Genome-Wide Association Study for Alcohol-Related Cirrhosis Identifies Risk Loci in MARC1 and HNRNPUL1.
Gastroenterology
; 159(4): 1276-1289.e7, 2020 10.
Article
em En
| MEDLINE
| ID: mdl-32561361
ABSTRACT
BACKGROUND AND AIMS:
Little is known about genetic factors that affect development of alcohol-related cirrhosis. We performed a genome-wide association study (GWAS) of samples from the United Kingdom Biobank (UKB) to identify polymorphisms associated with risk of alcohol-related liver disease.METHODS:
We performed a GWAS of 35,839 participants in the UKB with high intake of alcohol against markers of hepatic fibrosis (FIB-4, APRI, and Forns index scores) and hepatocellular injury (levels of aminotransferases). Loci identified in the discovery analysis were tested for their association with alcohol-related cirrhosis in 3 separate European cohorts (phase 1 validation cohort; n=2545). Variants associated with alcohol-related cirrhosis in the validation at a false discovery rate of less than 20% were then directly genotyped in 2 additional European validation cohorts (phase 2 validation, n=2068).RESULTS:
In the GWAS of the discovery cohort, we identified 50 independent risk loci with genome-wide significance (P < 5 × 10-8). Nine of these loci were significantly associated with alcohol-related cirrhosis in the phase 1 validation cohort; 6 of these 9 loci were significantly associated with alcohol-related cirrhosis in phase 2 validation cohort, at a false discovery rate below 5%. The loci included variants in the mitochondrial amidoxime reducing component 1 gene (MARC1) and the heterogeneous nuclear ribonucleoprotein U like 1 gene (HNRNPUL1). After we adjusted for age, sex, body mass index, and type-2 diabetes in the phase 2 validation cohort, the minor A allele of MARC1rs2642438 was associated with reduced risk of alcohol-related cirrhosis (adjusted odds ratio, 0.76; P=.0027); conversely, the minor C allele of HNRNPUL1rs15052 was associated with an increased risk of alcohol-related cirrhosis (adjusted odds ratio, 1.30; P=.020).CONCLUSIONS:
In a GWAS of samples from the UKB, we identified and validated (in 5 European cohorts) single-nucleotide polymorphisms that affect risk of alcohol-related cirrhosis in opposite directions the minor A allele in MARC1rs2642438 decreases risk, whereas the minor C allele in HNRNPUL1rs15052 increases risk.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Oxirredutases
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Fatores de Transcrição
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Proteínas Nucleares
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Polimorfismo de Nucleotídeo Único
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Proteínas Mitocondriais
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Ribonucleoproteínas Nucleares Heterogêneas
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Loci Gênicos
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Cirrose Hepática Alcoólica
Tipo de estudo:
Clinical_trials
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Diagnostic_studies
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Etiology_studies
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Prognostic_studies
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Risk_factors_studies
Limite:
Adult
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Aged
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Female
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Humans
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Male
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Middle aged
País/Região como assunto:
Europa
Idioma:
En
Ano de publicação:
2020
Tipo de documento:
Article