Circulation: Cardiovascular Genetics最新文献

{"title":"Surviving Sudden Death: Where Does Next-Generation Sequencing Fit in the Assessment of Sudden Death Victims and Their Families.","authors":"Robert M Hamilton, Kristopher S Cunningham, Elijah R Behr","doi":"10.1161/CIRCGENETICS.117.002015","DOIUrl":"https://doi.org/10.1161/CIRCGENETICS.117.002015","url":null,"abstract":"The investigation of sudden death is one of the few enduring responsibilities of the coronial system that had its origins in 11th century Britain and was formally established by the articles of Eyre in 1194.1 People finding a body from a sudden or unnatural death were required to raise a hue and cry and notify the coroner.\u0000\u0000See Article by Lin et al \u0000\u0000Although the familial nature of sudden death, including structural and electric cardiomyopathies, has been recognized for many decades, British pathologist MJ Davies2 in 1999 may have been the first to suggest that the family might be approached in the evaluation of sudden cardiac death (SCD). In the same year, Ackerman et al3 used molecular diagnosis to identify the cause of SCD in a 19-year-old who died after near-drowning, heralding the era of what would be called the molecular autopsy. (Of note, the decedent’s mother had a definitely prolonged QT interval) Shortly thereafter, clinical genetic testing for inherited arrhythmia conditions became increasingly available.\u0000\u0000Potential approaches to identifying heritable causes of SCD include family assessment, molecular assessment, or a combined approach (see Table).\u0000\u0000View this table:\u0000\u0000Table 1. \u0000Selected studies of clinical and/or genetic assessment of sudden cardiac death or arrest victims and their families\u0000\u0000\u0000\u0000Behr et al4 clinically evaluated 147 first-degree relatives of 32 sudden arrhythmia death syndrome victims with a 22% diagnostic yield for the cause of SCD, whereas more recently, in a larger cohort of victims, …","PeriodicalId":10277,"journal":{"name":"Circulation: Cardiovascular Genetics","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2017-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1161/CIRCGENETICS.117.002015","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35661572","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Analysis of 60 706 Exomes Questions the Role of De Novo Variants Previously Implicated in Cardiac Disease.","authors":"Christian Paludan-Müller,&nbsp;Gustav Ahlberg,&nbsp;Jonas Ghouse,&nbsp;Jesper H Svendsen,&nbsp;Stig Haunsø,&nbsp;Morten S Olesen","doi":"10.1161/CIRCGENETICS.117.001878","DOIUrl":"https://doi.org/10.1161/CIRCGENETICS.117.001878","url":null,"abstract":"<p><strong>Background: </strong>De novo variants in the exome occur at a rate of 1 per individual per generation, and because of the low reproductive fitness for de novo variants causing severe disease, the likelihood of finding these as standing variations in the general population is low. Therefore, this study sought to evaluate the pathogenicity of de novo variants previously associated with cardiac disease based on a large population-representative exome database.</p><p><strong>Methods and results: </strong>We performed a literature search for previous publications on de novo variants associated with severe arrhythmias and structural heart diseases and investigated whether these variants were present in the Exome Aggregation Consortium (ExAC) database (n=60 706). We identified monogenic variants in single case reports and smaller studies (≤200 subjects) and variants considered to increase susceptibility of disease in 3 larger trio studies (>1000 subjects). Of the monogenic variants, 11% (23/211) were present in ExAC, whereas 26% (802/3050) variants believed to increase susceptibility of disease were identified in ExAC. Monogenic de novo variants in ExAC had a total allele count of 109 and with ≈844 expected cases in ExAC, these variants would account for 13% of all cases in the studied diseases if truly monogenetic.</p><p><strong>Conclusions: </strong>We observed numerous de novo variants associated with cardiac disease as standing variation in ExAC, thus these variants are less likely monogenetic causes or major risk contributors for cardiac disease. This highlights the importance of investigating the pathogenicity of de novo variants because they are not as exclusive and pathogenically evident as presumed previously.