Vulnerability to alcohol‐associated liver disease: A tale of two systems

Genomewide association studies (GWAS) have contributed to a better understanding of the genetic determinants as well as the individual trajectories of chronic liver diseases, including alcoholassociated liver disease (AALD). Ethnic differences and twin studies provided first evidence for the role of genetic risk factors in alcoholuse disorders, with heritability as high as 50% in metaanalyses. [1] In addition to the robust association of alcohol dehydrogenase 1B and aldehyde dehydrogenase 2 family member enzyme variants, multiple additional genes might modulate alcoholuse disorder in European, African, and Asian populations. [2] The twin studies also highlighted that the risk genes for alcoholism are independent of those underlying the genetic predisposition for organspecific complications of alcohol abuse. In 2015, the results of the first GWAS in AALD in European populations were published, confirming a patatinlike phospholipase domaincontaining protein 3 (PNPLA3) variant, p.I148M, as an important risk locus for cirrhosis. [3] Genotype frequency varies between ethnic groups, approaching 50% in many populations worldwide. [4] Mutant PNPLA3 sequesters the coactivator, comparative gene identification 58, of the major triacylglycerol lipase, adipose triglyceride lipase, which results in decreased lipolysis, that is, it represents a “lossoffunction” variant. Of note, this mechanism drives the full spectrum of fatty liver diseases, ranging from fatty liver to steatohepatitis, progressive fibrosis, cirrhosis, and HCC. [5] In this issue of Hepatology, Kim et al.[6] used the KoGES (Korean Genome and Epidemiology Study) Health Examination cohort, comprising 40to 79yearold Korean persons from an urban area who were recruited from a national health examinee registry and genotyped by the National Biobank of Korea. [7] Based on questionnaires of 21,919 participants, they identified 782 (4.1%), 1,379 (9.5%), and 1,185 (34.5%) patients who presented with gammaglutamyl transferase (GGT)/alanine aminotransferase >2.5 or aspartate aminotransferase/ALT > 3.0 (used as indicators of AALD) without an overt drinking history or with a history of consuming less or more than 140 g (women) and 210 g (men) of alcohol per week, respectively. As is to be expected based on the AALD definition used by the researchers and the corresponding patient characteristics, the gene encoding GGT was associated with the phenotype in all groups. In addition, the researchers observed susceptible and protective genetic associations: An intronic variant of zinc finger protein 827 (ZNF827) was associated with increased risk (+30%) of AALD in “light drinkers” (LDs; <140 or 210 g of alcohol per week in women and men, respectively) as well as nondrinkers. Hepatocyte nuclear factor 1A (HNF1A) was associated with AALD risk, with the minor allele of singlenucleotide polymorphism rs1183910 showing a protective association from AALD in the LD group, but not in patients with higher alcohol consumption. HNF1A is known to regulate acutephase reactants, and HNF1A mutations underlie maturityonset diabetes of the young type 3. Of note, the researchers performed a replication test in a second KoGES cohort, which showed similar, albeit smaller and less significant, effects. The study by Kim et al.[6] highlights that genetic susceptibility to AALD is multifactorial and suggests that genetic vulnerability is modulated by the quantity of alcohol consumed. The observations are consistent with metaanalyses[8] reporting that alcohol consumption amplifies the genetic risk driven by PNPLA3. In fact, the study failed to replicate not only the association between AALD and PNPLA3 (in spite of the highrisk allele frequency in Korea),[4] but also the associations with transmembrane 6 superfamily member 2, membrane bound Oacyltransferase domaincontaining 7, or 17β hydroxysteroid dehydrogenase 13 variants (affecting hepatic VLDL secretion and phosphatidylinositol and retinol metabolism, respectively), which have been reported to be associated with AALD in other populations. [4] In the same line of thought, no associations with mitochondrial amidoximereducing component 1 or alpha1antitrypsin variants were observed in the Korean cohort either. Received: 12 December 2021 | Accepted: 12 December 2021