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1. Role of common and rare variants in SCN10A: results from the Brugada syndrome QRS locus gene discovery collaborative study

Author

Peter Weeke, Bram P. Prins, Yalda Jamshidi, Stefan Kääb, Margherita Torchio, Evmorfia Petropoulou, Dan M. Roden, Sanjay Sharma, Eline A. Nannenberg, Lia Crotti, Pascale Guicheney, Javad Jabbari, Julien Barc, Tao Yang, Peter J. Schwartz, Anders G. Holst, Eleonora Savio-Galimberti, Morten S. Olesen, Michael J. Ackerman, Connie R. Bezzina, Vincent Probst, Yuka Mizusawa, Dawood Darbar, Elijah R. Behr, Arthur A.M. Wilde, Myriam Berthet, Rachel Bastiaenan, Richard Redon, Antoine Leenhardt, Federica Dagradi, Stig Haunsø, Jacob Tfelt-Hansen, Behr, E, Savio-Galimberti, E, Barc, J, Holst, A, Petropoulou, E, Prins, B, Jabbari, J, Torchio, M, Berthet, M, Mizusawa, Y, Yang, T, Nannenberg, E, Dagradi, F, Weeke, P, Bastiaenan, R, Ackerman, M, Haunso, S, Leenhardt, A, Kääb, S, Probst, V, Redon, R, Sharma, S, Wilde, A, Tfelt-Hansen, J, Schwartz, P, Roden, D, Bezzina, C, Olesen, M, Darbar, D, Guicheney, P, Crotti, L, Jamshidi, Y, Academic Medical Center - Academisch Medisch Centrum [Amsterdam] (AMC), University of Amsterdam [Amsterdam] (UvA), Physiopathologie et thérapie du muscle strié, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR14-Institut National de la Santé et de la Recherche Médicale (INSERM), School of Chemical Engineering [Anshan], University of Science and Technology LiaoNing (USTL), Rigshospitalet [Copenhagen], Copenhagen University Hospital, Service de Cardiologie, AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-PRES Sorbonne Paris Cité-Centre de Référence Maladies Cardiaques Héréditaires, unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Unité de recherche de l'institut du thorax (ITX-lab), 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), Cardiology, ACS - Amsterdam Cardiovascular Sciences, and Human Genetics

Subjects
Male, SCN10A, Candidate gene, QRS duration, Heredity, Physiology, [SDV]Life Sciences [q-bio], DNA Mutational Analysis, Action Potentials, Gene Frequency, Risk Factors, Databases, Genetic, Odds Ratio, humans, Exome sequencing, Brugada syndrome, Genetics, adult, Single Nucleotide, Middle Aged, Pedigree, 3. Good health, Europe, Phenotype, Female, Corrigendum, Cardiology and Cardiovascular Medicine, Saudi Arabia, BIO/18 - GENETICA, Biology, Transfection, Polymorphism, Single Nucleotide, Sudden death, Cell Line, NAV1.8 Voltage-Gated Sodium Channel, Databases, Genetic, Physiology (medical), Cardiac conduction, medicine, Genetic Predisposition to Disease, Polymorphism, Allele, Allele frequency, Genetic Association Studies, MED/01 - STATISTICA MEDICA, Aged, Genetic heterogeneity, Computational Biology, Rare variant, Rare variants, Original Articles, MED/11 - MALATTIE DELL'APPARATO CARDIOVASCOLARE, medicine.disease, United States, Case-Control Studies
Abstract

