Transcriptomic Architecture of Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) Risk in Mexican Americans

Abstract

Highlights What are the main findings? Hepatic steatosis (neutral lipid) measures in iPSC-derived hepatocyte cultures showed statistically significant additive genetic heritability at baseline (h2 = 0.44, p ≤ 0.05) and post-lipid challenge (h2 = 0.42, p ≤ 0.05). Transcriptome-wide association analysis identified 1070 genes at baseline and 1229 genes post-lipid challenge whose expression was significantly (|β|≥0.24, Bonferroni p≤0.001) associated with hepatic steatosis measures. What are the implications of the main findings? Functional annotation and pathway enrichment analysis of these genes suggest fatty acid/cholesterol uptake, de novo lipogenesis, and high-turnover cellular stress responses driving the steatosis risk, whereas endosomal and autophagic clearance, cellular cytoskeleton, and hepatocytes’ epithelial integrity play a protective role. Our work demonstrated an epidemiological-scale use of an iPSC-derived hepatocyte model for mapping the transcriptomic determinants of MASLD-associated hepatic steatosis risk. Abstract Hispanics of Mexican American descent in South Texas show a very high prevalence of MASLD, with some studies reporting rates as high as 50% in adults. However, assessment of genetic risk factors underlying this prevalence is complicated by a high co-occurrence of other metabolic disorders and variable endogenous and exogenous environmental risk factors. To map the transcriptomic architecture of MASLD hepatic steatosis risk, we conducted an epidemiological-scale investigation using human induced pluripotent stem cell (iPSC)-derived hepatocyte cultures from 193 participants in our longitudinal South Texas Family Study (STFS). iPSC-based models offer greater power to map genetic risk factors by experimentally controlling for confounding organismal and environmental factors. We combined transcriptome-wide gene expression analysis with high-content cellular measurements of neutral lipids to define a core hepatic steatosis MASLD phenotype at baseline (vehicle-treated) and following a lipid challenge. The additive genetic heritability of hepatic steatosis measures was 0.44 (p-value = 0.03) at baseline and 0.42 (p-value = 0.03) at post-lipid challenge. Multivariable linear regression comparing each gene’s expression against hepatic steatosis measures identified 1070 genes at baseline and 1229 genes post-lipid challenge, whose expression showed a transcriptome-wide statistically significant association (standardized |β| ≥ 0.24; Bonferroni-corrected p-value ≤ 0.001) with baseline and post-lipid challenge hepatic steatosis measures, respectively. Functional annotation and pathway enrichment analyses of these genes implicated a broad range of hepatocellular functions, mapping an overall transcriptomic architecture of MASLD-associated steatosis risk in Mexican Americans. The genes whose expression was positively correlated with hepatic steatosis measures suggest a direct role of variation in fatty acid (FA) and cholesterol uptake, de novo lipogenesis (DNL), and carbohydrate shunts in hepatic steatosis risk, as well as a cellular stress-associated and high-turnover metabolic state marked by elevated FA-oxidation and ketogenesis. In contrast, the genes whose expression was inversely correlated with hepatic steatosis measures suggest a significant role of the cellular cytoskeleton, hepatocyte epithelial integrity, and endosomal and autophagic clearance machinery in steatosis risk.