; Mirny, Leonid; Milan, David J; Ellinor, Patrick T
Erschienen: Ovid Technologies (Wolters Kluwer Health), 2014
Erschienen in: Circulation, 130 (2014) suppl_2
Sprache: Englisch
DOI: 10.1161/circ.130.suppl_2.18865
ISSN: 1524-4539; 0009-7322
Schlagwörter: Physiology (medical) ; Cardiology and Cardiovascular Medicine
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Beschreibung: <jats:p> <jats:bold>Introduction:</jats:bold> Genome-wide association studies have identified 9 genomic loci associated with atrial fibrillation (AF). </jats:p> <jats:p> <jats:bold>Hypothesis:</jats:bold> We sought to identify the functional variant at the 1q24 locus for AF, located upstream of the paired related homeobox 1 gene ( <jats:italic>PRRX1</jats:italic> ). </jats:p> <jats:p> <jats:bold>Methods:</jats:bold> We used morpholino-mediated knockdown in zebrafish to assess the role of <jats:italic>PRRX1</jats:italic> in cardiac function and development. To identify potential enhancers at the <jats:italic>PRRX1</jats:italic> locus we analyzed DNase hypersensitivity, histone methylation, and mammalian conservation data from ENCODE. Tissue-specific enhancer activity was evaluated by microinjection of eGFP reporter constructs for each putative enhancer into zebrafish and luciferase assays in a mouse atrial myocyte (HL-1) cell line. To determine physical interaction between the AF-associated enhancer and <jats:italic>PRRX1</jats:italic> promoter we analyzed available Hi-C data and performed chromatin conformation capture (3C). The functional SNP was localized using luciferase assays in HL-1 cells. The effect of the functional SNP on gene expression in human left atrial tissue was measured by qPCR. </jats:p> <jats:p> <jats:bold>Results:</jats:bold> Knockdown of the <jats:italic>PRRX1</jats:italic> ortholog in zebrafish resulted in atrial dilation and shortening of atrial action potential duration (APD <jats:sub>80</jats:sub> : 114.8±2.2ms vs 126±1.5ms in controls, p=0.0004). Of the 4 regions tested at the 1q24 locus, 2 adjacent regions exhibited enhancer activity in the zebrafish myocardium. 3C demonstrated an increased interaction frequency between the enhancer and <jats:italic>PRRX1</jats:italic> promoter regions in cells of cardiac lineage when compared to controls (103±57%, p=0.038). Screening for functional SNPs within these regions revealed that the AF risk allele (C) at SNP rs577676 associated with ~4 fold increased enhancer activity as compared to the non-risk (T) allele in HL-1 cells. Finally, regional eQTL analysis of human atrial tissue showed that rs577676 correlated with <jats:italic>PRRX1</jats:italic> expression. </jats:p> <jats:p> <jats:bold>Conclusions:</jats:bold> We have implicated <jats:italic>PRRX1</jats:italic> in cardiac electrophysiology by demonstrating that knockdown of the gene results in atrial dilation and shortening of atrial action potential duration. Further, we have found that SNP rs577676 modifies an enhancer regulating <jats:italic>PRRX1</jats:italic> expression. </jats:p>
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