on October 12, 2009
Published online before print October 12, 2009, doi: 10.1161/CIRCULATIONAHA.109.879643
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Submitted on May 12, 2009
From the Section of Cardiology, Department of Lung, Blood, and Heart (L.C., P.J.S.), and Department of Heath Sciences (M.C.M.), University of Pavia, Pavia, Italy; Department of Cardiology (L.C., P.J.S.) and Molecular Cardiology Laboratory (L.C., R.I., P.J.S.), IRCCS Fondazione Policlinico San Matteo, Pavia, Italy; Division of Statistical Genetics, Department of Biostatistics, Mailman School of Public Health, and Psychiatry Department, Columbia University Medical Center, New York, NY (M.C.M., D.A.G.); University of Stellenbosch/Medical Research Council Centre for Molecular and Cellular Biology (A.G.) and Department of Internal Medicine (P.A.B., P.J.S.), University of Stellenbosch, Stellenbosch, South Africa; Laboratory of Cardiovascular Genetics, IRCCS Istituto Auxologico, Milan, Italy (P.J.S.); Cardiovascular Genetics Laboratory, Hatter Institute for Cardiovascular Research, University of Cape Town, Cape Town, South Africa (P.J.S.); and Department of Medicine (A.L.G.), Department of Pharmacology (A.L.G.), and Institute for Integrative Genomics (A.L.G.), Vanderbilt University, Nashville, Tenn. * To whom correspondence should be addressed. E-mail: al.george{at}vanderbilt.edu.
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.
Accepted on August 24, 2009
NOS1AP Is a Genetic Modifier of the Long-QT Syndrome
Lia Crotti MD, PhD,
Key words: arrhythmia • genetics • KCNQ1 protein, human • long-QT syndrome • nitric oxide synthase