NOS1AP is a genetic modifier of the long-QT syndrome

Circulation. 2009 Oct 27;120(17):1657-63. doi: 10.1161/CIRCULATIONAHA.109.879643. Epub 2009 Oct 12.

Abstract

Background: In congenital long-QT syndrome (LQTS), a genetically heterogeneous disorder that predisposes to sudden cardiac death, genetic factors other than the primary mutation may modify the probability of life-threatening events. Recent evidence indicates that common variants in NOS1AP are associated with the QT-interval duration in the general population.

Methods and results: We tested the hypothesis that common variants in NOS1AP modify the risk of clinical manifestations and the degree of QT-interval prolongation in a South African LQTS population (500 subjects, 205 mutation carriers) segregating a founder mutation in KCNQ1 (A341V) using a family-based association analysis. NOS1AP variants were significantly associated with the occurrence of symptoms (rs4657139, P=0.019; rs16847548, P=0.003), with clinical severity, as manifested by a greater probability for cardiac arrest and sudden death (rs4657139, P=0.028; rs16847548, P=0.014), and with greater likelihood of having a QT interval in the top 40% of values among all mutation carriers (rs4657139, P=0.03; rs16847548, P=0.03).

Conclusions: These findings indicate that NOS1AP, a gene first identified as affecting the QTc interval in a general population, also influences sudden death risk in subjects with LQTS. The association of NOS1AP genetic variants with risk for life-threatening arrhythmias suggests that this gene is a genetic modifier of LQTS, and this knowledge may be clinically useful for risk stratification for patients with this disease, after validation in other LQTS populations.

Publication types

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

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics*
  • Arrhythmias, Cardiac / genetics
  • Death, Sudden
  • Female
  • Genetic Markers / genetics
  • Genetic Variation / genetics*
  • Humans
  • Long QT Syndrome / diagnosis
  • Long QT Syndrome / genetics*
  • Male
  • Mutation
  • Risk Factors

Substances

  • Adaptor Proteins, Signal Transducing
  • Genetic Markers
  • NOS1AP protein, human