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

Overview

Journal Rev Cardiovasc Med

Specialty Cardiology & Vascular Diseases

Date 2024 Jul 30

PMID 39076954

Authors

Jingwen Liu

Mingyuan Xu

Bin Ni

Zhaohua Zhang

Xixi Gao

Dingkai Zhang

Liang Yang

Zhidong Ye

Jianyan Wen

Peng Liu

Affiliations

Soon will be listed here.

Abstract

Background: Identifying effective pharmacological interventions to prevent the progressive enlargement and rupture of aortic aneurysms (AAs) is critical. Previous studies have suggested links between metformin use and a decreased incidence of AAs. In this study, we employed Mendelian randomization (MR) to investigate causal effects of metformin's targets on AA risk and to explore the underlying mechanisms underlying these effects.

Methods: To examine the relationship between metformin use and AA risk, we implemented both two-sample MR and multivariable MR analyses. Utilizing genetic instrumental variables, we retrieved cis-expression quantitative trait loci (cis-eQTL) data for potential targets of metformin from the Expression Quantitative Trait Loci Genetics Consortium (eQTLGen) Consortium and Genotype-Tissue Expression (GTEx) project. Colocalization analysis was employed to ascertain the probability of shared causal genetic variants between single nucleotide polymorphisms (SNPs) associated with eQTLs and AA.

Results: Our findings reveal that metformin use reduces AA risk, exhibiting a protective effect with an odds ratio (OR) of 4.88 (95% confidence interval [CI]: 7.30 -0.33, = 0.01). Furthermore, the protective effect of type 2 diabetes on AA risk appears to be driven by metformin use ( = 1.34 , 95% CI: 3.97 -0.45, = 0.03). Significant Mendelian randomization (MR) results were observed for the expression of two metformin-related genes in the bloodstream: () and (), across two independent datasets ( = 1.35, 95% CI: 1.20-1.51, = 2.41 ; = 1.12; 95% CI: 1.07-1.17, = 1.69 ). The MR analysis of tissue-specific expression also demonstrated a positive correlation between increased NDUFA6 expression and heightened AA risk. Lastly, NDUFA6 exhibited evidence of colocalization with AA.

Conclusions: Our study suggests that metformin may play a significant role in lowering the risk of AA. This protective effect could potentially be linked to the mitigation of mitochondrial and immune dysfunction. Overall, has emerged as a potential mechanism through which metformin intervention may confer AA protection.

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