Common candidate gene variants are associated with QT interval duration in the general population

J Intern Med. 2009 Apr;265(4):448-58. doi: 10.1111/j.1365-2796.2008.02026.x. Epub 2009 Oct 25.


Objectives: 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics*
  • Adult
  • Aged
  • Aged, 80 and over
  • Cluster Analysis
  • Death, Sudden, Cardiac / etiology
  • Electrocardiography
  • Ether-A-Go-Go Potassium Channels / genetics
  • Female
  • Finland / epidemiology
  • Genetic Variation / genetics*
  • Genotype
  • Humans
  • Long QT Syndrome / epidemiology
  • Long QT Syndrome / genetics*
  • Long QT Syndrome / physiopathology
  • Male
  • Middle Aged
  • Polymorphism, Single Nucleotide*
  • Potassium Channels, Voltage-Gated / genetics*


  • Adaptor Proteins, Signal Transducing
  • Ether-A-Go-Go Potassium Channels
  • KCNE1 protein, human
  • NOS1AP protein, human
  • Potassium Channels, Voltage-Gated