Genome-wide association study and meta-analysis on alcohol-related liver cirrhosis identifies novel genetic risk factors

Autor: Sebastian Mueller, Tiebing Liang, Pierre Nahon, Florian Eyer, Suthat Liangpunsakul, Devanshi Seth, Michael Soyka, Romain Moirand, David Goldman, Sylvie Naveau, Timothy R. Morgan, Beat Muellhaupt, Pascal Perney, Jean-Marc Jacquet, Helmut K. Seitz, Heather J. Cordell, Munir Pirmohamed, Guruprasad P. Aithal, Felix Stickel, Christopher P. Day, Philippe Mathurin, Dermot Gleeson, Paul S. Haber, Greg Botwin, John Whitfield, Steven Masson, Tae-Hwi Schwantes-An, Ann K. Daly, Bertrand Nalpas, Andrew Thompson, Rebecca Darlay, Tatiana Foroud, Lawrence Lumeng
Přispěvatelé: Indiana University System, Newcastle University [Newcastle], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), University of Heidelberg, Medical Faculty, University of Nottingham, UK (UON), Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), Royal Hallamshire Hospital, University of Liverpool, University hospital of Zurich [Zurich], Klinikum der Universität [München], Service Addictologie [CHU Nîmes] (Pôle ICAGNE), Hôpital Universitaire de Réadaptation, de Rééducation et d'Addictologie du CHU de Nîmes [Grau-du-Roi] (CHU Nîmes), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes)-Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Nutrition, Métabolismes et Cancer (NuMeCan), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Hôpital Jean Verdier [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), AP-HP - Hôpital Antoine Béclère [Clamart], Veterans Affairs Long Beach Healthcare System (VA Long Beach Healthcare System), NSW Government, The University of Sydney, QIMR Berghofer Medical Research Institute, U01‐AA018389, National Institute on Alcohol Abuse and Alcoholism, APP1155320, National Health and Medical Research Council, Swiss Foundation for Alcohol Research, Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Jonchère, Laurent, Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)
Jazyk: angličtina
Rok vydání: 2021
Předmět:
Zdroj: Hepatology
Hepatology, Wiley-Blackwell, 2021, 14 (5), ⟨10.1002/hep.31535⟩
Hepatology, 2021, 14 (5), ⟨10.1002/hep.31535⟩
HEPATOLOGY
Hepatology, Wiley-Blackwell, 2020, 14, ⟨10.1002/hep.31535⟩
ISSN: 0270-9139
1527-3350
DOI: 10.1002/hep.31535⟩
Popis: International audience; Background and aims - Only a minority of heavy drinkers progress to alcohol-associated cirrhosis (ALC). The aim of this study was to identify common genetic variants that underlie risk for ALC. Approach and results - We analyzed data from 1,128 subjects of European ancestry with ALC and 614 heavy-drinking subjects without known liver disease from Australia, the United States, the United Kingdom, and three countries in Europe. A genome-wide association study (GWAS) was performed, adjusting for principal components and clinical covariates (alcohol use, age, sex, body mass index, and diabetes). We validated our GWAS findings using UK Biobank. We then performed a meta-analysis combining data from our study, the UK Biobank, and a previously published GWAS. Our GWAS found genome-wide significant risk association of rs738409 in patatin-like phospholipase domain containing 3 (PNPLA3) (odds ratio [OR] = 2.19 [G allele], P = 4.93 × 10 ) and rs4607179 near HSD17B13 (OR = 0.57 [C allele], P = 1.09 × 10 ) with ALC. Conditional analysis accounting for the PNPLA3 and HSD17B13 loci identified a protective association at rs374702773 in Fas-associated factor family member 2 (FAF2) (OR = 0.61 [del(T) allele], P = 2.56 × 10 ) for ALC. This association was replicated in the UK Biobank using conditional analysis (OR = 0.79, P = 0.001). Meta-analysis (without conditioning) confirmed genome-wide significance for the identified FAF2 locus as well as PNPLA3 and HSD17B13. Two other previously known loci (SERPINA1 and SUGP1/TM6SF2) were also genome-wide significant in the meta-analysis. GeneOntology pathway analysis identified lipid droplets as the target for several identified genes. In conclusion, our GWAS identified a locus at FAF2 associated with reduced risk of ALC among heavy drinkers. Like the PNPLA3 and HSD17B13 gene products, the FAF2 product has been localized to fat droplets in hepatocytes. Conclusions - Our genetic findings implicate lipid droplets in the biological pathway(s) underlying ALC.
Databáze: OpenAIRE
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