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

Abstract

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.

• Authors: James J Beaudoin, Tiebing Liang, Qing Tang, Bubu A Banini, Vijay H Shah, Arun J Sanyal, Naga P Chalasani, Samer Gawrieh
• Journal: Alcoholism, clinical and experimental research (Alcohol Clin Exp Res) Vol. 45 Issue 4 Pg. 709-719 (04 2021) ISSN: 1530-0277 [Electronic] England
• PMID: 33616244 (Publication Type: Journal Article, Multicenter Study, Research Support, N.I.H., Extramural)
• Copyright: © 2021 by the Research Society on Alcoholism.

Chemical References

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

Topics

• 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, mortality)
• Humans
• Lipase (genetics)
• Male
• Membrane Proteins (genetics)
• Middle Aged
• Severity of Illness Index
• Virginia (epidemiology)