International audience; AIMS: Brugada syndrome (BrS) remains genetically heterogeneous and is associated with slowed cardiac conduction. We aimed to identify genetic variation in BrS cases at loci associated with QRS duration. METHODS AND RESULTS: A multi-centre study sequenced seven candidate genes (SCN10A, HAND1, PLN, CASQ2, TKT, TBX3, and TBX5) in 156 Caucasian SCN5A mutation-negative BrS patients (80% male; mean age 48) with symptoms (64%) and/or a family history of sudden death (47%) or BrS (18%). Forty-nine variants were identified: 18 were rare (MAF \textless1%) and non-synonymous; and 11/18 (61.1%), mostly in SCN10A, were predicted as pathogenic using multiple bioinformatics tools. Allele frequencies were compared with the Exome Sequencing and UK10K Projects. SKAT methods tested rare variation in SCN10A finding no statistically significant difference between cases and controls. Co-segregation analysis was possible for four of seven probands carrying a novel pathogenic variant. Only one pedigree (I671V/G1299A in SCN10A) showed co-segregation. The SCN10A SNP V1073 was, however, associated strongly with BrS [66.9 vs. 40.1% (UK10K) OR (95% CI) = 3.02 (2.35-3.87), P = 8.07 × 10-19]. Voltage-clamp experiments for NaV1.8 were performed for SCN10A common variants V1073, A1073, and rare variants of interest: A200V and I671V. V1073, A200V and I671V, demonstrated significant reductions in peak INa compared with ancestral allele A1073 (rs6795970). CONCLUSION: Rare variants in the screened QRS-associated genes (including SCN10A) are not responsible for a significant proportion of SCN5A mutation negative BrS. The common SNP SCN10A V1073 was strongly associated with BrS and demonstrated loss of NaV1.8 function, as did rare variants in isolated patients.

Published
2015
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3. Prevalence of Subclinical Coronary Artery Disease in Masters Endurance Athletes With a Low Atherosclerotic Risk Profile.

Author

Merghani A, Maestrini V, Rosmini S, Cox AT, Dhutia H, Bastiaenan R, David S, Yeo TJ, Narain R, Malhotra A, Papadakis M, Wilson MG, Tome M, AlFakih K, Moon JC, and Sharma S

Subjects
Adult, Aged, Aged, 80 and over, Cohort Studies, Coronary Artery Disease epidemiology, Coronary Artery Disease physiopathology, Exercise Test methods, Female, Humans, Male, Middle Aged, Plaque, Atherosclerotic epidemiology, Plaque, Atherosclerotic physiopathology, Prevalence, Risk Factors, Athletes, Bicycling physiology, Coronary Artery Disease diagnostic imaging, Physical Endurance physiology, Plaque, Atherosclerotic diagnostic imaging, Running physiology
Abstract

Background: Studies in middle-age and older (masters) athletes with atherosclerotic risk factors for coronary artery disease report higher coronary artery calcium (CAC) scores compared with sedentary individuals. Few studies have assessed the prevalence of coronary artery disease in masters athletes with a low atherosclerotic risk profile., Methods: We assessed 152 masters athletes 54.4±8.5 years of age (70% male) and 92 controls of similar age, sex, and low Framingham 10-year coronary artery disease risk scores with an echocardiogram, exercise stress test, computerized tomographic coronary angiogram, and cardiovascular magnetic resonance imaging with late gadolinium enhancement and a 24-hour Holter. Athletes had participated in endurance exercise for an average of 31±12.6 years. The majority (77%) were runners, with a median of 13 marathon runs per athlete., Results: Most athletes (60%) and controls (63%) had a normal CAC score. Male athletes had a higher prevalence of atherosclerotic plaques of any luminal irregularity (44.3% versus 22.2%; P =0.009) compared with sedentary males, and only male athletes showed a CAC ≥300 Agatston units (11.3%) and a luminal stenosis ≥50% (7.5%). Male athletes demonstrated predominantly calcific plaques (72.7%), whereas sedentary males showed predominantly mixed morphology plaques (61.5%). The number of years of training was the only independent variable associated with increased risk of CAC >70th percentile for age or luminal stenosis ≥50% in male athletes (odds ratio, 1.08; 95% confidence interval, 1.01-1.15; P =0.016); 15 (14%) male athletes but none of the controls revealed late gadolinium enhancement on cardiovascular magnetic resonance imaging. Of these athletes, 7 had a pattern consistent with previous myocardial infarction, including 3(42%) with a luminal stenosis ≥50% in the corresponding artery., Conclusions: Most lifelong masters endurance athletes with a low atherosclerotic risk profile have normal CAC scores. Male athletes are more likely to have a CAC score >300 Agatston units or coronary plaques compared with sedentary males with a similar risk profile. The significance of these observations is uncertain, but the predominantly calcific morphology of the plaques in athletes indicates potentially different pathophysiological mechanisms for plaque formation in athletic versus sedentary men. Coronary plaques are more abundant in athletes, whereas their stable nature could mitigate the risk of plaque rupture and acute myocardial infarction., (© 2017 American Heart Association, Inc.)

