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Review
. 2024 Oct;18(Suppl 2):848-860.
doi: 10.1007/s12072-024-10667-5. Epub 2024 Apr 25.

The contribution of genetics and epigenetics to MAFLD susceptibility

Vittoria Moretti  1 , Stefano Romeo  2 , Luca Valenti  3   4
Affiliations
Review

The contribution of genetics and epigenetics to MAFLD susceptibility

Vittoria Moretti et al. Hepatol Int. 2024 Oct.

Abstract

Metabolic dysfunction-associated fatty liver disease (MAFLD) is the most common liver disease worldwide. The risk of developing MAFLD varies among individuals, due to a combination of environmental inherited and acquired genetic factors. Genome-wide association and next-generation sequencing studies are leading to the discovery of the common and rare genetic determinants of MAFLD. Thanks to the great advances in genomic technologies and bioinformatics analysis, genetic and epigenetic factors involved in the disease can be used to develop genetic risk scores specific for liver-related complications, which can improve risk stratification. Genetic and epigenetic factors lead to the identification of specific sub-phenotypes of MAFLD, and predict the individual response to a pharmacological therapy. Moreover, the variant transcripts and protein themselves represent new therapeutic targets. This review will discuss the current status of research into genetic as well as epigenetic modifiers of MAFLD development and progression.

Keywords: Epigenetic factors; GWAS; MAFLD; Next-generation sequencing; Therapeutic targets.

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Conflict of interest statement

Vittoria Moretti, Stefano Romeo, and Luca Valenti have no conflicts of interest to declare that are relevant to the content of this article.

Figures

Fig. 1
Fig. 1
Heterogeneous factors lead to MAFLD, including ethnicity, sex, dietary habits, genetic predisposition, age, gut microbiota, and metabolic status. MAFLD is present if hepatic steatosis occurs with either obesity or overweight (BMI > 25 kg/m2 in white and >23 kg/m2 in Asian individuals), type 2 diabetes mellitus or evidence of metabolic dysregulation. At least two metabolic risk factors should be present for definition of metabolic dysregulation: waist circumference ≥102/88 cm in white male and female or ≥90/80 cm in Asian male and female; prediabetes; inflammation with elevated high-sensitive serum C-reactive protein level; elevated blood pressure or specific drug treatment; decreased HDL-cholesterol levels; increased plasma triglycerides levels. Heterogeneous factors lead to MAFLD, including ethnicity, sex, dietary habits, genetic predisposition, age, gut microbiota, and metabolic status
Fig. 2
Fig. 2
Genomic approaches to investigate MAFLD genetic determinants: GWAS to discovery the main common genetic variants; biological and pathways analysis to provide details regarding GWAS-prioritized tissues, and genes; PheWAS of MAFLD-risk-increasing alleles to identify distinct biological subgroupings; Mendelian randomization (MR) to estimate variant-MAFLD casual effect; PRS to stratify MAFLD risk in individuals with metabolic disorders; NGS techniques to identify rare variants involved in disease progression
Fig. 3
Fig. 3
Genetic determinants of MAFLD, classified according to the biological processes by which the encoded proteins are thought to contribute to the pathogenesis. Red arrows indicate pathological processes/lipid fluxes, whereas green arrows indicate beneficial pathways. Pathophysiological processes are indicated in red, while genes, and cellular and liver compartments in black
Fig. 4
Fig. 4
Genomic studies to develop new MAFLD therapeutics and precision medicine approach
See this image and copyright information in PMC

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