DEFINITION OF THE GENOMIC LANDSCAPE OF MASLD

The Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) is a leading cause of chronic liver disease globally, with a prevalence exceeding 30% in the population. MASLD is strictly associated with insulin resistance and cardiometabolic conditions, and in 20-30% of cases, it can progress to steatohepatitis (MASH), which is characterized by progressive liver damage and inflammation. In patients at higher risk, the disease can lead to the onset of advanced fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). One of the main problems in the clinical management of MASLD is the absence of specific risk biomarkers and the lack of effective treatments, especially for patients with advanced-stage disease.

MASLD has a well-documented and enormous genetic component, with studies having identified several common variants associated with this pathology, such as those in the PNPLA3, TM6SF2, and MBOAT7 genes. However, these variants identified so far only explain a small part of MASLD's heritability, suggesting the contribution of rare loss-of-function (LoF) variants as well. Furthermore, scientific evidence indicates that the accumulation of somatic variants, both in hepatocytes and myeloid cells, could also play a key role in MASLD progression. In particular, clonal hematopoiesis of indeterminate potential (CHIP), which is a condition characterized by the presence of hematopoietic clones with somatic mutations often associated with leukemia and cardiovascular diseases, might favor the onset of hepatocellular carcinoma. However, the evidence available to date is still limited and requires further investigation and studies on larger cohorts.

The current study therefore aims to deepen this aspect through the analysis of the genetic profile using a Whole-Genome Sequencing (WGS) approach. DNA samples from peripheral blood from patients with advanced MASLD and peripheral blood DNA samples from controls presenting various associated metabolic risk factors will be sequenced.

In addition, 80 liver tissue samples from patients with advanced MASLD will also be sequenced to identify specific somatic mutations. The expected results from this study include the identification of new genetic variants associated with MASLD progression, the improvement of risk stratification through the development of polygenic risk scores, and the identification of potential therapeutic targets. This study represents a fundamental step for understanding the biology of MASLD and could have important clinical implications for disease management.