Iris C R M Kolder1, Michael W T Tanck1, Pieter G Postema1, Jean-Jacques Schott1, Eric Schulze-Bahr1, Connie R Bezzina1, Julien Barc1, Moritz F Sinner1, Sven Zumhagen1, Anja Husemann1, Birgit Stallmeyer1, Tamara T Koopmann1, Nynke Hofman1, Arne Pfeufer1, Peter Lichtner1, Thomas Meitinger1, Britt M Beckmann1, Robert J Myerburg1, Nanette H Bishopric1, Dan M Roden1, Stefan Kääb1, Arthur A M Wilde1. 1. Department of Clinical and Experimental Cardiology (I.C.R.M.K., P.G.P., J.B., T.T.K., A.A.M.W., C.R.B.), Department of Clinical Epidemiology, Biostatistics and Bioinformatics (I.C.R.M.K., M.W.T.T.), and Department of Clinical Genetics (N.H.), Academic Medical Center, Amsterdam, the Netherlands; ICIN (Netherlands Heart Institute) (J.B., A.A.M.W., C.R.B.), Utrecht, the Netherlands; Institut National de la Santé et de la Recherche Médicale (INSERM) Unité Mixte de Recherche (UMR) 1087, L'Institut du Thorax, Nantes, France (J.B., J.-J.S.); Centre National de la Recherche Scientifique (CNRS) UMR 6291, Nantes, France (J.B., J.-J.S.); Université de Nantes, Nantes, France (J.B., J.-J.S.); Department of Medicine I, University Hospital Munich, Campus Grosshadern and Innenstadt, Ludwig-Maximilians University, Munich, Germany (M.F.S., B.M.B., S.K.); German Center for Cardiovascular Research (DZHK), Munich Heart Alliance, Munich, Germany (S.K.T.M.); Institute for Genetics of Heart Diseases, Department of Cardiovascular Medicine, University Hospital Münster, Münster, Germany (S.Z., A.H., B.S., E.S.-B.); Interdisciplinary Centre for Clinical Research (IZKF) of the University of Münster, Münster, Germany (S.Z., A.H., B.S., E.S.-B.); Institute of Bioinformatics and Systems Biology (A.P.), and Institute of Human Genetics (A.P., P.L., T.M.), Helmholtz Zentrum München, Neuherberg, Germany; Institute of Human Genetics, Technische Universität München, Munich, Germany (A.P., P.L., T.M.); Department of Medicine (R.J.M., N.H.B.), Department of Molecular and Cellular Pharmacology (R.J.M., N.H.B.), and Hussmann Institute of Human Genomics (R.J.M., N.H.B.), University of Miami Miller School of Medicine, FL; Department of Medicine and Pharmacology, Vanderbilt University School of Medicine, Nashville, TN (D.M.R.); Princess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders, Jeddah, Kingdom of Saudi Arabia (A.A.M.W.); and Centre Hospitalier Universitaire (CHU) Nantes, L'Institut du Thorax, Service de Cardiologie, Nantes, France (J.-J.S.).
Abstract
BACKGROUND: Considerable interest exists in the identification of genetic modifiers of disease severity in the long-QT syndrome (LQTS) as their identification may contribute to refinement of risk stratification. METHODS AND RESULTS: We searched for single-nucleotide polymorphisms (SNPs) that modulate the corrected QT (QTc)-interval and the occurrence of cardiac events in 639 patients harboring different mutations in KCNH2. We analyzed 1201 SNPs in and around 18 candidate genes, and in another approach investigated 22 independent SNPs previously identified as modulators of QTc-interval in genome-wide association studies in the general population. In an analysis for quantitative effects on the QTc-interval, 3 independent SNPs at NOS1AP (rs10494366, P=9.5×10(-8); rs12143842, P=4.8×10(-7); and rs2880058, P=8.6×10(-7)) were strongly associated with the QTc-interval with marked effects (>12 ms/allele). Analysis of patients versus general population controls uncovered enrichment of QTc-prolonging alleles in patients for 2 SNPs, located respectively at NOS1AP (rs12029454; odds ratio, 1.85; 95% confidence interval, 1.32-2.59; P=3×10(-4)) and KCNQ1 (rs12576239; odds ratio, 1.84; 95% confidence interval, 1.31-2.60; P=5×10(-4)). An analysis of the cumulative effect of the 6 NOS1AP SNPs by means of a multilocus genetic risk score (GRS(NOS1AP)) uncovered a strong linear relationship between GRS(NOS1AP) and the QTc-interval (P=4.2×10(-7)). Furthermore, patients with a GRS(NOS1AP) in the lowest quartile had a lower relative risk of cardiac events compared with patients in the other quartiles combined (P=0.039). CONCLUSIONS: We uncovered unexpectedly large effects of NOS1AP SNPs on the QTc-interval and a trend for effects on risk of cardiac events. For the first time, we linked common genetic variation at KCNQ1 with risk of long-QT syndrome.
BACKGROUND: Considerable interest exists in the identification of genetic modifiers of disease severity in the long-QT syndrome (LQTS) as their identification may contribute to refinement of risk stratification. METHODS AND RESULTS: We searched for single-nucleotide polymorphisms (SNPs) that modulate the corrected QT (QTc)-interval and the occurrence of cardiac events in 639 patients harboring different mutations in KCNH2. We analyzed 1201 SNPs in and around 18 candidate genes, and in another approach investigated 22 independent SNPs previously identified as modulators of QTc-interval in genome-wide association studies in the general population. In an analysis for quantitative effects on the QTc-interval, 3 independent SNPs at NOS1AP (rs10494366, P=9.5×10(-8); rs12143842, P=4.8×10(-7); and rs2880058, P=8.6×10(-7)) were strongly associated with the QTc-interval with marked effects (>12 ms/allele). Analysis of patients versus general population controls uncovered enrichment of QTc-prolonging alleles in patients for 2 SNPs, located respectively at NOS1AP (rs12029454; odds ratio, 1.85; 95% confidence interval, 1.32-2.59; P=3×10(-4)) and KCNQ1 (rs12576239; odds ratio, 1.84; 95% confidence interval, 1.31-2.60; P=5×10(-4)). An analysis of the cumulative effect of the 6 NOS1AP SNPs by means of a multilocus genetic risk score (GRS(NOS1AP)) uncovered a strong linear relationship between GRS(NOS1AP) and the QTc-interval (P=4.2×10(-7)). Furthermore, patients with a GRS(NOS1AP) in the lowest quartile had a lower relative risk of cardiac events compared with patients in the other quartiles combined (P=0.039). CONCLUSIONS: We uncovered unexpectedly large effects of NOS1AP SNPs on the QTc-interval and a trend for effects on risk of cardiac events. For the first time, we linked common genetic variation at KCNQ1 with risk of long-QT syndrome.
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