Relationship between NAFLD and coronary artery disease: A Mendelian randomization study

Area of Science:

• Cardiovascular Disease Epidemiology
• Hepatology and Liver Disease
• Genetic Epidemiology

Background:

• The role of non-alcoholic fatty liver disease (NAFLD) in the development of coronary artery disease (CAD) remains debated.
• Distinguishing between NAFLD as a cause or bystander in CAD pathogenesis is crucial for clinical understanding.

Purpose of the Study:

• To investigate the potential causal relationship between NAFLD and CAD using genetic data.
• To assess if NAFLD is an independent risk factor for CAD development.

Main Methods:

• Two-sample Mendelian randomization (MR) analyses were conducted using summary-level genetic data.
• Genetically predicted NAFLD, including chronically elevated serum alanine aminotransferase (cALT) levels, imaging-based, and biopsy-confirmed NAFLD, were assessed against CAD risk.
• Analyses were repeated after excluding genes associated with very-low-density lipoprotein (VLDL) secretion to address potential pleiotropy.

Main Results:

• Genetically predicted cALT showed a statistically significant association with increased CAD risk (OR: 1.116).
• After excluding genes linked to impaired VLDL secretion, robust associations were observed for all NAFLD measures (cALT, imaging-based, and biopsy-confirmed) with CAD.
• These associations remained consistent even with more stringent criteria and MR methods, and MR-Egger regression indicated no significant directional pleiotropy in the refined analyses.

Conclusions:

• Genetically predicted NAFLD demonstrates a robust causal association with an increased risk of coronary artery disease.
• The findings support NAFLD as an active contributor to CAD pathogenesis, independent of VLDL secretion pathways.