1. SCN5A Mutation Type and a Genetic Risk Score Associate Variably with Brugada Syndrome Phenotype in SCN5A Families
- Author
-
Peter Lichtner, Thomas Meitinger, Wataru Shimizu, Alison Muir, F. Kyndt, Michael W.T. Tanck, Seiko Ohno, Martina Muggenthaler, Michael J. Ackerman, Vincent Probst, Stephen P. Page, Jean-Jacques Schott, Silvia Castelletti, Hariharan Raju, Jean-Baptiste Gourraud, Joseph Galvin, Taisuke Ishikawa, Eline A. Nannenberg, Dan M. Roden, Doris Škorić-Milosavljević, Kazuhiro Takahashi, Pascal P. McKeown, Federica Dagradi, Lia Crotti, Yanushi D. Wijeyeratne, Julien Barc, Yuka Mizusawa, Peter J. Schwartz, Michael Papadakis, Margherita Torchio, Sanjay Sharma, Velislav N. Batchvarov, Naomasa Makita, Richard Redon, Christian Veltmann, Elijah R. Behr, Takeshi Aiba, Martin Borggrefe, Rafik Tadros, Connie R. Bezzina, J. Martijn Bos, David J. Tester, Isabelle Denjoy, Minoru Horie, Arthur A.M. Wilde, St George's, University of London, Academic Medical Center - Academisch Medisch Centrum [Amsterdam] (AMC), University of Amsterdam [Amsterdam] (UvA), unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Centro Cardiologico Monzino [Milano], Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS)-Dpt di Scienze Cliniche e di Comunità [Milano] (DISCCO), Università degli Studi di Milano [Milano] (UNIMI)-Università degli Studi di Milano [Milano] (UNIMI), Mayo Clinic [Rochester], Belfast Health and Social Care Trust, Hannover Medical School [Hannover] (MHH), University of Shiga Prefecture, National Cerebral and Cardiovascular Center (NCCC - OSAKA), Osaka University [Osaka], Leeds Teaching Hospitals NHS Trust, University of Dublin, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Helmholtz-Zentrum München (HZM), Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), Iwate Prefectural University [Takizawa], Vanderbilt University School of Medicine [Nashville], University of Heidelberg, Medical Faculty, Wijeyeratne, Y, Tanck, M, Mizusawa, Y, Batchvarov, V, Barc, J, Crotti, L, Bos, J, Tester, D, Muir, A, Veltmann, C, Ohno, S, Page, S, Galvin, J, Tadros, R, Muggenthaler, M, Raju, H, Denjoy, I, Schott, J, Gourraud, J, Skoric-Milosavljevic, D, Nannenberg, E, Redon, R, Papadakis, M, Kyndt, F, Dagradi, F, Castelletti, S, Torchio, M, Meitinger, T, Lichtner, P, Ishikawa, T, Wilde, A, Takahashi, K, Sharma, S, Roden, D, Borggrefe, M, Mckeown, P, Shimizu, W, Horie, M, Makita, N, Aiba, T, Ackerman, M, Schwartz, P, Probst, V, Bezzina, C, Behr, E, Unité de recherche de l'institut du thorax (ITX-lab), Dpt di Scienze Cliniche e di Comunità [Milano] (DISCCO), Università degli Studi di Milano = University of Milan (UNIMI)-Università degli Studi di Milano = University of Milan (UNIMI)-Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Helmholtz Zentrum München = German Research Center for Environmental Health, HAL-SU, Gestionnaire, Epidemiology and Data Science, APH - Methodology, Graduate School, ACS - Heart failure & arrhythmias, Amsterdam Reproduction & Development (AR&D), Human Genetics, Cardiology, ACS - Pulmonary hypertension & thrombosis, and ACS - Atherosclerosis & ischemic syndromes
- Subjects
genetics, human ,congenital, hereditary, and neonatal diseases and abnormalities ,Scn5a gene ,phenotype ,BIO/18 - GENETICA ,030204 cardiovascular system & hematology ,risk score ,03 medical and health sciences ,0302 clinical medicine ,Brugada Syndrome ,Genetics, Human ,Penetrance ,Phenotype ,Risk Score ,Medicine ,genetics ,Brugada syndrome ,030212 general & internal medicine ,human ,cardiovascular diseases ,Genetic risk ,penetrance ,Genetics ,Framingham Risk Score ,[SDV.MHEP] Life Sciences [q-bio]/Human health and pathology ,business.industry ,fungi ,General Medicine ,Original Articles ,MED/11 - MALATTIE DELL'APPARATO CARDIOVASCOLARE ,medicine.disease ,Human genetics ,3. Good health ,Brugada ECG Pattern ,ComputingMethodologies_DOCUMENTANDTEXTPROCESSING ,cardiovascular system ,business ,[SDV.MHEP]Life Sciences [q-bio]/Human health and pathology - Abstract
Supplemental Digital Content is available in the text., Background: Brugada syndrome (BrS) is characterized by the type 1 Brugada ECG pattern. Pathogenic rare variants in SCN5A (mutations) are identified in 20% of BrS families in whom incomplete penetrance and genotype-negative phenotype-positive individuals are observed. E1784K-SCN5A is the most common SCN5A mutation identified. We determined the association of a BrS genetic risk score (BrS-GRS) and SCN5A mutation type on BrS phenotype in BrS families with SCN5A mutations. Methods: Subjects with a spontaneous type 1 pattern or positive/negative drug challenge from cohorts harboring SCN5A mutations were recruited from 16 centers (n=312). Single nucleotide polymorphisms previously associated with BrS at genome-wide significance were studied in both cohorts: rs11708996, rs10428132, and rs9388451. An additive linear genetic model for the BrS-GRS was assumed (6 single nucleotide polymorphism risk alleles). Results: In the total population (n=312), BrS-GRS ≥4 risk alleles yielded an odds ratio of 4.15 for BrS phenotype ([95% CI, 1.45–11.85]; P=0.0078). Among SCN5A-positive individuals (n=258), BrS-GRS ≥4 risk alleles yielded an odds ratio of 2.35 ([95% CI, 0.89–6.22]; P=0.0846). In SCN5A-negative relatives (n=54), BrS-GRS ≥4 alleles yielded an odds ratio of 22.29 ([95% CI, 1.84–269.30]; P=0.0146). Among E1784K-SCN5A positive family members (n=79), hosting ≥4 risk alleles gave an odds ratio=5.12 ([95% CI, 1.93–13.62]; P=0.0011). Conclusions: Common genetic variation is associated with variable expressivity of BrS phenotype in SCN5A families, explaining in part incomplete penetrance and genotype-negative phenotype-positive individuals. SCN5A mutation genotype and a BrS-GRS associate with BrS phenotype, but the strength of association varies according to presence of a SCN5A mutation and severity of loss of function.
- Published
- 2020
- Full Text
- View/download PDF