The long non-coding RNA TRIB1AL links metabolic dysfunction-associated steatotic liver disease, cardiometabolic risk and human lifespan

Genome-wide association studies (GWAS) have identified dozens of genetic loci linked with metabolic dysfunction-associated steatotic liver disease (MASLD). 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, as well as RNA sequencing of liver samples and genome-wide genotyping of 504 individuals of the Quebec Obesity Biobank. 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, decreased atherosclerotic cardiovascular disease risk, and increased human lifespan. 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.