ENPP2/Autotaxin: The potential drug target for alcoholic liver disease identified through Mendelian randomization analysis

Background and aims: At present, there is still a lack of radical drug targets for intervention in alcoholic liver disease (ALD), and drug discovery through randomized controlled trials is a lengthy, risky, and expensive undertaking, so we aimed to identify effective drug targets based on human genetics.

Methods: We used Mendelian randomization (MR) and Bayesian colocalization analysis to investigate 2639 genes encoding druggable proteins and examined the causal effects on ALD (PMID 34737426: 456348 European with 451 cases and 455 897 controls). In addition, we conducted the mediation analysis to explore the potential mechanism using the genome-wide association study (GWAS) data of blood biomarkers as mediators.

Results: We finally identified the drug target: ENPP2/Autotaxin and genetically proxied ENPP2/Autotaxin was causally associated with the risk of ALD (OR = 2.28, 95% CI: 1.64 to 3.16, p = 7.49E-7). In addition, we found that the effect of ENPP2/Autotaxin on ALD may be partly mediated by effector memory CD8⁺ T cell (the proportion of mediation effect: 8.49%).

Conclusions: Our integrative analysis suggested that genetically determined levels of circulating ENPP2/Autotaxin have a causal effect on ALD risk and are a promising drug target.