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Multicenter Study
. 2021 Apr;45(4):709-719.
doi: 10.1111/acer.14581. Epub 2021 Apr 20.

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

James J Beaudoin  1 , Tiebing Liang  2 , Qing Tang  3 , Bubu A Banini  4 , Vijay H Shah  5 , Arun J Sanyal  4 , Naga P Chalasani  2 , Samer Gawrieh  2
Affiliations
Multicenter Study

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

James J Beaudoin et al. Alcohol Clin Exp Res. 2021 Apr.

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.

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

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Figures

Figure 1.
Figure 1.. Allele frequencies (A, C, E, G, I) and genotype distributions (B, D, F, H, J) of rs738409 (PNPLA3), rs72613567 (HSD17B13), rs58542926 (TM6SF2), rs641738 (MBOAT7) and HP in patients with AH (n = 211) and heavy drinking controls (n = 176).
Chi-squared tests were performed to derive P-values. AH, alcoholic hepatitis; HP, haptoglobin; HSD17B13, hydroxysteroid 17-beta dehydrogenase 13; MBOAT7, membrane bound O-acyltransferase domain containing 7; N.D., not determined; PNPLA3: patatin-like phospholipase domain-containing protein 3; TM6SF2, transmembrane 6 superfamily member 2.
Figure 2.
Figure 2.. Relationship between PNPLA3 rs738409 genotype and risk of AH among heavy drinkers with each HSD17B13 rs72613567 genotype.
The y-axis represents the ratio of AH cases to controls for each of the nine PNPLA3 rs738409 and HSD17B13 rs72613567 combined genotypes. The presented P-value corresponds to the interaction term between PNPLA3 rs738409 and HSD17B13 rs72613567 in a logistic regression model (Table 2, multivariate model VII). Vertical bars indicate 95% confidence intervals. AH, alcoholic hepatitis; HSD17B13, hydroxysteroid 17-beta dehydrogenase 13, PNPLA3: patatin-like phospholipase domain-containing protein 3.
See this image and copyright information in PMC

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