Multi-omics methods in developing biomarkers of MASLD: Genomics and transcriptomics
TL;DR
Genomic and transcriptomic biomarkers represent important factors in the pathogenic processes of MASLD and offer promise as a non-invasive alternative to liver biopsy for disease diagnosis, staging, and longitudinal monitoring.
Abstract
The multifactorial nature of metabolic dysfunction–associated steatotic liver disease (MASLD) reflects the interplay of genetic susceptibility, epigenetic regulation, and environmental influences. Genetic and epigenetic biomarkers are therefore valuable for early diagnosis, risk stratification, and monitoring progression from steatosis to more advanced disease stages. Several genetic variants have been significantly associated with MASLD. Among these, polymorphisms in the patatin-like phospholipase domain-containing 3 (PNPLA3), transmembrane 6 superfamily member 2 (TM6SF2), and membrane-bound O-acyltransferase domain-containing 7 (MBOAT7) genes are the most extensively studied. These variants influence hepatic lipid metabolism, triglyceride accumulation, and inflammatory responses. Epigenetic mechanisms, particularly microribonucleic acids (miRNA, miR), play a critical role in post-transcriptional gene regulation and disease progression. Among these, miR-122 is the most abundant liver-specific miRNA. It is upregulated in early steatosis but declines during the transition to steatohepatitis and fibrosis, suggesting a stage-dependent regulatory function. Along with miR-21, miR-34a promotes triglyceride accumulation in hepatocytes during early disease stages and contributes to the activation of inflammatory and fibrotic pathways as MASLD advances. Inhibition of miR-192, a negative regulator of hepatic lipid metabolism, increases the expression of enzymes involved in monounsaturated fatty acid synthesis, thereby promoting triglyceride accumulation. miR-155 activates signalling pathways that enhance hepatic cholesterol and triglyceride synthesis, while miR-375 upregulates genes associated with triglyceride synthesis and lipid droplet formation. Genomic and transcriptomic biomarkers represent important factors in the pathogenic processes of MASLD. Their combined assessment offers promise as a non-invasive alternative to liver biopsy for disease diagnosis, staging, and longitudinal monitoring.