Genetic and epigenetic variants influencing the development of nonalcoholic fatty liver disease

Nonalcoholic fatty liver disease(NAFLD) is common worldwide.The importance of genetic and epigenetic changes in etiology and pathogenesis of NAFLD has been increasingly recognized.However,the exact mechanism is largely unknown.A large number of single nucleotide polymorphisms(SNPs) related to NAFLD has been documented by candidate gene studies(CGSs).Among these genes,peroxisome proliferatoractivated receptor-γ,adiponectin,leptin and tumor necrosis factor-α were frequently reported.Since the introduction of genome-wide association studies(GWASs),there have been significant advances in our understanding of genomic variations of NAFLD.Patatinlike phospholipase domain containing family member A3(PNPLA3,SNP rs738409,encoding I148M),also termed adiponutrin,has caught most attention.The evidence that PNPLA3 is associated with increased hepatic fat levels and hepatic inflammation has been validated by a series of studies.Epigenetic modification refers to phenotypic changes caused by an adaptive mechanism unrelated to alteration of primary DNA sequences.Epigenetic regulation mainly includes microRNAs(miRs),DNA methylation,histone modifications and ubiquitination,among which miRs are studied most extensively.miRs are small natural single stranded RNA molecules regulating mRNA degradation or translation inhibition,subsequently altering protein expression of target genes.The miR-122,a highly abundant miR accounting for nearly 70% of all miRs in the liver,is significantly under-expressed in NAFLD subjects.Inhibition of miR-122 with an antisense oligonucleotide results in decreased mRNA expression of lipogenic genes and improvement of liver steatosis.The investigation into epigenetic involvement in NAFLD pathogenesis is just at the beginning and needs to be refined.This review summarizes the roles of genetics and epigenetics in the development of NAFLD.The progress made in this field may provide novel diagnostic biomarkers and therapeutic targets for NAFLD management.

Nonalcoholic fatty liver disease （NAFLD） is common worldwide. The importance of genetic and epigen- eric changes in etiology and pathogenesis of NAFLD has been increasingly recognized. However, the ex- act mechanism is largely unknown. A large number of single nucleotide polymorphisms （SNPs） related to NAFLD has been documented by candidate gene studies （CGSs）. Among these genes, peroxisome pro- liferatoractivated receptor-γ, adiponectin, leptin and tumor necrosis factor-α were frequently reported. Since the introduction of genome-wide association studies （GWASs）, there have been significant advances in our understanding of genomic variations of NAFLD. Patatin- like phospholipase domain containing family member A3 （PNPLA3, SNP rs738409, encoding I148M）, also termed adiponutrin, has caught most attention. The evidence that PNPLA3 is associated with increased hepatic fat levels and hepatic inflammation has been validated by a series of studies. Epigenetic modification refers to phenotypic changes caused by an adaptive mechanism unrelated to alteration of primary DNA se- quences. Epigenetic regulation mainly includes microR- NAs （miRs）, DNA methylation, histone modifications and ubiquitination, among which miRs are studied most extensively, miRs are small natural single stranded RNA molecules regulating mRNA degradation or translation inhibition, subsequently altering protein expression of target genes. The miR-122, a highly abundant miR ac- counting for nearly 70% of all miRs in the liver, is sig- nificantly under-expressed in NAFLD subjects. Inhibition of miR-122 with an antisense oligonucleotide results in decreased mRNA expression of lipogenJc genes and improvement of liver steatosis. The investigation into epigenetic involvement in NAFLD pathogenesis is just at the beginning and needs to be refined. This review summarizes the roles of genetics and epigenetics in the development of NAFLD. The progress made in this field may provide novel diagnostic biomarkers and therapeu- tic targets for NAFLD management.