Genetics of alcoholic liver disease and non-alcoholic steatohepatitis

Abstract

The factors that mediate disease progression in both ARLD and NAFLD have been shown to involve a complex interplay between environmental risk factors (eg sustained high levels of alcohol consumption or a sedentary lifestyle and poor diet, features of the metabolic syndrome) and genetic risk factors. To date, this interplay and all the factors involved are incompletely understood.

Genome-Wide Association Study for Alcohol-Related Cirrhosis Identifies Risk Loci in MARC1 and HNRNPUL1

“…37 To that end, we examined how good this score performed at predicting first-time hospitalization for cirrhosis among UKB participants with risk factors for NAFLD, a disease that shows great overlap and multiple similarities (including the underlying host genetics) with alcohol-related liver disease. 54 Although individuals with a risk score in the top quintile had more than 3 times the risk of cirrhosis vs individuals in the lowest quintile, the C statistic indicated that by itself, this score is unlikely to offer adequate discrimination for effective clinical decision making. Further validation in an independent population of heavy drinkers is clearly warranted.…”

Parental non‐alcoholic fatty liver disease increases risk of non‐alcoholic fatty liver disease in offspring

“…However, the GRS did not fully explain the heritability of NAFLD and additional genes may also contribute to NAFLD genetic risk. A variant in the locus for the membrane bound O‐acyltransferase domain‐containing 7 gene ( MBOAT7 or LPIAT1) was recently associated with increased liver fat in alcoholic and non‐alcoholic fatty liver disease, though its role in NAFLD is not yet completely understood . The transmembrane 6 superfamily 2 ( TM6SF2) gene has also been associated with NAFLD in multiple studies though it did not reach the genome‐wide significant threshold in the GWAS study used to create the GRS .…”

“…A variant in the locus for the membrane bound O-acyltransferase domain-containing 7 gene (MBOAT7 or LPIAT1) was recently associated with increased liver fat in alcoholic and non-alcoholic fatty liver disease, 27 though its role in NAFLD is not yet completely understood. 28 The transmembrane 6 superfamily 2 (TM6SF2) gene has also been associated with NAFLD in multiple studies [29][30][31] though it did not reach the genome-wide significant threshold in the GWAS study used to create the GRS. 8 Additional genes, including rare variants, which have yet to be identified, may add to our understanding of NAFLD genetics.…”

Improvements in Histologic Features and Diagnosis Associated With Improvement in Fibrosis in Nonalcoholic Steatohepatitis: Results From the Nonalcoholic Steatohepatitis Clinical Research Network Treatment Trials

“…The only other baseline clinical feature that differentiated improvers versus nonimprovers was enrichment of GG homozygosity for PNPLA3 Rs738409 in nonimprovers in PIVENS; no PNPLA3 information was available for FLINT subjects. This single‐nucleotide polymorphism has been associated with development of steatosis, inflammation, and fibrosis in NAFLD …”