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A meta-analysis of genome-wide association studies of the electrocardiographic early repolarization pattern.

ABSTRACT: The early repolarization pattern (ERP) is common and associated with risk of sudden cardiac death. ERP is heritable, and mutations have been described in syndromatic cases.To conduct a meta-analysis of genome-wide association studies to identify common genetic variants influencing ERP.We ascertained ERP on the basis of electrocardiograms in 3 large community-based cohorts from Europe and the United States: the Framingham Heart Study, the Health 2000 Study, and the KORA F4 Study. We analyzed genome-wide association studies in participants with and without ERP by logistic regression assuming an additive genetic model and meta-analyzed individual cohort results. We then sought to strengthen support for findings that reached P ? 1 × 10(-5) in independent individuals by direct genotyping or in-silico analysis of genome-wide data. We meta-analyzed the results from both stages.Of 7482 individuals in the discovery stage, 452 showed ERP (ERP positive: mean age 46.9 ± 8.9 years, 30.3% women; ERP negative: 47.5 ± 9.4 years, 54.2% women). After meta-analysis, 8 single nucleotide polymorphisms reached P ? 1 × 10(-5): The most significant finding was intergenic rs11653989 (odds ratio 0.47; 95% confidence interval 0.36-0.61; P = 6.9 × 10(-9)). The most biologically relevant finding was intronic to KCND3: rs17029069 (odds ratio 1.46; 95% confidence interval 1.25-1.69; P = 8.5 × 10(-7)). In the replication step (7151 individuals), none of the 8 variants replicated, and combined meta-analysis results failed to reach genome-wide significance.In a genome-wide association study, we were not able to reliably identify genetic variants predisposing to ERP, presumably due to insufficient statistical power and phenotype heterogeneity. The reported heritability of ERP warrants continued investigation in larger well-phenotyped populations.

SUBMITTER: Sinner MF

PROVIDER: S-EPMC3459269 | biostudies-literature | 2012 Oct

REPOSITORIES: biostudies-literature

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A meta-analysis of genome-wide association studies of the electrocardiographic early repolarization pattern.

Sinner Moritz F MF Porthan Kimmo K Noseworthy Peter A PA Havulinna Aki S AS Tikkanen Jani T JT Müller-Nurasyid Martina M Peloso Gina G Ulivi Sheila S Beckmann Britt Maria BM Brockhaus A Catharina AC Cooper Rebecca R RR Gasparini Paolo P Hengstenberg Christian C Hwang Shih-Jen SJ Iorio Annamaria A Junttila M Juhani MJ Klopp Norman N Kähönen Mika M Laaksonen Maarit A MA Lehtimäki Terho T Lichtner Peter P Lyytikäinen Leo-Pekka LP Martens Eimo E Meisinger Christa C Meitinger Thomas T Merchant Faisal M FM Nieminen Markku S MS Peters Annette A Pietilä Arto A Perz Siegfried S Oikarinen Lasse L Raitakari Olli O Reinhard Wibke W Silander Kaisa K Thorand Barbara B Wichmann H-Erich HE Sinagra Gianfranco G Viikari Jorma J O'Donnell Christopher J CJ Ellinor Patrick T PT Huikuri Heikki V HV Kääb Stefan S Newton-Cheh Christopher C Salomaa Veikko V

Heart rhythm 20120606 10

<h4>Background</h4>The early repolarization pattern (ERP) is common and associated with risk of sudden cardiac death. ERP is heritable, and mutations have been described in syndromatic cases.<h4>Objective</h4>To conduct a meta-analysis of genome-wide association studies to identify common genetic variants influencing ERP.<h4>Methods</h4>We ascertained ERP on the basis of electrocardiograms in 3 large community-based cohorts from Europe and the United States: the Framingham Heart Study, the Healt ...[more]

PMID: 22683750

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Project description:Background Early repolarization pattern (ERP) is considered a common training-related and benign ECG finding in young adult athletes. Few data exist on ERP in the pediatric athletes population. Therefore, we aimed to evaluate the ERP prevalence, characteristics, and prognosis in pediatric athletes aged ≤16 years. Methods and Results Eight-hundred eighty-six consecutive pediatric athletes engaged in 17 different sports (mean age, 11.7±2.5 years; 7-16 years) were enrolled and prospectively evaluated with medical history, physical examination, resting and exercise ECGs, and transthoracic echocardiography during their preparticipation screening. Known cardiovascular diseases associated with sudden cardiac death was considered exclusion criteria. Athletes were followed up yearly for 4 years. The prevalence of ERP was 117 (13.2%), equally distributed in both sexes (P=0.072), irrespectively of body mass index and classification of sports. The most common ERP localizations were inferolateral and inferior leads (53.8% and 27.3%, respectively). Notching J-point morphology was the most prevalent (70%), and rapidly ascending ST elevation (96%) was the most common ST-segment morphology. Athletes with ERP were older (P<0.001) had lower rest and recovery heart rates (P<0.001), increased precordial and limb R-wave voltages (P<0.001), increased R/S Sokolow index (P<0.001), and longer PR interval (P=0.006) in comparison with the athletes without ERP. Neither major cardiovascular nor arrhythmic events, nor sudden cardiac death were recorded over a median follow-up of 4.2 years. One hundred seventeen (80.3%) athletes with ERP exhibited a persistent ERP. ERP localization and J-point morphology changed during follow-up in 11 (11.7%) and 17 (18%) of athletes, respectively. Conclusions ERP is common in pediatric athletes. It was mostly located in the inferolateral leads and associated with concave ascending ST segment with other training-related ECG changes. The lack of either sudden cardiac death or cardiomyopathies linked to sudden cardiac death over follow-up suggests that in pediatric athletes, ERP may be considered a benign training-related ECG phenomenon with a potential dynamic pattern.

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A meta-analysis of genome-wide association studies of the electrocardiographic early repolarization pattern.

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A meta-analysis of genome-wide association studies of the electrocardiographic early repolarization pattern.

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