Published
2017
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4. Role of common and rare variants in SCN10A: results from the Brugada syndrome QRS locus gene discovery collaborative study.

Author

Behr ER, Savio-Galimberti E, Barc J, Holst AG, Petropoulou E, Prins BP, Jabbari J, Torchio M, Berthet M, Mizusawa Y, Yang T, Nannenberg EA, Dagradi F, Weeke P, Bastiaenan R, Ackerman MJ, Haunso S, Leenhardt A, Kääb S, Probst V, Redon R, Sharma S, Wilde A, Tfelt-Hansen J, Schwartz P, Roden DM, Bezzina CR, Olesen M, Darbar D, Guicheney P, Crotti L, and Jamshidi Y

Subjects
Action Potentials, Adult, Aged, Brugada Syndrome diagnosis, Brugada Syndrome physiopathology, Case-Control Studies, Cell Line, Computational Biology, DNA Mutational Analysis, Databases, Genetic, Europe, Female, Gene Frequency, Genetic Association Studies, Genetic Predisposition to Disease, Heredity, Humans, Male, Middle Aged, NAV1.8 Voltage-Gated Sodium Channel metabolism, Odds Ratio, Pedigree, Phenotype, Risk Factors, Saudi Arabia, Transfection, United States, Brugada Syndrome genetics, NAV1.8 Voltage-Gated Sodium Channel genetics, Polymorphism, Single Nucleotide
Abstract

Aims: Brugada syndrome (BrS) remains genetically heterogeneous and is associated with slowed cardiac conduction. We aimed to identify genetic variation in BrS cases at loci associated with QRS duration., Methods and Results: A multi-centre study sequenced seven candidate genes (SCN10A, HAND1, PLN, CASQ2, TKT, TBX3, and TBX5) in 156 Caucasian SCN5A mutation-negative BrS patients (80% male; mean age 48) with symptoms (64%) and/or a family history of sudden death (47%) or BrS (18%). Forty-nine variants were identified: 18 were rare (MAF <1%) and non-synonymous; and 11/18 (61.1%), mostly in SCN10A, were predicted as pathogenic using multiple bioinformatics tools. Allele frequencies were compared with the Exome Sequencing and UK10K Projects. SKAT methods tested rare variation in SCN10A finding no statistically significant difference between cases and controls. Co-segregation analysis was possible for four of seven probands carrying a novel pathogenic variant. Only one pedigree (I671V/G1299A in SCN10A) showed co-segregation. The SCN10A SNP V1073 was, however, associated strongly with BrS [66.9 vs. 40.1% (UK10K) OR (95% CI) = 3.02 (2.35-3.87), P = 8.07 × 10-19]. Voltage-clamp experiments for NaV1.8 were performed for SCN10A common variants V1073, A1073, and rare variants of interest: A200V and I671V. V1073, A200V and I671V, demonstrated significant reductions in peak INa compared with ancestral allele A1073 (rs6795970)., Conclusion: Rare variants in the screened QRS-associated genes (including SCN10A) are not responsible for a significant proportion of SCN5A mutation negative BrS. The common SNP SCN10A V1073 was strongly associated with BrS and demonstrated loss of NaV1.8 function, as did rare variants in isolated patients., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.)

Published
2015
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