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A genetic etiology for alcohol-induced cardiac toxicity

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Title: A genetic etiology for alcohol-induced cardiac toxicity
Authors: Ware, JS
Amor-Salamanca, A
Tayal, U
Govind, R
Serrano, I
Salazar-Mendiguchia, J
Garcia-Pinilla, JM
Pascual-Figal, DA
Nunez, J
Guzzo-Merello, G
Gonzalez-Vioque, E
Bardaji, A
Manito, N
Lopez-Garrido, MA
Padron-Barthe, L
Edwards, E
Whiffin, N
Walsh, R
Buchan, RJ
Midwinter, W
Wilk, A
Prasad, S
Pantazis, A
Baski, J
O'Regan, DP
Alsonso-Pulpon, A
Cook, SA
Lara-Pezzi, E
Barton, PJ
Garcia-Pavia, P
Item Type: Journal Article
Abstract: Background: Alcoholic cardiomyopathy (ACM) is defined by a dilated and impaired left ventricle due to chronic excess alcohol consumption. It is largely unknown what factors determine cardiac toxicity on exposure to alcohol. Objectives: We 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 DCM severity. Methods: We characterized 141 ACM cases, 716 dilated cardiomyopathy (DCM) cases and 445 healthy volunteers. We compared the prevalence of rare, protein-altering variants in 9 genes associated with inherited DCM. We evaluated the effect of genotype and alcohol-consumption on phenotype in DCM. Results: Variants in well-characterized DCM-causing genes were more prevalent in patients with ACM than controls (13.5% vs 2.9%; P=1.2e-05), 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% CI -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. Conclusions: TTNtv represent a prevalent genetic predisposition for ACM, and are also associated with a worse LVEF in DCM patients who consume alcohol above recommended levels. Familial evaluation and genetic testing should be considered in patients presenting with ACM.
Issue Date: 22-May-2018
Date of Acceptance: 1-Mar-2018
URI: http://hdl.handle.net/10044/1/58376
DOI: https://dx.doi.org/10.1016/j.jacc.2018.03.462
ISSN: 0735-1097
Publisher: Elsevier
Start Page: 2293
End Page: 2302
Journal / Book Title: Journal of the American College of Cardiology
Volume: 71
Issue: 20
Copyright Statement: © 2018 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation. This is an open access article under the CC BY Licence (http://creativecommons.org/licenses/by/4.0/)
Sponsor/Funder: Imperial College Healthcare NHS Trust- BRC Funding
Fondation Leducq
Fondation Leducq
National Institute for Health Research
Wellcome Trust
Royal Brompton & Harefield NHS Foundation Trust
Department of Health
Wellcome Trust
Medical Research Council
Imperial College Healthcare NHS Trust- BRC Funding
Imperial College Healthcare NHS Trust- BRC Funding
Funder's Grant Number: RD410
11 CVD-01
11 CVD-01
RDB02 79560
100134/Z/12/Z
RBHT6179
HICF-R6-373
107469/Z/15/Z
MR/M003191/1
RDC04
RDB02
Keywords: Science & Technology
Life Sciences & Biomedicine
Cardiac & Cardiovascular Systems
Cardiovascular System & Cardiology
alcohol
dilated cardiomyopathy
genetics
titin
variant
DILATED CARDIOMYOPATHY
MUTATIONS
CONSUMPTION
GENOMICS
1102 Cardiovascular Medicine And Haematology
1117 Public Health And Health Services
Cardiovascular System & Hematology
Publication Status: Published
Online Publication Date: 2018-05-14
Appears in Collections:Clinical Sciences
Imaging Sciences
National Heart and Lung Institute
Faculty of Medicine



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