</p>","PeriodicalId":10277,"journal":{"name":"Circulation: Cardiovascular Genetics","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2017-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1161/CIRCGENETICS.117.001878","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35653274","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Does Computer Simulation Help Facilitate Personalized Precision Medicine for the Use of Warfarin?","authors":"Shinichi Goto,&nbsp;Shinya Goto","doi":"10.1161/CIRCGENETICS.117.001969","DOIUrl":"https://doi.org/10.1161/CIRCGENETICS.117.001969","url":null,"abstract":"In this issue of Circulation: Cardiovascular Genetics , Ravvaz et al1 presented an interesting report on the evaluation of warfarin dosing protocols among patients with atrial fibrillation with various different clinical backgrounds. This article is unique in reporting a new method using a computer simulation–based approach.\u0000\u0000See Article by Ravvaz et al \u0000\u0000To date, anticoagulation effects of warfarin are monitored by prothrombin time international normalized ratio (PT-INR).2 The appropriate warfarin dose to achieve the target PT-INR is affected by various factors, including age, sex, comorbidity, concomitant drug,3 and genetic polymorphisms of specific enzymes related to warfarin metabolism, such as vitamin K epoxide reductase complex and CYP2C9 .4 After clarification of warfarin metabolism, the impact of genetics on the PT-INR control with warfarin was of particular interest. Conflicting results have been published to date on the improvement of PT-INR control using genotype-guided warfarin dosing.5–8 Despite speculated impacts of the 2 enzymes directly related to warfarin metabolism, prediction of appropriate warfarin dose in individual patients using genotype information had less impact than expected. Furthermore, the impact of genotype-guided warfarin dose adjustment strategy on the clinical outcome rather than achieving target PT-INR is difficult to prove because clinical outcomes are influenced by multiple factors including those that could not be monitored by PT-INR control. Randomized clinical trials give us strong scientific evidences but require substantial numbers of real patients who agree to participate into the trials. Constructive …","PeriodicalId":10277,"journal":{"name":"Circulation: Cardiovascular Genetics","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2017-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1161/CIRCGENETICS.117.001969","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35653276","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Metabolic Profiling of Adiponectin Levels in Adults: Mendelian Randomization Analysis.","authors":"Maria Carolina Borges, Aluísio J D Barros, Diana L Santos Ferreira, Juan Pablo Casas, Bernardo Lessa Horta, Mika Kivimaki, Meena Kumari, Usha Menon, Tom R Gaunt, Yoav Ben-Shlomo, Deise F Freitas, Isabel O Oliveira, Aleksandra Gentry-Maharaj, Evangelia Fourkala, Debbie A Lawlor, Aroon D Hingorani","doi":"10.1161/CIRCGENETICS.117.001837","DOIUrl":"10.1161/CIRCGENETICS.117.001837","url":null,"abstract":"<p><strong>Background: </strong>Adiponectin, a circulating adipocyte-derived protein, has insulin-sensitizing, anti-inflammatory, antiatherogenic, and cardiomyocyte-protective properties in animal models. However, the systemic effects of adiponectin in humans are unknown. Our aims were to define the metabolic profile associated with higher blood adiponectin concentration and investigate whether variation in adiponectin concentration affects the systemic metabolic profile.</p><p><strong>Methods and results: </strong>We applied multivariable regression in ≤5909 adults and Mendelian randomization (using <i>cis</i>-acting genetic variants in the vicinity of the adiponectin gene as instrumental variables) for analyzing the causal effect of adiponectin in the metabolic profile of ≤37 545 adults. Participants were largely European from 6 longitudinal studies and 1 genome-wide association consortium. In the multivariable regression analyses, higher circulating adiponectin was associated with higher high-density lipoprotein lipids and lower very-low-density lipoprotein lipids, glucose levels, branched-chain amino acids, and inflammatory markers. However, these findings were not supported by Mendelian randomization analyses for most metabolites. Findings were consistent between sexes and after excluding high-risk groups (defined by age and occurrence of previous cardiovascular event) and 1 study with admixed population.