Genetic predisposition in nonalcoholic fatty liver disease

Abstract

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease whose prevalence has reached global epidemic proportions. Although the disease is relatively benign in the early stages, when severe clinical forms, including nonalcoholic steatohepatitis (NASH), cirrhosis and even hepatocellular carcinoma, occur, they result in worsening the long-term prognosis. A growing body of evidence indicates that NAFLD develops from a complex process in which many factors, including genetic susceptibility and environmental insults, are involved. In this review, we focused on the genetic component of NAFLD, with special emphasis on the role of genetics in the disease pathogenesis and natural history. Insights into the topic of the genetic susceptibility in lean individuals with NAFLD and the potential use of genetic tests in identifying individuals at risk are also discussed.

Keywords: NASH; PNPLA3; TM6SF2; alcoholic liver disease; gene variants.

Figure 1.

NAFLD, is a polygenic and heritable disease. Picture summarizes different approaches that have been used to date to explore the genetic component of NAFLD. Familial aggregation studies are typically conducted in order to identify the genetic component of complex diseases; the goal of this strategy is to assess clustering of the disease within families. Twin genetic studies have also contributed to the knowledge of the genetic susceptibility of complex diseases; large twin registries are highly beneficial resources for comparing the genetic risk of a disease between monozygotic and dizygotic twins. GWAS and EWAS, which include a global survey of sequence variants across the entire genome or variants in the coding regions, respectively, have shed light onto the genetic component of NAFLD, as well as other complex diseases in the last decade. Candidate gene association studies are focused on loci selected on the basis of their known or presumed function or on their biological plausibility in the disease pathophysiology. Finally, functional and experimental studies aim to provide mechanistic insights into the role of a variant or locus of interest in the explored phenotype. NAFLD, nonalcoholic fatty liver disease; GWAS, genome-wide association study; EWAS, exome-wide association study.

Figure 2.

Heritability estimates of NAFLD. Picture summarizes results of studies that estimated the heritability of NAFLD. NAFLD, nonalcoholic fatty liver disease; MRI-PDFF, magnetic resonance imaging−proton-density fat fraction; MRE, magnetic resonance elastography; Liver US, liver ultrasound.

Figure 3.

Knowledge gained on the role of common variants in the genetic risk of NAFLD and the missing heritability. Figure illustrates milestones in the knowledge of NAFLD, including the genetic component of the disease. In early 1950, the description of cirrhosis in patients with type 2 diabetes not only provided the first clinical characterization of NAFLD as a disease in which hepatomegaly was primarily explained by fatty infiltration but also introduced the notion of the natural history of the disease, implying that fatty liver can develop into an end-stage outcome. In 1999, Elizabeth Brunt and colleagues provided a thorough characterization of the histological phenotype underpinning future studies on the role of inflammation, ballooning degeneration and fibrosis in the disease biology. The result of the first NAFLD-GWAS was a major breakthrough, as the rs738409 was identified as the largest ever replicated variant in the history of hepatology that not only explains the genetic component of NAFLD but other liver diseases as well, including chronic viral hepatitis and HCC [76]. The picture finally illustrates areas in which knowledge of the genetic component of NAFLD is insufficient or absent, also referred as “missing heritability”, including the role of rare variants, structural variation, and interactions between genes and environment. T2D, type 2 diabetes; NASH, nonalcoholic steatohepatitis; PNPLA3, patatin-like phospholipase domain containing 3; GCKR, glucokinase gene regulator; TM6SF2, transmembrane 6 superfamily member 2; OR, odds ratio; MAF, minor allele frequency; G_XG, gene by gene interaction; G_XE, gene by environment interaction; mtDNA, mitochondrial DNA. # The association of Laennec's cirrhosis with diabetes mellitus [61]. *Scoring systems described by Brunt et al (1999) [62]