THE GLOBAL rise in obesity has paralleled an alarming increase in steatotic liver disease (SLD), a spectrum of conditions marked by excessive lipid accumulation, particularly triglycerides, within the liver. These lipids can trigger inflammation, fibrosis, and in severe cases, progress to cirrhosis or liver cancer. A significant subset of SLD, metabolic dysfunction-associated steatotic liver disease (MASLD), is closely tied to metabolic issues like visceral fat, insulin resistance, and hypertension, heightening risks for cardiovascular and kidney diseases. Intriguingly, while cardiovascular disease is the leading cause of death in MASLD patients, some individuals exhibit rapid liver disease progression even with minimal metabolic derangement.
Genetics play a pivotal role in MASLD as variants impairing hepatocyte lipid metabolism can drive MASLD progression but paradoxically offer protection against cardiovascular disease. Over the past 15 years, genome-wide association studies (GWAS) have identified several genetic loci linked to liver triglyceride content. However, traditional adjustments for body mass index (BMI) in these studies often fail to account for visceral adiposity, a key contributor to insulin resistance. Advanced measures like visceral fat volume and bioelectrical impedance analysis are proving more effective in refining GWAS precision.
Recent research highlights the discovery of 17 novel loci associated with liver triglycerides and 9 linked to liver inflammation, emphasising the complex interplay between genetic predisposition and adiposity. This work also identifies two distinct MASLD subtypes: a liver-specific form and one integrated with systemic cardiometabolic dysfunction. These findings underscore the need for tailored treatments targeting these distinct pathways.
Partitioned polygenic risk scores (pPRSs) derived from genetic variants further illuminate MASLD’s heterogeneity. A discordant pPRS correlates with liver-specific disease but reduced cardiovascular risk, while a concordant score predicts broader cardiometabolic disease. Such nuanced genetic insights pave the way for precision medicine, promising targeted interventions for MASLD and associated conditions.
While these findings advance our understanding, they are limited by a European-focused dataset and require functional validation. Future research must expand to diverse populations to unlock MASLD’s full genetic and clinical complexity, ultimately guiding effective therapies.
Katie Wright, EMJ
Reference
Jamialahmadi O et al. Partitioned polygenic risk scores identify distinct types of metabolic dysfunction-associated steatotic liver disease. Nat Med. 2024;DOI:10.1038/s41591-024-03284-0.