</p><p><strong>Conclusions: </strong>Our findings indicate that blood adiponectin concentration is more likely to be an epiphenomenon in the context of metabolic disease than a key determinant.</p>","PeriodicalId":10277,"journal":{"name":"Circulation: Cardiovascular Genetics","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2017-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5736126/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35653867","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genetic Variants Contributing to Circulating Matrix Metalloproteinase 8 Levels and Their Association With Cardiovascular Diseases: A Genome-Wide Analysis.","authors":"Aino Salminen,&nbsp;Efthymia Vlachopoulou,&nbsp;Aki S Havulinna,&nbsp;Taina Tervahartiala,&nbsp;Wolfgang Sattler,&nbsp;Marja-Liisa Lokki,&nbsp;Markku S Nieminen,&nbsp;Markus Perola,&nbsp;Veikko Salomaa,&nbsp;Juha Sinisalo,&nbsp;Seppo Meri,&nbsp;Timo Sorsa,&nbsp;Pirkko J Pussinen","doi":"10.1161/CIRCGENETICS.117.001731","DOIUrl":"https://doi.org/10.1161/CIRCGENETICS.117.001731","url":null,"abstract":"<p><strong>Background: </strong>Matrix metalloproteinase 8 (MMP-8) is a proinflammatory enzyme expressed mainly by neutrophils. Elevated serum and plasma concentrations of MMP-8 are associated with the risk for and outcome of cardiovascular diseases (CVDs). The origin of circulating MMP-8 is not completely clear.</p><p><strong>Methods and results: </strong>We performed a genome-wide association study of serum MMP-8 levels in 2 populations comprising altogether 6049 individuals. Moreover, we studied whether MMP-8-associated variants are linked to increased risk of CVDs and overall mortality in >20 000 subjects. The strongest association with serum MMP-8 was found in locus 1q31.3, containing the gene for complement factor H (lead single nucleotide polymorphism: rs800292; <i>P</i>=2.4×10^-35). In functional experiments, activation of the alternative pathway of complement in the carriers of rs800292 minor allele (Ile62 in factor H) led to decreased release of MMP-8 from neutrophils compared with the major allele (Val62 in factor H). Another association was detected in 1q21.3, containing genes <i>S100A8</i>, <i>S100A9</i>, and <i>S100A12</i> (strongest association: rs1560833; <i>P</i>=5.3×10^-15). The minor allele of rs1560833 was inversely associated with CVD (odds ratio [95% confidence interval]: 0.90 [0.82-0.99]; <i>P</i>=0.032) and the time to incident CVD event (hazard ratio [95% confidence interval]: 0.91 [0.84-0.99]; <i>P</i>=0.032) in men but not in women.</p><p><strong>Conclusions: </strong>According to our results, the activation of the alternative pathway of the complement system strongly contributes to serum MMP-8 concentration. Genetic polymorphism in <i>S100A9-S100A12-S100A8</i> locus affects serum and plasma MMP-8 and shows a suggestive association with the risk of CVDs. Our results show that genetic variation determines a significant portion of circulating MMP-8 concentrations.</p>","PeriodicalId":10277,"journal":{"name":"Circulation: Cardiovascular Genetics","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2017-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1161/CIRCGENETICS.117.001731","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35318158","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Is Left Ventricular Noncompaction a Trait, Phenotype, or Disease? The Evidence Points to Phenotype.","authors":"Ray E Hershberger,&nbsp;Ana Morales,&nbsp;Jason Cowan","doi":"10.1161/CIRCGENETICS.117.001968","DOIUrl":"https://doi.org/10.1161/CIRCGENETICS.117.001968","url":null,"abstract":"The question is is left ventricular noncompaction (LVNC) a trait, phenotype, or disease? By trait, we refer to a discrete and measurable characteristic like eye color. The term phenotype expands this definition to include multiple observable traits derived from diverse genetic factors (genotype) and to recognize additional roles for the environment in shaping visible expression of a genetically defined trait. Pathological phenotypes, with their myriad signs, symptoms, diagnoses, and prognoses, are recognized as diseases and are most often associated with adverse clinical manifestations or need for medical or surgical intervention.