Integrative genetic and liver transcriptomic analyses identify TRIB1AL as a target for steatotic liver disease.

CONTEXT: Genome-wide association studies (GWAS) have identified dozens of genetic loci linked with metabolic dysfunction-associated steatotic liver disease (MASLD).

OBJECTIVE: To identify liver-expressed genes that may represent therapeutic candidates for MASLD.

METHODS: 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 β). More specifically, we found a strong and positive effect of long noncoding (lnc)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 UK Biobank participants 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 lncRNA 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.

CONCLUSION: These results open the door to liver-targeted therapeutics silencing of the noncoding genome for the prevention and treatment of MASLD and cardiometabolic diseases.