Calbindin 2 as a Novel Biomarker and Therapeutic Target for Abdominal Aortic Aneurysm: Integrative Analysis of Human Proteomes and Genetics.

BACKGROUND

Abdominal aortic aneurysm (AAA) is a clinical life-threatening issue. No pharmacological treatments are currently approved for the prevention and treatment of AAA. Therefore, identifying novel biomarkers and therapeutic targets is crucial for improving AAA management and outcomes.

METHODS

To identify plasma proteins with potential causal effects on AAA, we integrated genetic evidence from proteome-wide Mendelian randomization, genetic correlation, and colocalization analysis. The role of identified proteins in AAA was further explored through the phenome-wide association study and mediation analysis. Multiomics data analysis, including bulk RNA sequencing, single-cell/single-nucleus RNA sequencing, and spatial transcriptomics, was employed to characterize the expression patterns of these proteins. Experimental validation was performed using an AAA model in apolipoprotein E-deficient mice infused with angiotensin II. Druggability analysis was conducted to identify drug candidates, which were tested in preclinical mouse models.

RESULTS

CALB2 (calbindin 2) was identified as having a causal effect on AAA and may influence the progression of AAA through the regulation of lipid metabolism. Multiomics analysis revealed that CALB2 is predominantly expressed in the mesothelial cells of adipose tissues. Inhibition of CALB2 in an AAA mouse model alleviated AAA progression. Druggability analysis identified lenalidomide and genistein as potential therapeutic candidates, and experiments confirmed their efficacy in preventing AAA development.

CONCLUSIONS

This study identifies CALB2 as being associated with an increased risk of AAA and suggests that i might be a novel biomarker and therapeutic molecule for AAA management. Lenalidomide and genistein hold promising potential as treatments for patients with AAA.