Abstract
CONTEXT: Genome-wide association studies (GWAS) have identified dozens of genetic loci linked with metabolic dysfunction-associated steatotic liver disease (MASLD).
METHODS: To identify liver-expressed genes that may represent therapeutic candidates for MASLD, we conducted a new GWAS meta-analysis including 16,532 cases and 1,240,188 controls. We also generated RNA sequencing data of liver samples and genome-wide genotyping of 504 individuals of the Quebec Obesity Biobank.
RESULTS: Using Mendelian randomization (MR) and genetic colocalization, we confirm the implication of genes previously linked with MASLD and identified novel ones including AKNA (AT-hook transcription factor), EPHA2 (EPH receptor A2), CHEK2 (encoding Checkpoint kinase 2) and PCCB (Propionyl-CoA carboxylase subunit beta). More specifically, we found a strong and positive effect of the long non-coding RNA TRIB1AL on MASLD. The lead genetic variant was not linked with expression levels of the nearby protein-coding gene TRIB1 (Tribbles Pseudokinase 1). In participants of the UK Biobank with whole exome sequencing data available, rare loss-of-function variants in TRIB1 were not associated with liver fat accumulation or plasma triglyceride levels, suggesting that the long non-coding RNA TRIB1AL may carry cardiometabolic effects independently of TRIB1. Targeted- and phenome-wide MR also identified lower liver-expressed TRIB1AL as being associated with reduced liver fat accumulation, lower plasma lipoprotein-lipid levels and decreased atherosclerotic cardiovascular disease risk.
CONCLUSIONS: These results open the door to liver-targeted therapeutics silencing of the non-coding genome for the prevention and treatment of MASLD and cardiometabolic diseases.