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Abstract
Non-alcoholic fatty liver disease (NAFLD) is now recognised as the most common liver
disease worldwide. It encompasses a broad spectrum of conditions, from simple steatosis,
through non-alcoholic steatohepatitis, to fibrosis and ultimately cirrhosis and hepatocellular
carcinoma. A hallmark of NAFLD is the substantial inter-patient variation in disease
progression. NAFLD is considered a complex disease trait such that interactions between
the environment and a susceptible polygenic host background determine disease phenotype
and influence progression. Recent years have witnessed multiple genome-wide association
and large candidate gene studies, which have enriched our understanding of the genetic
basis of NAFLD. Notably, the I148M PNPLA3 variant has been identified as the major
common genetic determinant of NAFLD. Variants with moderate effect size in TM6SF2,
MBOAT7 and GCKR have also been shown to have a significant contribution. The premise
for this review is to discuss the status of research into important genetic and epigenetic
modifiers of NAFLD progression. The potential to translate the accumulating wealth
of genetic data into the design of novel therapeutics and the clinical implementation
of diagnostic/prognostic biomarkers will be explored. Finally, personalised medicine
and the opportunities for future research and challenges in the immediate post genetics
era will be illustrated and discussed.