Sinner Moritz F, Pfeufer Arne, Akyol Mahmut, Beckmann Britt-Maria, Hinterseer Martin, Wacker Annette, Perz Siegfried, Sauter Wiebke, Illig Thomas, Näbauer Michael, Schmitt Claus, Wichmann H-Erich, Schömig Albert, Steinbeck Gerhard, Meitinger Thomas, Kääb Stefan
Department of Medicine I, Ludwig-Maximilians-University Munich, Klinikum Grosshadern, Marchioninistr. 15, Munich D-81377, Germany.
Eur Heart J. 2008 Apr;29(7):907-14. doi: 10.1093/eurheartj/ehm619. Epub 2008 Jan 25.
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 I(Kr)-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.
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.
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.
心房颤动（AF）是人类最常见的心律失常。存在罕见的家族性形式。最近的证据表明对常见形式的AF存在遗传易感性。由KCNH2基因编码的心肌I(Kr)通道的α亚基对心室和心房复极至关重要。KCNH2发生突变的患者AF发生率更高。已表明KCNH2中的常见变异可改变心室复极。我们旨在研究此类变异是否也可能调节心房复极并易患AF。
在一项两阶段关联研究中，我们分析了1207例AF病例和2475例对照。在第一阶段，对671例AF病例和694例对照进行了KCNH2基因组区域的40个标签单核苷酸多态性（tagSNP）基因分型。在五个相关变异中，KCNH2-K897T变异的常见K897等位基因在第二阶段的n = 536例独立AF病例和n = 1781例对照中得到重复验证[总体优势比1.25，95%置信区间1.11 - 1.41，P = 0.00033]。在对性别和年龄进行调整后，这种关联仍然显著。
我们报告了一项遗传关联发现，包括K897等位基因与较高AF发生率之间的阳性重复验证。这为AF复杂的遗传易感性提供了分子关联。K897T变异在心房水平的后果需要进一步的功能研究。
