title: Common candidate gene variants are associated with QT interval duration in the general population.
abstract: OBJECTIVE
  QT interval prolongation is associated with increased risk of sudden cardiac death at the population level. As 30-40% of the QT-interval variability is heritable, we tested the association of common LQTS and NOS1AP gene variants with QT interval in a Finnish population-based sample.
  
  
  METHODS
  We genotyped 12 common LQTS and NOS1AP genetic variants in Health 2000, an epidemiological sample of 5043 Finnish individuals, using Sequenom MALDI-TOF mass spectrometry. ECG parameters were measured from digital 12-lead ECGs and QT intervals were adjusted for age, gender and heart rate with a nomogram (Nc) method derived from the present study population.
  
  
  RESULTS
  The KCNE1 D85N minor allele (frequency 1.4%) was associated with a 10.5 ms (SE 1.6) or 0.57 SD prolongation of the adjusted QT(Nc) interval (P=3.6 x 10(-11)) in gender-pooled analysis. In agreement with previous studies, we replicated the association with QT(Nc) interval with minor alleles of KCNH2 intronic SNP rs3807375 [1.6 ms (SE 0.4) or 0.08 SD, P=4.7 x 10(-5)], KCNH2 K897T [-2.6 ms (SE 0.5) or -0.14 SD, P=2.1 x 10(-7)] and NOSA1P variants including rs2880058 [4.0 ms (SE 0.4) or 0.22 SD, P=3.2 x 10(-24)] under additive models.
  
  
  CONCLUSIONS
  We demonstrate that each additional copy of the KCNE1 D85N minor allele is associated with a considerable 10.5 ms prolongation of the age-, gender- and heart rate-adjusted QT interval and could thus modulate repolarization-related arrhythmia susceptibility at the population level. In addition, we robustly confirm the previous findings that three independent KCNH2 and NOSA1P variants are associated with adjusted QT interval.
authors.affiliation: Research Program in Molecular Medicine, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland.
authors.forename: A
authors.initials: A
authors.lastname: Marjamaa
authors.forename: C
authors.initials: C
authors.lastname: Newton-Cheh
authors.forename: K
authors.initials: K
authors.lastname: Porthan
authors.forename: A
authors.initials: A
authors.lastname: Reunanen
authors.forename: P
authors.initials: P
authors.lastname: Lahermo
authors.forename: H
authors.initials: H
authors.lastname: Väänänen
authors.forename: A
authors.initials: A
authors.lastname: Jula
authors.forename: H
authors.initials: H
authors.lastname: Karanko
authors.forename: H
authors.initials: H
authors.lastname: Swan
authors.forename: L
authors.initials: L
authors.lastname: Toivonen
authors.forename: M S
authors.initials: MS
authors.lastname: Nieminen
authors.forename: M
authors.initials: M
authors.lastname: Viitasalo
authors.forename: L
authors.initials: L
authors.lastname: Peltonen
authors.forename: L
authors.initials: L
authors.lastname: Oikarinen
authors.forename: A
authors.initials: A
authors.lastname: Palotie
authors.forename: K
authors.initials: K
authors.lastname: Kontula
authors.forename: V
authors.initials: V
authors.lastname: Salomaa
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016000:Cluster Analysis; D016757:Death, Sudden, Cardiac / Q000209:etiology; D004562:Electrocardiography; D051638:Ether-A-Go-Go Potassium Channels / Q000235:genetics; D005260:Female; D005387:Finland / Q000453:epidemiology; D014644:Genetic Variation / Q000235:genetics*; D005838:Genotype; D006801:Humans; D008133:Long QT Syndrome / Q000453:epidemiology / Q000235:genetics* / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D024642:Potassium Channels, Voltage-Gated / Q000235:genetics*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051638:Ether-A-Go-Go Potassium Channels; C489622:KCNE1 protein, human; C488081:NOS1AP protein, human; D024642:Potassium Channels, Voltage-Gated