Gene Variants Implicated in Steatotic Liver Disease: Opportunities for Diagnostics and Therapeutics

Gary Huang; Daniel F Wallace; Elizabeth E Powell; Tony Rahman; Paul J Clark; V Nathan Subramaniam

doi:10.3390/biomedicines11102809

Gene Variants Implicated in Steatotic Liver Disease: Opportunities for Diagnostics and Therapeutics

Biomedicines. 2023 Oct 17;11(10):2809. doi: 10.3390/biomedicines11102809.

Authors

Gary Huang^{1

2

3}, Daniel F Wallace^{2

3

4}, Elizabeth E Powell^{5

6

7}, Tony Rahman⁸, Paul J Clark⁹, V Nathan Subramaniam^{1

2

3}

Affiliations

¹ Hepatogenomics Research Group, Queensland University of Technology (QUT), Brisbane, QLD 4059, Australia.
² Centre for Genomics and Personalised Health, Queensland University of Technology (QUT), Brisbane, QLD 4059, Australia.
³ School of Biomedical Sciences, Queensland University of Technology (QUT), Brisbane, QLD 4059, Australia.
⁴ Metallogenomics Laboratory, Queensland University of Technology (QUT), Brisbane, QLD 4059, Australia.
⁵ QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia.
⁶ Department of Gastroenterology and Hepatology, Princess Alexandra Hospital, Brisbane, QLD 4102, Australia.
⁷ Centre for Liver Disease Research, Translational Research Institute, Faculty of Medicine, The University of Queensland, Brisbane, QLD 4101, Australia.
⁸ Department of Gastroenterology and Hepatology, Prince Charles Hospital, Brisbane, QLD 4032, Australia.
⁹ Mater Adult Hospital, Faculty of Medicine, The University of Queensland, Brisbane, QLD 4101, Australia.

Abstract

Non-alcoholic fatty liver disease (NAFLD) describes a steatotic (or fatty) liver occurring as a consequence of a combination of metabolic, environmental, and genetic factors, in the absence of significant alcohol consumption and other liver diseases. NAFLD is a spectrum of conditions. Steatosis in the absence of inflammation is relatively benign, but the disease can progress into more severe forms like non-alcoholic steatohepatitis (NASH), liver cirrhosis, and hepatocellular carcinoma. NAFLD onset and progression are complex, as it is affected by many risk factors. The interaction between genetic predisposition and other factors partially explains the large variability of NAFLD phenotype and natural history. Numerous genes and variants have been identified through large-scale genome-wide association studies (GWAS) that are associated with NAFLD and one or more subtypes of the disease. Among them, the largest effect size and most consistent association have been patatin-like phospholipase domain-containing protein 3 (PNPLA3), transmembrane 6 superfamily member 2 (TM6SF2), and membrane-bound O-acyltransferase domain containing 7 (MBOAT7) genes. Extensive in vitro and in vivo studies have been conducted on these variants to validate these associations. The focus of this review is to highlight the genetics underpinning the molecular mechanisms driving the onset and progression of NAFLD and how they could potentially be used to improve genetic-based diagnostic testing of the disease and develop personalized, targeted therapeutics.

Keywords: MASH; MASLD; NAFLD; NASH; genetics; lipid metabolism; steatotic liver disease; variants.

Publication types

Review

Grants and funding

G.H. is a recipient of the QUT Postgraduate Scholarship Award. V.N.S. is the recipient of an NHMRC Senior Research Fellowship (GNT1118888). This work was supported in part by a grant from the Centre for Genomics and Personalised Health, Queensland University of Technology (QUT) to G.H. and V.N.S.