Interaction between Genome and Heavy Metals in Nonalcoholic Fatty Liver Disease

ABSTRACT The ultimate goal of this project is to discover and validate the gene Х heavy metal (GXM) interactions in human livers and to understand their role in nonalcoholic fatty liver disease (NAFLD). NAFLD is the most common chronic liver disease affecting over 30% of the U.S population, resulting in a heavy social burden. NAFLD is characterized by a spectrum of histological changes with multiple cells involved. Currently, no approved drug treatment is available for NAFLD. Therefore, it is an urgent need to identify both genetic and environmental risk factors to facilitate the development of new diagnostic, preventive, and therapeutic strategies. NAFLD is a typical complex disease involving gene-environment (GXE) interactions. Over the past decade, while GWAS for NAFLD have identified numerous genetic risk alleles, a growing body of research has demonstrated that exposure to heavy metals (Pb, Cd, Hg, As, etc.) are associated with increased NAFLD risk. However, there is no compelling study thus far to assess the correlation between various naturally accumulated metals in human livers and the NAFLD histology, especially in clinically defined patient cohorts. More importantly, there lacks critical knowledge about how naturally and chronically accumulated metals interact with the liver genome and together confer risks for NAFLD. Our preliminary studies in human liver tissues have successfully demonstrated that multiple metals are indeed correlated with NAFLD. By leveraging our previously collected multi-omics data, we have preliminarily identified numerous metal-response genes (MR-genes), expression quantitative traits loci (eQTLs), and allele-specific expression loci (ASEs), which are further enriched to NAFLD and its related pathways. We aim in this study to further expand our study to a large-scale, highly detailed, and integrated analysis to thoroughly understand the role of GXM interactions in NAFLD in humans. To this end, our team has been collaborating to establish collections for human liver tissue, cells and NAFLD patient cohorts. We have also developed various technical platforms e.g. bulk/single cell (Sc) RNAseq and ATAC-seq, as well as multiple bioinformatics and statistical tools for GXE data analyses. With these preparations, we specifically aim: 1) To profile heavy metals in frozen human liver tissues (n=560), identify MR-genes, eQTLs/ASEs, and test their associations with NAFLD; 2) To treat the primary liver cell populations with various metals and to elucidate how the genome of different liver cells respond to metals with Sc-RNAseq and ATAC-seq, and 3) To validate the association between GXM interactions and NAFLD histology severity in a large clinically defined NAFLD patient cohort (n=1313). Our study will for the first time evaluate the role and mechanism of GXM interactions in NAFLD and will provide the scientific community important data to open new avenues to NAFLD research, drug discovery, and beyond.