An exploratory genome-wide analysis of genetic risk for alcoholic hepatitis

James J. Beaudoin, Nanye Long, Suthat Liangpunsakul, Puneet Puri, Patrick S. Kamath, Vijay Shah, Arun J. Sanyal, David Crabb, Naga Chalasani, Thomas J. Urban

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Objectives: To elucidate the genetic variability between heavy drinkers with and without alcoholic hepatitis (AH). Materials and methods: An exploratory genome-wide association study (GWAS; NCT02172898) was conducted comparing 90 AH cases with 93 heavy drinking matched controls without liver disease in order to identify variants or genes associated with risk for AH. Individuals were genotyped using the multi-ethnic genotyping array, after which the data underwent conventional quality control. Using bioinformatics tools, pathways associated with AH were explored on the basis of individual variants, and based on genes with a higher ’burden’ of functional variation. Results: Although no single variant reached genome-wide significance, an association signal was observed for PNPLA3 rs738409 (p = .01, OR 1.9, 95% CI 1.1–3.1), a common single nucleotide polymorphism that has been associated with a variety of liver-related pathologies including alcoholic cirrhosis. Using the improved gene set enrichment analysis for GWAS tool, it was shown that, based on the single variants’ trait-association p-values, multiple pathways were associated with risk for AH with high confidence (false discovery rate [FDR] < 0.05), including several pathways involved in lymphocyte activation and chemokine signaling, which coincides with findings from other research groups. Several Tox Functions and Canonical Pathways were highlighted using Ingenuity Pathway Analysis, with an especially conspicuous role for pathways related to ethanol degradation, which is not surprising considering the phenotype of the genotyped individuals. Conclusion: This preliminary analysis suggests a role for PNPLA3 variation and several gene sets/pathways that may influence risk for AH among heavy drinkers.

Original languageEnglish (US)
Pages (from-to)1-7
Number of pages7
JournalScandinavian Journal of Gastroenterology
DOIs
StateAccepted/In press - Aug 3 2017

Fingerprint

Alcoholic Hepatitis
Genome
Genome-Wide Association Study
Genes
Alcoholic Liver Cirrhosis
Lymphocyte Activation
Computational Biology
Chemokines
Quality Control
Drinking
Single Nucleotide Polymorphism
Liver Diseases
Ethanol
Pathology
Phenotype
Liver
Research

Keywords

  • Alcoholic hepatitis
  • genetic risk
  • genome-wide association study
  • pathway enrichment
  • single nucleotide polymorphism

ASJC Scopus subject areas

  • Medicine(all)
  • Gastroenterology

Cite this

An exploratory genome-wide analysis of genetic risk for alcoholic hepatitis. / Beaudoin, James J.; Long, Nanye; Liangpunsakul, Suthat; Puri, Puneet; Kamath, Patrick S.; Shah, Vijay; Sanyal, Arun J.; Crabb, David; Chalasani, Naga; Urban, Thomas J.

In: Scandinavian Journal of Gastroenterology, 03.08.2017, p. 1-7.

Research output: Contribution to journalArticle

Beaudoin, James J. ; Long, Nanye ; Liangpunsakul, Suthat ; Puri, Puneet ; Kamath, Patrick S. ; Shah, Vijay ; Sanyal, Arun J. ; Crabb, David ; Chalasani, Naga ; Urban, Thomas J. / An exploratory genome-wide analysis of genetic risk for alcoholic hepatitis. In: Scandinavian Journal of Gastroenterology. 2017 ; pp. 1-7.
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