Functional identification of non-coding variants associated with metabolic dysfunction-associated steatotic liver disease

Abstract/Project Summary Metabolic dysfunction-associated steatotic liver disease (MASLD) typically initiates as a benign and reversible condition. However, a subgroup of MASLD patients progresses to a severe stage known as metabolic dysfunction-associated steatohepatitis (MASH), often leading to hepatocellular carcinoma and liver failure. Given the global prevalence of MASLD, the significant heterogeneity among patients emphasizes the necessity to efficiently allocate medical resources by identifying those at high risk. Like many other complex diseases, MASLD's occurrence and progression stem from a combination of genetic background and environmental factors. Although genome-wide association studies (GWAS) have identified numerous genetic variants associated with MASLD, their causality and functional roles, especially in non-coding regions, remain largely unexplored. To bridge this gap, we curated a list of non-coding variants from GWAS and prioritized them based on cis-regulatory activity. Integrating in vitro and in vivo analyses of cis-regulatory activity led to the identification of potentially functional regulatory variants (FrVar), hypothesized to predict MASLD genetic risk. Leveraging the Candidate's expertise in functional genomics and bioinformatics, the proposed research aims to elucidate the cis-regulatory function of FrVar in a cell-type-specific manner by manipulating their activity in iPSC-derived liver cells and organoids (Aim 1). Furthermore, the study will investigate alterations in transcription factor binding by FrVar, with a particular focus on EGR1, in iPSC-derived liver cultures modeling MASLD/MASH (Aim 2). Finally, to comprehensively evaluate the clinical value of FrVar, polygenic risk scores will be constructed and their predictive power assessed using biobank data (Aim 3). These endeavors seek to unravel the molecular mechanisms and translational values of non-coding variants in MASLD onset and progression, offering insights into patient risk stratification and management. The accomplishment of these objectives will enhance the Candidate's growth in MASLD studies, emphasizing a stronger focus on human relevance. This proposal will also facilitate the Candidate's professional development in laboratory management and leadership, thereby establishing a solid foundation for an independent research program in the MASLD field.