\u0000\u0000See Article by Miller et al \u0000\u0000So where in this conceptual framework do we place LVNC? This is a well-debated topic1,2 and one that has been recently systematically and expertly reviewed in much greater depth than afforded by this editorial.1–4 Although LVNC has increasingly been recognized as a cardiomyopathy5—itself a term with clear disease connotations—mounting evidence now points to reclassification of LVNC as a distinct but not necessarily pathological phenotype. More specifically, the degree of compacted to noncompacted (NC) myocardium, by itself alone, does not seem to cause disease.\u0000\u0000Why phenotype rather than trait? Traits are considered to be genetically driven and not malleable by the environment. As defined above, genetics interacting with environment are best labeled as phenotype. Left ventricular (LV) morphology is not fixed for certain characteristics, including LV wall thickness or LV size. The former is well known to increase with severe hypertension or aortic stenosis, and the latter increases with volume overload from aortic insufficiency. With medical or surgical therapy, both conditions will regress. A similar paradigm has been observed with dilated cardiomyopathy—a disease phenotype associated with heart failure and arrhythmia for which the dilated or remodeled left ventricle will reverse remodel with appropriate medical therapy. Characteristics such …","PeriodicalId":10277,"journal":{"name":"Circulation: Cardiovascular Genetics","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2017-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1161/CIRCGENETICS.117.001968","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35318162","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction.","authors":"","doi":"10.1161/HCG.0000000000000042","DOIUrl":"https://doi.org/10.1161/HCG.0000000000000042","url":null,"abstract":"","PeriodicalId":10277,"journal":{"name":"Circulation: Cardiovascular Genetics","volume":" ","pages":"e000042"},"PeriodicalIF":0.0,"publicationDate":"2017-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1161/HCG.0000000000000042","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36849923","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Transcriptome and Functional Profile of Cardiac Myocytes Is Influenced by Biological Sex.","authors":"Christa L Trexler,&nbsp;Aaron T Odell,&nbsp;Mark Y Jeong,&nbsp;Robin D Dowell,&nbsp;Leslie A Leinwand","doi":"10.1161/CIRCGENETICS.117.001770","DOIUrl":"https://doi.org/10.1161/CIRCGENETICS.117.001770","url":null,"abstract":"<p><strong>Background: </strong>Although cardiovascular disease is the primary killer of women in the United States, women and female animals have traditionally been omitted from research studies. In reports that do include both sexes, significant sexual dimorphisms have been demonstrated in development, presentation, and outcome of cardiovascular disease. However, there is little understanding of the mechanisms underlying these observations. A more thorough understanding of sex-specific cardiovascular differences both at baseline and in disease is required to effectively consider and treat all patients with cardiovascular disease.</p><p><strong>Methods and results: </strong>We analyzed contractility in the whole rat heart, adult rat ventricular myocytes (ARVMs), and myofibrils from both sexes of rats and observed functional sex differences at all levels. Hearts and ARVMs from female rats displayed greater fractional shortening than males, and female ARVMs and myofibrils took longer to relax. To define factors underlying these functional differences, we performed an RNA sequencing experiment on ARVMs from male and female rats and identified ≈600 genes were expressed in a sexually dimorphic manner. Further analysis revealed sex-specific enrichment of signaling pathways and key regulators. At the protein level, female ARVMs exhibited higher protein kinase A activity, consistent with pathway enrichment identified through RNA sequencing. In addition, activating the protein kinase A pathway diminished the contractile sexual dimorphisms previously observed.</p><p><strong>Conclusions: </strong>These data support the notion that sex-specific gene expression differences at baseline influence cardiac function, particularly through the protein kinase A pathway, and could potentially be responsible for differences in cardiovascular disease presentation and outcomes.