Gender and effects of a common genetic variant in the NOS1 regulator NOS1AP on cardiac repolarization in 3761 individuals from two independent populations

Martin D Tobin, Mika Kähönen, Peter Braund, Tuomo Nieminen, Cother Hajat, Maciej Tomaszewski, Jari Viik, Rami Lehtinen, G Andre Ng, Peter W Macfarlane, Paul R Burton, Terho Lehtimäki, Nilesh J Samani

Research output: Contribution to journalArticle (Academic Journal)peer-review

40 Citations (Scopus)

Abstract

BACKGROUND: A longer heart-rate corrected QT interval (QTc) is associated with increased risk of ventricular arrhythmias. Women have longer resting QTc and are more likely than men to develop drug-induced QT prolongation. Recent studies have shown association between resting QTc and a common variant (rs10494366) of the NOS1 regulator, NOS1AP. We investigated the association between rs10494366 in NOS1AP and QTc, and assessed gender-specific NOS1AP associations with QTc during rest and after exercise.

METHODS: We investigated the SNP associations with resting QTc in 919 women and 918 men from 504 representative families in the UK GRAPHIC study, and with QTc at rest and at 3 min recovery after exercise in 699 women and 1225 men referred for exercise testing in the Finnish FINCAVAS study.

RESULTS: In the GRAPHIC study the minor allele (G) of the NOS1AP SNP rs10494366 prolonged QTc by 4.59 ms (95% CI 2.77-6.40; P = 7.63/10(7)) in women, but only by 1.62 ms (95% CI -0.15 to 3.38; P = 0.073) in men (gender-SNP interaction term P = 0.025). In the FINCAVAS study the G allele significantly prolonged QTc in both women (P = 0.0063) and men (P = 0.0043) at 3 min recovery after exercise, but at rest an association was only seen in women (P = 0.020 excluding outliers).

CONCLUSIONS: A common NOS1AP variant prolongs QTc with a difference between genders. Further studies should aim to confirm this finding and to assess whether NOS1AP genotype influences the risk of drug-induced QT prolongation and risk of consequent arrhythmias.

Original languageEnglish
Pages (from-to)1132-41
Number of pages10
JournalInternational Journal of Epidemiology
Volume37
Issue number5
DOIs
Publication statusPublished - Oct 2008

Keywords

  • Adaptor Proteins, Signal Transducing
  • Adult
  • Alleles
  • Electrocardiography
  • Exercise
  • Female
  • Finland
  • Genetic Variation
  • Genotype
  • Great Britain
  • Health Surveys
  • Heart
  • Heart Rate
  • Humans
  • Linear Models
  • Long QT Syndrome
  • Male
  • Middle Aged
  • Sex Factors

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