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  • Review Article
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The genetics of NAFLD

Abstract

NAFLD is a disease spectrum ranging from simple steatosis, through steatohepatitis to fibrosis and, ultimately, cirrhosis. This condition is characterized by considerable interpatient variability in terms of severity and rate of progression: although a substantial proportion of the population is at risk of progressive disease, only a minority experience associated morbidity. As such, NAFLD is best considered a complex disease trait resulting from environmental exposures acting on a susceptible polygenic background and comprising multiple independent modifiers. Much ongoing research is focused on identifying the genetic factors that contribute to NAFLD pathogenesis. This Review describes the current status of the field, discussing specific genetic and epigenetic modifiers, including the mechanisms through which genes identified by genome-wide association studies, including PNPLA3, influence disease progression.

Key Points

  • NAFLD is a spectrum of progressive liver disease encompassing steatosis, NASH, fibrosis and cirrhosis

  • NAFLD is a common and underdiagnosed condition that is strongly associated with features of the metabolic syndrome, particularly abdominal obesity and type 2 diabetes mellitus

  • Considerable interindividual variation exists in terms of NAFLD severity and risk of morbidity and mortality that might be influenced by a combination of genetic and environmental factors

  • Candidate-gene studies and hypothesis-generating genome-wide association studies have provided key insights into the pathogenesis of NAFLD, with multiple genetic modifiers being described

  • PNPLA3 remains the most well-validated gene associated with all aspects of the NAFLD spectrum

  • Although considerable progress has been made in elucidating how the PNPLA3 rs738409 (encoding Ile148Met) variant promotes NAFLD, it remains unclear why this gene also associates so strongly with inflammatory and fibrosis

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Figure 1: Commonality between the largest GWAS in NAFLD.

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Acknowledgements

Q. M. Anstee is the recipient of a Clinical Senior Lectureship Award from the Higher Education Funding Council for England (HEFCE). Q. M. Anstee and C. P. Day are members of the FLIP (Fatty Liver Inhibition of Progression) research consortium funded by the EU Seventh Framework Programme (FP7/2007-2013) under grant agreement Health-F2-2009-24762 and the UK GoLD (Genetics of Liver Disease) consortium.

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Q. M. Anstee and C. P. Day both devised, wrote, reviewed and approved the completed manuscript.

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Correspondence to Quentin M. Anstee.

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Supplementary Table 1

Summary of genetic modifiers of NAFLD (DOC 57 kb)

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Anstee, Q., Day, C. The genetics of NAFLD. Nat Rev Gastroenterol Hepatol 10, 645–655 (2013). https://doi.org/10.1038/nrgastro.2013.182

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