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

Peiqiong Luo1,2, Xuefeng Yu1,2

  • 1Division of Endocrinology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.

Liver International : Official Journal of the International Association for the Study of the Liver
|March 22, 2024
PubMed
Abstract

Insights

Identifying druggable targets for alcoholic liver disease (ALD) is crucial. Genetic analysis revealed ENPP2/Autotaxin as a causal factor and a promising therapeutic target for ALD.

Area of Science:

  • Genetics
  • Hepatology
  • Pharmacology

Background:

  • Alcoholic liver disease (ALD) lacks effective drug targets.
  • Drug discovery for ALD is time-consuming and costly.
  • Human genetics offers a pathway to identify novel therapeutic targets.

Purpose of the Study:

  • To identify genetic drug targets for alcoholic liver disease.
  • To investigate the causal relationship between genes and ALD risk.
  • To explore potential mechanisms underlying ALD pathogenesis.

Main Methods:

  • Mendelian randomization (MR) analysis of 2639 druggable genes.
  • Bayesian colocalization analysis in a large European cohort.
  • Genome-wide association study (GWAS) mediation analysis using blood biomarkers.

Main Results:

  • ENPP2/Autotaxin was identified as a significant drug target.
  • Genetically proxied ENPP2/Autotaxin showed a causal association with ALD risk (OR=2.28).
  • The effect of ENPP2/Autotaxin on ALD was partly mediated by effector memory CD8+ T cells.

Conclusions:

  • Genetically determined ENPP2/Autotaxin levels causally influence ALD risk.
  • ENPP2/Autotaxin represents a promising therapeutic target for ALD.
  • Integrative genetic analysis provides a robust approach for drug target identification.
Keywords:
Bayesian colocalization analysisENPP2/AutotaxinMendelian randomization analysisalcoholic liver diseasedrug targetsmediation analysis

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