</p>","PeriodicalId":10277,"journal":{"name":"Circulation: Cardiovascular Genetics","volume":"10 5","pages":""},"PeriodicalIF":0.0,"publicationDate":"2017-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1161/CIRCGENETICS.117.001770","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9344678","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impact of Selection Bias on Estimation of Subsequent Event Risk.","authors":"Yi-Juan Hu, Amand F Schmidt, Frank Dudbridge, Michael V Holmes, James M Brophy, Vinicius Tragante, Ziyi Li, Peizhou Liao, Arshed A Quyyumi, Raymond O McCubrey, Benjamin D Horne, Aroon D Hingorani, Folkert W Asselbergs, Riyaz S Patel, Qi Long","doi":"10.1161/CIRCGENETICS.116.001616","DOIUrl":"10.1161/CIRCGENETICS.116.001616","url":null,"abstract":"<p><strong>Background: </strong>Studies of recurrent or subsequent disease events may be susceptible to bias caused by selection of subjects who both experience and survive the primary indexing event. Currently, the magnitude of any selection bias, particularly for subsequent time-to-event analysis in genetic association studies, is unknown.</p><p><strong>Methods and results: </strong>We used empirically inspired simulation studies to explore the impact of selection bias on the marginal hazard ratio for risk of subsequent events among those with established coronary heart disease. The extent of selection bias was determined by the magnitudes of genetic and nongenetic effects on the indexing (first) coronary heart disease event. Unless the genetic hazard ratio was unrealistically large (>1.6 per allele) and assuming the sum of all nongenetic hazard ratios was <10, bias was usually <10% (downward toward the null). Despite the low bias, the probability that a confidence interval included the true effect decreased (undercoverage) with increasing sample size because of increasing precision. Importantly, false-positive rates were not affected by selection bias.</p><p><strong>Conclusions: </strong>In most empirical settings, selection bias is expected to have a limited impact on genetic effect estimates of subsequent event risk. Nevertheless, because of undercoverage increasing with sample size, most confidence intervals will be over precise (not wide enough). When there is no effect modification by history of coronary heart disease, the false-positive rates of association tests will be close to nominal.</p>","PeriodicalId":10277,"journal":{"name":"Circulation: Cardiovascular Genetics","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2017-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5659743/pdf/nihms902022.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35479273","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Diminished <i>PRRX1</i> Expression Is Associated With Increased Risk of Atrial Fibrillation and Shortening of the Cardiac Action Potential.","authors":"Nathan R Tucker,&nbsp;Elena V Dolmatova,&nbsp;Honghuang Lin,&nbsp;Rebecca R Cooper,&nbsp;Jiangchuan Ye,&nbsp;William J Hucker,&nbsp;Heather S Jameson,&nbsp;Victoria A Parsons,&nbsp;Lu-Chen Weng,&nbsp;Robert W Mills,&nbsp;Moritz F Sinner,&nbsp;Maxim Imakaev,&nbsp;Jordan Leyton-Mange,&nbsp;Gus Vlahakes,&nbsp;Emelia J Benjamin,&nbsp;Kathryn L Lunetta,&nbsp;Steven A Lubitz,&nbsp;Leonid Mirny,&nbsp;David J Milan,&nbsp;Patrick T Ellinor","doi":"10.1161/CIRCGENETICS.117.001902","DOIUrl":"https://doi.org/10.1161/CIRCGENETICS.117.001902","url":null,"abstract":"<p><strong>Background: </strong>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 identify the molecular mechanism, whereby variation at 1q24 may lead to AF susceptibility.</p><p><strong>Methods and results: </strong>We sequenced a ≈158 kb region encompassing <i>PRRX1</i> 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 <i>PRRX1</i> 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 <i>PRRX1</i> expression in human left atria. We found that suppression of <i>PRRX1</i> in human embryonic stem cell-derived cardiomyocytes and embryonic zebrafish resulted in shortening of the atrial action potential duration, a hallmark of AF.</p><p><strong>Conclusions: </strong>We have identified a functional genetic variant that alters <i>PRRX1</i> expression, ultimately resulting in electrophysiological alterations in atrial myocytes that may promote AF.</p>","PeriodicalId":10277,"journal":{"name":"Circulation: Cardiovascular Genetics","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2017-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1161/CIRCGENETICS.117.001902","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35569342","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}