Metabolic dysfunction-associated fatty liver disease: Advances in genetic and epigenetic implications

Abstract

Purpose of reviewFatty liver associated with metabolic dysfunction, also known under the acronym NAFLD (nonalcoholic fatty liver disease) is the leading global cause of chronic liver disease. In this review, we address the state of research on genetics and epigenetics of NAFLD with focus on key discoveries and conceptual advances over the past 2 years.Recent findingsThe analysis of NAFLD-associated genetic variant effects on the whole-transcriptome, including quantitative trait loci (QTL) associated with gene expression (eQTL) or splicing (sQTL) may explain pleiotropic effects. Functional experiments on NAFLD-epigenetics, including profiling of liver chromatin accessibility quantitative trait loci (caQTL) show co-localization with numerous genome-wide association study signals linked to metabolic and cardiovascular traits. Novel studies provide insights into the modulation of the hepatic transcriptome and epigenome by tissue microbiotas. Genetic variation of components of the liver cellular respirasome may result in broad cellular and metabolic effects. Mitochondrial noncoding RNAs may regulate liver inflammation and fibrogenesis. RNA modifications as N6-methyladenosine may explain sex-specific differences in liver gene transcription linked to lipid traits.SummaryThe latest developments in the field of NAFLD-genomics can be leveraged for identifying novel disease mechanisms and therapeutic targets that may prevent the morbidity and mortality associated with disease progression.