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
alcohol
dilated cardiomyopathy
genetics
titin
variant
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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