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

被引:34
|
作者
Tucker, Nathan R. [1 ]
Dolmatova, Elena V. [1 ]
Lin, Honghuang [3 ,4 ,5 ]
Cooper, Rebecca R. [1 ]
Ye, Jiangchuan [1 ]
Hucker, William J. [1 ]
Jameson, Heather S. [1 ]
Parsons, Victoria A. [1 ]
Weng, Lu-Chen [1 ]
Mills, Robert W. [1 ]
Sinner, Moritz F. [8 ]
Imakaev, Maxim [9 ]
Leyton-Mange, Jordan [1 ]
Vlahakes, Gus [2 ]
Benjamin, Emelia J. [3 ,4 ,6 ,7 ,10 ]
Lunetta, Kathryn L. [3 ,4 ,11 ]
Lubitz, Steven A. [1 ,12 ]
Mirny, Leonid [9 ]
Milan, David J. [1 ,12 ]
Ellinor, Patrick T. [1 ,12 ]
机构
[1] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02129 USA
[2] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02129 USA
[3] NHLBI, Boston, MA USA
[4] Boston Univ Framingham Heart, Boston, MA USA
[5] Boston Univ, Sch Med, Dept Med, Computat Biomed Sect, Boston, MA 02215 USA
[6] Boston Univ, Sch Med, Dept Med, Cardiol Sect, Boston, MA 02215 USA
[7] Boston Univ, Sch Med, Dept Med, Prevent Med Sect, Boston, MA 02215 USA
[8] Ludwig Maximilians Univ Munchen, Univ Hosp Munich, Dept Med 1, Campus Grosshadern, Munich, Germany
[9] MIT, Inst Med Engn & Sci, Cambridge, MA 02139 USA
[10] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02215 USA
[11] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02215 USA
[12] Broad Inst, Program Med & Populat Genet, Cambridge, MA USA
关键词
atrial fibrillation; genetics; genome-wide association study; genomics; pulmonary veins; NONCODING VARIANT; GENES; PATTERNS; LOCI; EPIDEMIOLOGY; INITIATION; HEART; ZFHX3; PRX1;
D O I
10.1161/CIRCGENETICS.117.001902
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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 approximate to 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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页数:79
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