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European Heart Journal Advance Access published online on January 25, 2008
European Heart Journal, doi:10.1093/eurheartj/ehm619
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2008. For permissions please email: journals.permissions@oxfordjournals.org

The non-synonymous coding IKr-channel variant KCNH2-K897T is associated with atrial fibrillation: results from a systematic candidate gene-based analysis of KCNH2 (HERG)

Moritz F. Sinner1,2,{dagger}, Arne Pfeufer2,3,{dagger}, Mahmut Akyol2,3, Britt-Maria Beckmann1, Martin Hinterseer1, Annette Wacker4, Siegfried Perz5, Wiebke Sauter6, Thomas Illig6, Michael Näbauer1, Claus Schmitt7, H.-Erich Wichmann6, Albert Schömig8,9, Gerhard Steinbeck1, Thomas Meitinger2,3 and Stefan Kääb1,*

1 Department of Medicine I, Ludwig-Maximilians-University Munich, Klinikum Großhadern, Marchioninistr. 15, Munich D-81377, Germany
2 Institute of Human Genetics, GSF National Research Centre of Environment and Health, Ingolstädter Landstr. 1, Neuherberg D-85764, Germany
3 Institute of Human Genetics, Technical University Munich, Klinikum rechts der Isar, Trogerstr. 32, Munich D-81675, Germany
4 Department of Pediatric Cardiology, University of Tübingen, Children’s Hospital, Hoppe-Seyler-Str. 1, Tübingen 72076, Germany
5 Institute of Medical Informatics, GSF National Research Centre of Environment and Health, Ingolstädter Landstr. 1, Neuherberg 85764, Germany
6 Institute of Epidemiology, GSF National Research Centre of Environment and Health, Ingolstädter Landstr. 1, Neuherberg 85764, Germany
7 Hospital of Karlsruhe, Moltkestr. 90, Karlsruhe 76133, Germany
8 Department of Cardiovascular Diseases, The German Heart Centre, Lazarettstr. 36, Munich 80636, Germany
9 Medical Department I, Technical University Munich, Klinikum rechts der Isar, Ismaninger Str. 22, Munich 81675, Germany

Received 4 July 2007; revised 6 December 2007; accepted 13 December 2007.

* Corresponding author. Tel: +49 89 7095 3049, Fax: +49 89 7095 6076, Email: stefan.kaab{at}med.uni-muenchen.de

Aims: Atrial fibrillation (AF) is the most frequent arrhythmia in humans. Rare familial forms exist. Recent evidence indicates a genetic susceptibility to common forms of AF. The {alpha}-subunit of the myocardial IKr-channel, encoded by the KCNH2 gene, is crucial to ventricular and atrial repolarization. Patients with mutations in KCNH2 present with higher incidence of AF. Common variants in KCNH2 have been shown to modify ventricular repolarization. We intended to investigate, whether such variants may also modulate atrial repolarization and predispose to AF.

Methods and results: In a two-stage association study we analysed 1207 AF-cases and 2475 controls. In stage I 40 tagSNPs (single nucleotide polymorphisms) from the KCNH2 genomic region were genotyped in 671 AF-cases and 694 controls. Of five associated variants, the common K897-allele of the KCNH2-K897T variant was replicated in n = 536 independent AF cases and n = 1781 controls in stage II [overall odds ratio 1.25, 95% confidence interval 1.11–1.41, P = 0.00033]. This association remained significant after adjustment for gender and age.

Conclusion: We report a genetic association finding including positive replication between the K897-allele and higher incidence of AF. This provides a molecular correlate for complex genetic predispositions to AF. The consequences of the K897T variant at the atrial level will require further functional investigations.

Key Words: Atrial fibrillation • KCNH2 • Gene • Single nucleotide polymorphism • Potassium channel

{dagger} These authors contributed equally to the work.


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