Genome‐wide Association Study and Meta‐analysis on Alcohol‐Associated Liver Cirrhosis Identifies Genetic Risk Factors

Genome‐wide Association Study and Meta‐analysis on Alcohol‐Associated Liver Cirrhosis Identifies Genetic Risk Factors.

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Item Type: Article
Status: Published
Official URL: https://doi.org/10.1002/hep.31535
Journal or Publication Title: Hepatology
Volume: 73
Number: 5
Page Range: pp. 1920-1931
Date: 2021
Divisions: Alcoholic Liver Disease
Depositing User: General Admin
Identification Number: 10.1002/hep.31535
ISSN: 0270-9139
Date Deposited: 10 Jun 2021 05:36
Abstract:

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 × 10-17 ) and rs4607179 near HSD17B13 (OR = 0.57 [C allele], P = 1.09 × 10-10 ) 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 × 10-8 ) 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.

© 2020 by the American Association for the Study of Liver Diseases.

Creators:
Creators
Email
Schwantes‐An, Tae‐Hwi
UNSPECIFIED
Darlay, Rebecca
UNSPECIFIED
Mathurin, Philippe
UNSPECIFIED
Masson, Steven
UNSPECIFIED
Liangpunsakul, Suthat
UNSPECIFIED
Mueller, Sebastian
UNSPECIFIED
Aithal, Guruprasad P.
UNSPECIFIED
Eyer, Florian
UNSPECIFIED
Gleeson, Dermot
UNSPECIFIED
Thompson, Andrew
UNSPECIFIED
Muellhaupt, Beat
UNSPECIFIED
Stickel, Felix
UNSPECIFIED
Soyka, Michael
UNSPECIFIED
Goldman, David
UNSPECIFIED
Liang, Tiebing
UNSPECIFIED
Lumeng, Lawrence
UNSPECIFIED
Pirmohamed, Munir
UNSPECIFIED
Nalpas, Bertrand
UNSPECIFIED
Jacquet, Jean‐Marc
UNSPECIFIED
Moirand, Romain
UNSPECIFIED
Nahon, Pierre
UNSPECIFIED
Naveau, Sylvie
UNSPECIFIED
Perney, Pascal
UNSPECIFIED
Botwin, Greg
UNSPECIFIED
Haber, Paul S.
UNSPECIFIED
Seitz, Helmut K.
UNSPECIFIED
Day, Christopher P.
UNSPECIFIED
Foroud, Tatiana M.
UNSPECIFIED
Daly, Ann K.
UNSPECIFIED
Cordell, Heather J.
UNSPECIFIED
Whitfield, John B.
UNSPECIFIED
Morgan, Timothy R.
UNSPECIFIED
Seth, Devanshi
UNSPECIFIED
Last Modified: 10 Jun 2021 05:36
URI: https://eprints.centenary.org.au/id/eprint/978

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