NOS1AP is a genetic modifier of the long-QT syndrome

Alfred L. George, Lia Crotti, Maria Cristina Monti, Roberto Insolia, Anna Peljto, Althea Goosen, Paul A. Brink, David A. Greenberg, Peter J. Schwartz

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)1657-1663
Number of pages7
Issue number17
Publication statusPublished - Oct 2009


  • Arrhythmia
  • Genetics
  • KCNQ1 protein, human
  • Long-QT syndrome
  • Nitric oxide synthase

ASJC Scopus subject areas

  • Physiology (medical)
  • Cardiology and Cardiovascular Medicine


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