Role of candidate gene variants in modulating the risk and severity of alcoholic hepatitis

Alcohol Clin Exp Res. 2021 Apr;45(4):709-719. doi: 10.1111/acer.14581. Epub 2021 Apr 20.


Background: Alcoholic hepatitis (AH) is a severe and life-threatening alcohol-associated liver disease. Only a minority of heavy drinkers acquires AH and severity varies among affected individuals, suggesting a genetic basis for the susceptibility to and severity of AH.

Methods: A cohort consisting of 211 patients with AH and 176 heavy drinking controls was genotyped for five variants in five candidate genes that have been associated with chronic liver diseases: rs738409 in patatin-like phospholipase domain-containing protein 3 (PNPLA3), rs72613567 in hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13), rs58542926 in transmembrane 6 superfamily member 2 (TM6SF2), rs641738 in membrane bound O-acyltransferase domain containing 7 (MBOAT7), and a copy number variant in the haptoglobin (HP) gene. We tested the effects of individual variants and the combined/interacting effects of variants on AH risk and severity.

Results: We found significant associations between AH risk and the risk alleles of rs738409 (p = 0.0081) and HP (p = 0.0371), but not rs72613567 (p = 0.3132), rs58542926 (p = 0.2180), or rs641738 (p = 0.7630), after adjusting for patient's age and sex. A multiple regression model indicated that PNPLA3 rs738409:G [OR = 1.59 (95% CI: 1.15-2.22), p = 0.0055] and HP*2 [OR = 1.38 (95% CI: 1.04-1.82), p = 0.0245], when combined and adjusted for age and sex also had a large influence on AH risk among heavy drinkers. In the entire cohort, variants in PNPLA3 and HP were associated with increased total bilirubin and Model for End-stage Liver Disease (MELD) score, both measures of AH severity. The HSD17B13 rs72613567:AA allele was not found to reduce risk of AH in patients carrying the G allele of PNPLA3 rs738409 (p = 0.0921).

Conclusion: PNPLA3 and HP genetic variants increase AH risk and are associated with total bilirubin and MELD score, surrogates of AH severity.

Keywords: HSD17B13; PNPLA3; alcoholic liver disease; genetic risk; haptoglobin.

Publication types

  • Multicenter Study
  • Research Support, N.I.H., Extramural

MeSH terms

  • 17-Hydroxysteroid Dehydrogenases / genetics*
  • Acyltransferases / genetics*
  • Adult
  • Case-Control Studies
  • Cohort Studies
  • Female
  • Gene Frequency
  • Genetic Predisposition to Disease
  • Great Lakes Region / epidemiology
  • Haptoglobins / genetics*
  • Hepatitis, Alcoholic / genetics*
  • Hepatitis, Alcoholic / mortality
  • Humans
  • Lipase / genetics*
  • Male
  • Membrane Proteins / genetics*
  • Middle Aged
  • Severity of Illness Index
  • Virginia / epidemiology


  • HP protein, human
  • Haptoglobins
  • Membrane Proteins
  • TM6SF2 protein, human
  • 17-Hydroxysteroid Dehydrogenases
  • HSD17B13 protein, human
  • Acyltransferases
  • MBOAT7 protein, human
  • Lipase
  • adiponutrin, human