title: Common genetic variants in ANK2 modulate QT interval: results from the KORA study.
abstract: 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.
  
  
  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.
authors.affiliation: Klinik und Poliklinik für Innere Medizin II, Universitätsklinikum Regensburg, Regensburg, Germany.
authors.forename: Kamil
authors.initials: K
authors.lastname: Sedlacek
authors.forename: Klaus
authors.initials: K
authors.lastname: Stark
authors.forename: Shane R
authors.initials: SR
authors.lastname: Cunha
authors.forename: Arne
authors.initials: A
authors.lastname: Pfeufer
authors.forename: Stefan
authors.initials: S
authors.lastname: Weber
authors.forename: Iris
authors.initials: I
authors.lastname: Berger
authors.forename: Siegfried
authors.initials: S
authors.lastname: Perz
authors.forename: Stefan
authors.initials: S
authors.lastname: Kääb
authors.forename: Hans-Erich
authors.initials: HE
authors.lastname: Wichmann
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Mohler
authors.forename: Christian
authors.initials: C
authors.lastname: Hengstenberg
authors.forename: Andreas
authors.initials: A
authors.lastname: Jeron
mesh_terms: D000328:Adult; D000368:Aged; D017487:Ankyrins / Q000235:genetics*; D004562:Electrocardiography; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006720:Homozygote; D006801:Humans; D008133:Long QT Syndrome / Q000235:genetics; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012044:Regression Analysis
chemical_list: C498994:ANK2 protein, human; D017487:Ankyrins