Published Online
on December 9, 2008

A more recent version of this article appeared on December 1, 2008

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Original Article

Common genetic variants in ANK2 modulate QT interval - Results from the KORA study

Kamil Sedlacek¹; Klaus Stark²; Shane R. Cunha³; Arne Pfeufer⁴; Stefan Weber²; Iris Berger²; Siegfried Perz⁴; Hans-Erich Wichmann⁴; Stefan Kääb⁵; Peter J. Mohler³; Christian Hengstenberg^2,6 and Andreas Jeron²

¹ Universitätsklinikum Regensburg, Regensburg, Germany and IKEM, Prague, Czech Republic;
² Universitätsklinikum Regensburg, Regensburg, Germany;
³ University of Iowa, Iowa City, IA;
⁴ HelmholtzZentrum München, Neuherberg, Germany;
⁵ Klinikum Großhadern, München, Germany

⁶ E-mail: christian.hengstenberg{at}klinik.uni-regensburg.de

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 WHO MONICA general population survey (KORA S3). Corrected QT interval was calculated using population specific linear regression formulas. A total of 22 SNPs in the genomic region of ANK2 gene were genotyped using TaqMan technology. In a replication study, six SNPs were genotyped in 3890 individuals from a second population study (KORA S4). The rare variant of the SNP rs6850768 (allele frequency 0.28) highly 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 [1.48-5.58], P = 0.001 and P = 0.0008 for log-additive and dominant model, respectively) in KORA S3 and 2.94 ms (95% CI [1.11-4.77], P = 0.001 and P = 0.006 for log-additive and dominant genetic model, respectively) in KORA S4. A common two-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. RT-PCR expression analysis of the human ANK2 5' genomic region in the human left ventricular tissue revealed two 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 electrical activity.

Key Words: arrhythmia • genetics • long-QT syndrome • physiology • sudden cardiac death

Author contributions: Kamil Sedlacek and Klaus Stark contributed equally to this work.