| Title: | Integrative genetic and liver transcriptomic analyses identify TRIB1AL as a target for steatotic liver disease |
| Journal: | The Journal of Clinical Endocrinology & Metabolism |
| Published: | 4 Feb 2026 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/41635218/ |
| DOI: | https://doi.org/10.1210/clinem/dgag043 |
Publication 18369
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Abstract
CONTEXT: Genome-wide association studies (GWAS) have identified dozens of genetic loci linked with metabolic dysfunction-associated steatotic liver disease (MASLD).</p>
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.</p>
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.</p>
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.</p>
19 Authors
- Émilie Gobeil
- Jérôme Bourgault
- Eloi Gagnon
- Nolwenn Samson
- Louis-Jacques Ruel
- Valérie Côté
- Patricia L Mitchell
- Clarisse Gotti
- Florence Roux-Dalvai
- Arnaud Droit
- Yohan Bossé
- Patrick Mathieu
- Fannie Lajeunesse-Trempe
- Marie-Claude Vohl
- Alexandre Caron
- André Tchernof
- Sébastien Thériault
- Mathieu Laplante
- Benoit J Arsenault
1 Application
| Application ID | Title |
|---|---|
| 25205 | Identification and characterization of functional variants with a causal role in chronic cardiopulmonary diseases |
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