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Published on: May 16, 2025
Anti-diabetic drug target perturbation modulates susceptibility to aortic aneurysm
Ranran Kong1, Zhihui Kuang2, Xia Wu3
1Department of Cardiology, Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation, Nanfang Hospital, Southern Medical University, Guangzhou, China.
Background:
Aortic aneurysms (AAs), including abdominal AA (AAA) and thoracic AA (TAA), are life-threatening conditions for which effective preventive therapies are lacking. Despite the promising results of anti-diabetic drugs in treating AAs, conclusive evidence supporting their efficacy remains lacking. Identifying effective anti-diabetic drugs for AAs is of considerable clinical importance.
Methods:
Herein, we performed drug-target Mendelian randomisation (MR) using summary statistics from the largest genome-wide meta-analyses of AAA/TAA (FinnGen R10 and UK Biobank) and gene expression data from the eQTLGen consortium. Analyses included inverse-variance weighted MR, mediation MR (common risk factors), colocalisation, phenome-wide MR and animal experiment to validate causality and pleiotropy of the genes.
Results:
Among the 10 anti-diabetic drug targets analysed, PRKAB1 (metformin target) showed protective effects against AAA (discovery OR = 0.92, 95 % CI: 0.88-0.97, P = 0.003; meta-OR = 0.93, 95 % CI: 0.89-0.97, P < 0.001) and TAA (discovery OR = 0.90, 95 % CI: 0.86-0.94, P < 0.001; meta-OR = 0.92, 95 % CI: 0.88-0.96, P = 0.002). Mediation MR demonstrated that 15.3 % (P = 0.021) and 11.7 % (P = 0.038) of the effects of PRKAB1 were mediated by elevated concentrations of high-density lipoprotein and reduced levels of triglycerides, respectively; insulin receptor reduced TAA risk (discovery OR = 0.86, 95 % CI: 0.75-0.99, P = 0.037; replication OR = 0.54, 95 % CI: 0.36-0.80, P = 0.002; meta-OR = 0.82, 95 % CI: 0.72-0.93, P = 0.012).
Conclusions:
These results highlight the pivotal role of PRKAB1 in preventing AA formation, particularly by regulating lipid levels. Additionally, the insulin receptor may have a role in reducing TAA incidence. Our findings provide valuable early-stage evidence for developing targeted AA therapies based on anti-diabetic drug target perturbation.
Insights
Metformin
Area of Science:
- Genetics
- Cardiovascular Research
- Pharmacology
Background:
- Aortic aneurysms (AAs), encompassing abdominal (AAA) and thoracic (TAA) types, are critical conditions lacking effective preventive treatments.
- While anti-diabetic drugs show promise for AA treatment, conclusive evidence is still needed.
- Identifying effective anti-diabetic drugs for AAs is crucial for clinical application.
Purpose of the Study:
- To investigate the potential of anti-diabetic drug targets in preventing aortic aneurysms.
- To establish a causal link between specific anti-diabetic drug targets and AA risk.
- To explore the mechanisms underlying the protective effects of these targets.
Main Methods:
- Drug-target Mendelian randomization (MR) was employed using large-scale genome-wide association studies (GWAS) for AAA/TAA and gene expression data.
- Analyses included inverse-variance weighted MR, mediation MR, colocalization, phenome-wide MR, and animal experiments.
- These methods were used to confirm causality and assess pleiotropy of identified genes.
Main Results:
- PRKAB1, a target of metformin, demonstrated protective effects against both AAA and TAA.
- Mediation analysis indicated that PRKAB1's effects were partly mediated by high-density lipoprotein and triglyceride levels.
- The insulin receptor was also found to reduce the risk of TAA.
Conclusions:
- PRKAB1 plays a significant role in preventing aortic aneurysm formation, primarily through lipid regulation.
- The insulin receptor may contribute to reducing thoracic aortic aneurysm incidence.
- Findings offer early evidence for developing targeted AA therapies by modulating anti-diabetic drug targets.
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