Genetic etiology for alcohol-induced cardiac toxicity
Ware, James S. (Imperial College London. National Heart and Lung Institute)
Amor-Salamanca, Almudena (Hospital Universitario Puerta de Hierro Majadahonda (Madrid))
Tayal, Upasana (Imperial College London. National Heart and Lung Institute)
Govind, Risha (Imperial College London. National Heart and Lung Institute)
Serrano, Isabel (Hospital Universitari Joan XXIII de Tarragona)
Salazar-Mendiguchía, Joel (Universitat Autònoma de Barcelona. Departament de Genètica i de Microbiologia)
García-Pinilla, José Manuel (Hospital Universitario Virgen de la Victoria (Màlaga, Andalusia))
Pascual-Figal, Domingo A. (Hospital Universitario Virgen de la Arrixaca (Múrcia))
Núñez, Julio (Centro de Investigación Biomédica en Red en Enfermedades Cardiovasculares)
Guzzo-Merello, Gonzalo (Hospital Universitario Puerta de Hierro Majadahonda (Madrid))
González-Vioque, Emiliano (Hospital Universitario Puerta de Hierro Majadahonda (Madrid))
Bardají, Alfredo (Hospital Universitari Joan XXIII de Tarragona)
Manito, Nicolas (Hospital Universitari de Bellvitge)
López-Garrido, Miguel A. (Hospital Universitario Virgen de la Victoria (Màlaga, Andalusia))
Padron-Barthe, Laura (Hospital Universitario Puerta de Hierro Majadahonda (Madrid))
Edwards, Elizabeth (Imperial College London. National Heart and Lung Institute)
Whiffin, Nicola (Imperial College London. National Heart and Lung Institute)
Walsh, Roddy (Imperial College London. National Heart and Lung Institute)
Buchan, Rachel J. (Imperial College London. National Heart and Lung Institute)
Midwinter, William (Imperial College London. National Heart and Lung Institute)
Wilk, Alicja (Imperial College London. National Heart and Lung Institute)
Prasad, Sanjay (Imperial College London. National Heart and Lung Institute)
Pantazis, Antonis (Royal Brompton and Harefield. Cardiovascular Research Centre)
Baski, John (Royal Brompton and Harefield. Cardiovascular Research Centre)
O'Regan, Declan P. (Imperial College London. MRC London Institute of Medical Sciences)
Alonso-Pulpón, Luis (Hospital Universitario Puerta de Hierro Majadahonda (Madrid))
Cook, Stuart A. (Imperial College London. National Heart and Lung Institute)
Lara-Pezzi, Enrique (Centro de Investigación Biomédica en Red en Enfermedades Cardiovasculares)
Barton, Paul J. (Imperial College London. National Heart and Lung Institute)
García-Pavía, Pablo (Universidad Francisco de Vitoria)

Date:	2018
Abstract:	Alcoholic cardiomyopathy (ACM) is defined by a dilated and impaired left ventricle due to chronic excess alcohol consumption. It is largely unknown which factors determine cardiac toxicity on exposure to alcohol. This study sought to evaluate the role of variation in cardiomyopathy-associated genes in the pathophysiology of ACM, and to examine the effects of alcohol intake and genotype on dilated cardiomyopathy (DCM) severity. The authors characterized 141 ACM cases, 716 DCM cases, and 445 healthy volunteers. The authors compared the prevalence of rare, protein-altering variants in 9 genes associated with inherited DCM. They evaluated the effect of genotype and alcohol consumption on phenotype in DCM. Variants in well-characterized DCM-causing genes were more prevalent in patients with ACM than control subjects (13. 5% vs. 2. 9%; p = 1. 2 ×10 ⁻⁵), but similar between patients with ACM and DCM (19. 4%; p = 0. 12) and with a predominant burden of titin truncating variants (TTNtv) (9. 9%). Separately, we identified an interaction between TTN genotype and excess alcohol consumption in a cohort of DCM patients not meeting ACM criteria. On multivariate analysis, DCM patients with a TTNtv who consumed excess alcohol had an 8. 7% absolute reduction in ejection fraction (95% confidence interval: −2. 3% to −15. 1%; p < 0. 007) compared with those without TTNtv and excess alcohol consumption. The presence of TTNtv did not predict phenotype, outcome, or functional recovery on treatment in ACM patients. TTNtv represent a prevalent genetic predisposition for ACM, and are also associated with a worse left ventricular ejection fraction in DCM patients who consume alcohol above recommended levels. Familial evaluation and genetic testing should be considered in patients presenting with ACM.
Grants:	Instituto de Salud Carlos III PI15/01551 Ministerio de Economía y Competitividad SAF2015-71863-REDT Ministerio de Economía y Competitividad SEV-2015-0505
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	Alcohol ; Dilated cardiomyopathy ; Genetics ; Titin ; Variant ; ACM, alcoholic cardiomyopathy ; DCM, dilated cardiomyopathy ; ExAC, Exome Aggregation Consortium ; LVEF, left ventricular ejection fraction ; TTNtv, titin truncating variant
Published in:	Journal of the American College of Cardiology, Vol. 71, issue 20 (May 2018) , p. 2293-2302, ISSN 1558-3597

DOI: 10.1016/j.jacc.2018.03.462
PMID: 29773157

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