title: 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).
abstract: OBJECTIVE
  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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Medicine I, Ludwig-Maximilians-University Munich, Klinikum Grosshadern, Marchioninistr. 15, Munich D-81377, Germany.
authors.forename: Moritz F
authors.initials: MF
authors.lastname: Sinner
authors.forename: Arne
authors.initials: A
authors.lastname: Pfeufer
authors.forename: Mahmut
authors.initials: M
authors.lastname: Akyol
authors.forename: Britt-Maria
authors.initials: BM
authors.lastname: Beckmann
authors.forename: Martin
authors.initials: M
authors.lastname: Hinterseer
authors.forename: Annette
authors.initials: A
authors.lastname: Wacker
authors.forename: Siegfried
authors.initials: S
authors.lastname: Perz
authors.forename: Wiebke
authors.initials: W
authors.lastname: Sauter
authors.forename: Thomas
authors.initials: T
authors.lastname: Illig
authors.forename: Michael
authors.initials: M
authors.lastname: Näbauer
authors.forename: Claus
authors.initials: C
authors.lastname: Schmitt
authors.forename: H-Erich
authors.initials: HE
authors.lastname: Wichmann
authors.forename: Albert
authors.initials: A
authors.lastname: Schömig
authors.forename: Gerhard
authors.initials: G
authors.lastname: Steinbeck
authors.forename: Thomas
authors.initials: T
authors.lastname: Meitinger
authors.forename: Stefan
authors.initials: S
authors.lastname: Kääb
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001281:Atrial Fibrillation / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000235:genetics* / Q000302:isolation & purification; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005838:Genotype; D006239:Haplotypes / Q000235:genetics* / Q000502:physiology; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D015221:Potassium Channels / Q000235:genetics; D018709:Statistics, Nonparametric; D015534:Trans-Activators / Q000235:genetics / Q000302:isolation & purification; D000071230:Transcriptional Regulator ERG
chemical_list: D004268:DNA-Binding Proteins; C072312:ERG protein, human; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; D015221:Potassium Channels; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG