Genetic Modifiers of Liver Injury in Hereditary Liver Disease

Abstract

The genetic background of patients with liver diseases modulates hepatic injury, with some individuals being predisposed to better defenses and regenerative capacity. In this review, we focus our description of this phenomenon on inherited disorders affecting the liver, with a particular emphasis on Wilson disease (WD), genetic hemochromatosis, and α-1 anti-trypsin disease (A1-AT). Wide variations in the clinical phenotype of WD may in part be related to the mutations of the ATP7B genotype, though modifier genes and environmental factors also likely play an important role. There is also a significant variability in the expression of iron overload in patients with genetic hemochromatosis that are homozygous for the C282Y mutation. Homozygosity for the A1-ATZ mutation is generally required for the development of liver disease in A1-AT although there is increasing evidence for modifier effects from a heterozygous genotype in other liver diseases.

Whole‐exome sequencing identifies novel pathogenic variants across the ATP7B gene and some modifiers of Wilson's disease phenotype

“…No allelic variant in genes previously reported as associating with WD phenotype ( COMMD1, ATOX1, XIAP, APOE, DMT1 (SLC11A2), ATP7A, MTHFR and PRNP ) presented a statistically significant difference (at a nominal p‐value of 0.05) in allele frequency in the comparison between hepatological and neurological manifestations.…”

“…Although the variation in the WD phenotype may relate to the ATP7B genotype, high genetic heterogeneity and the disease rarity cause difficulties in assessing a relationship between WD genotypes and phenotypes . In addition, the clinical effects of disease‐causing ATP7B mutations can be modified by gene‐gene and gene‐environmental interactions.…”

A Next Generation Multiscale View of Inborn Errors of Metabolism

“…Examples of diseases where modifiers have been successfully identified include the more common monogenetic diseases such as cystic fibrosis (Cutting, 2010; Gallati, 2014), sickle cell anemia (Lettre, 2012), thalassemias (Lettre, 2012) and most recently Huntington disease (Becanovic et al, 2015; Consortium, 2015b), which have incidences between 1:2,000 and 1:10,000. There are relatively fewer success stories in IEM, many of which have been by identified using candidate gene approaches such as in Smith-Lemli-Opitz syndrome (Lanthaler et al, 2013), inherited hemochromatosis (Ala and Schilsky, 2011) and GD (Alfonso et al, 2013; Lo et al, 2012; Mistry et al, 2002). Inherent challenges exist in successfully applying association or linkage approaches to genetic modifier discovery in IEM.…”

Chronic hepatitis in man and in dog: a comparative update

“…ATP7B transports excess copper across the hepatocyte apical membrane into bile canalicula for subsequent biliary excretion. Mutation in the ATP7B gene occurring in Wilson's disease, results in defective ATP7B protein that cannot perform these functions (48). The consequent progressive copper accumulation ultimately compromise hepatic function; when the hepatic storage capacity is 206 exceeded, unbound copper spills out of the liver and is deposited in other organs and tissues, where it also provokes damage and dysfunction.…”