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


Abstract

Only a minority of heavy drinkers progress to alcohol-related cirrhosis (ALC). The aim of this study was to identify common genetic variants that underlie risk for ALC. 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. Genome-wide association study (GWAS) was performed, adjusting for principal components and clinical covariates (alcohol use, age, sex, BMI, 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 PNPLA3 (Odds Ratio (OR)=2.19 (G allele), p-value=4.93x10-17 ) and rs4607179 near HSD17B13 (OR=0.57 (C allele), p-value=1.09x10-10 ) with ALC. Conditional analysis accounting for the PNPLA3 and HSD17B13 loci identified a new protective association at rs374702773 in Fas Associated Factor family member 2 (FAF2) (OR=0.61 (del(T) allele), p-value=2.56x10-8 ) for ALC. This association was replicated in the UK Biobank using conditional analysis (OR=0.79, p-value=0.001). Meta-analysis (without conditioning) confirmed genome-wide significance for the newly identified FAF2 locus as well as PNPLA3 and HSD17B13. Two other previously known loci (SERPINA1, 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 new 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. Our genetic findings implicate lipid droplets in the biological pathway(s) underlying ALC.

Abstract

Only a minority of heavy drinkers progress to alcohol-related cirrhosis (ALC). The aim of this study was to identify common genetic variants that underlie risk for ALC. 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. Genome-wide association study (GWAS) was performed, adjusting for principal components and clinical covariates (alcohol use, age, sex, BMI, 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 PNPLA3 (Odds Ratio (OR)=2.19 (G allele), p-value=4.93x10-17 ) and rs4607179 near HSD17B13 (OR=0.57 (C allele), p-value=1.09x10-10 ) with ALC. Conditional analysis accounting for the PNPLA3 and HSD17B13 loci identified a new protective association at rs374702773 in Fas Associated Factor family member 2 (FAF2) (OR=0.61 (del(T) allele), p-value=2.56x10-8 ) for ALC. This association was replicated in the UK Biobank using conditional analysis (OR=0.79, p-value=0.001). Meta-analysis (without conditioning) confirmed genome-wide significance for the newly identified FAF2 locus as well as PNPLA3 and HSD17B13. Two other previously known loci (SERPINA1, 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 new 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. Our genetic findings implicate lipid droplets in the biological pathway(s) underlying ALC.

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Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Clinic for Gastroenterology and Hepatology
Dewey Decimal Classification:610 Medicine & health
Language:German
Date:27 August 2020
Deposited On:27 Oct 2020 16:01
Last Modified:27 Oct 2020 16:01
Publisher:Wiley-Blackwell Publishing, Inc.
ISSN:0270-9139
OA Status:Closed
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1002/hep.31535
PubMed ID:32853455

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