NOS1AP Is a Genetic Modifier of the Long-QT Syndrome

• Published in: Circulation (New York, N.Y.) Vol. 120; no. 17; pp. 1657 - 1663
• Main Authors: Crotti, Lia, Monti, Maria Cristina, Insolia, Roberto, Peljto, Anna, Goosen, Althea, Brink, Paul A., Greenberg, David A., Schwartz, Peter J., George, Alfred L.
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD Lippincott Williams & Wilkins 27.10.2009
• Subjects: Adaptor Proteins, Signal Transducing - genetics; Arrhythmias, Cardiac - genetics; Biological and medical sciences; Blood and lymphatic vessels; Cardiology. Vascular system; Death, Sudden; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; Female; Genetic Markers - genetics; Genetic Variation - genetics; Humans; Long QT Syndrome - diagnosis; Long QT Syndrome - genetics; Male; Medical sciences; Mutation; Risk Factors; Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis; Human; Arrhythmia; Enzyme; Prolonged QT interval; Cardiovascular disease; Conduction disorder; Nitric-oxide synthase; long-QT syndrome; genetics; Heart block; Heart disease; Oxidoreductases; nitric oxide synthase; KCNQ1 protein, human
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/CIRCULATIONAHA.109.879643

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.