Published online before print December 9, 2008, doi: 10.1161/CIRCGENETICS.108.792192
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Original Articles |
Common Genetic Variants in ANK2 Modulate QT Interval
Results From the KORA Study
From the Klinik und Poliklinik für Innere Medizin II, Universitätsklinikum Regensburg, Regensburg, Germany (Ka.S., Kl.S., S.W., I.B., C.H., A.J.); Clinic of Cardiology and Center for Cardiovascular Research, IKEM, Prague, Czech Republic (Ka.S.); Departments of Internal Medicine, Molecular Physiology, and Biophysics, University of Iowa Carver College of Medicine, Iowa City, Iowa (S.R.C., P.J.M.); Institut für Humangenetik (A.P.), HelmholtzZentrum München, Neuherberg, Germany; Institute for Biological and Medical Imaging (S.P.), HelmholtzZentrum München, Neuherberg, Germany; Medizinische Klinik und Poliklinik I (S.K.), Klinikum Großhadern, München, Germany; and Institut für Epidemiologie (H.E.W.), HelmholtzZentrum München, Neuherberg, Germany.
Correspondence to Christian Hengstenberg, MD, Clinic for Internal Medicine II–Cardiology, University Hospital of Regensburg, Franz-Josef-Strauss-Allee 11, 93053 Regensburg, Germany. E-mail christian.hengstenberg{at}klinik.uni-regensburg.de
Received May 14, 2008; accepted October 16, 2008.
Background— Spatial and timely variations in QT interval, even within its normal range, may underlie susceptibility to cardiac arrhythmias and sudden cardiac death. Given its important role in cardiac electrophysiology, we hypothesized that common genetic variation in ankyrin-B gene (ANK2) might modify QT interval length.
Methods and Results— The study population consisted of 1188 participants of the World Health Organizational Multinational Monitoring of Trends and Determinants in Cardiovascular Disease (WHO MONICA) general population survey Cooperative Health Research in the Region of Augsburg (KORA S3). Corrected QT interval was calculated using population specific linear regression formulas. A total of 22 single-nucleotide polymorphisms in the genomic region of ANK2 gene were genotyped using TaqMan technology. In a replication study, 6 single nucleotide polymorphisms were genotyped in 3890 individuals from a second population study (KORA S4). The rare variant of the single-nucleotide polymorphism rs6850768 (allele frequency, 0.28) significantly influenced duration of the QT interval, both in KORA S3 and KORA S4 populations. In homozygotes, the shortening of the QT interval was 3.79 ms (95% CI, 1.48 to 5.58; P=0.001 and P=0.0008 for log-additive and dominant model, respectively) in KORA S3 and 2.94 ms (95% CI, 1.11 to 4.77; P=0.001 and P=0.006 for log-additive and dominant genetic model, respectively) in KORA S4. A common 2-locus haplotype (rs11098171-rs6850768; population frequency, 28%) was associated with a QT interval difference of 2.85 ms (permutation; P=0.006) in KORA S3 and 1.23 ms (permutation; P=0.009) in KORA S4. Reverse transcription–polymerase chain reaction expression analysis of the human ANK2 5' genomic region in the human left ventricular tissue revealed 2 previously unidentified ANK2 5' exons in the proximity of the identified variants.
Conclusions— Common genetic variants juxtaposed with novel exons in the distant 5' genomic region of ANK2 influence the QT interval length in the general population. These findings support the role of ankyrin-B in normal cardiac electric activity.
Key Words: arrhythmia • genetics • long-QT syndrome • physiology • sudden cardiac death
Kamil Sedlacek, Klaus Stark, Christian Hengstenberg and Andreas Jaron contributed equally to this work.
The online-only Data Supplement is available at http://circgenetics.ahajournals.org/cgi/content/full/CIRCGENETICS.108.792192/DC1.