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.