Metformin Therapeutic Targets for Aortic Aneurysms: A Mendelian Randomization and Colocalization Study

Area of Science:

• Pharmacology and Genetics
• Cardiovascular Research
• Metabolic Disease Mechanisms

Background:

• Aortic aneurysms (AAs) pose a critical health risk, necessitating effective pharmacological interventions.
• Previous research suggests a potential link between metformin use and reduced AA incidence.
• Understanding the causal relationship and mechanisms is vital for developing preventative strategies.

Purpose of the Study:

• To investigate the causal effects of metformin targets on aortic aneurysm (AA) risk using Mendelian randomization (MR).
• To explore the underlying mechanisms through which metformin may influence AA development.
• To assess the role of specific genes, such as NDUFA6 and CYB5B, in this relationship.

Main Methods:

• Employed two-sample and multivariable Mendelian randomization (MR) analyses.
• Utilized cis-expression quantitative trait loci (cis-eQTL) data from eQTLGen and GTEx for metformin targets.
• Performed colocalization analysis to identify shared genetic variants between eQTLs and AA.

Main Results:

• Metformin use demonstrated a significant protective effect against aortic aneurysms (AAs) (OR = 4.88).
• Metformin use appears to mediate the protective effect of type 2 diabetes on AA risk.
• MR analysis identified significant associations for NDUFA6 and CYB5B gene expression with AA risk, with NDUFA6 showing colocalization with AA.

Conclusions:

• Metformin significantly lowers the risk of aortic aneurysms (AAs).
• The protective effect may involve the mitigation of mitochondrial and immune dysfunction.
• NDUFA6 is identified as a potential key mechanism mediating metformin's protective role in AA prevention.