The causal association between plasma amino acid levels and abdominal aortic aneurysm: insights from Mendelian randomization and an experimental validation.

Abstract

Abdominal aortic aneurysm (AAA) is a severe vascular condition with a high mortality rate upon rupture. Emerging evidence suggests that metabolic factors, particularly plasma amino acids, may influence AAA risk, though specific causal roles remain unclear. This study investigates the causal relationship between plasma amino acids and AAA using Mendelian randomization (MR) and in vivo validation. A bidirectional two-sample MR analysis was conducted using genome-wide association study (GWAS) data. Genetic variants associated with amino acid levels and AAA served as instrumental variables, with inverse variance weighting as the primary method. Sensitivity analyses, including MR-Egger, weighted median, and leave-one-out tests, were performed to assess robustness and pleiotropy. In vivo experiments in an elastase-induced AAA mouse model evaluated the therapeutic potential of proline supplementation. MR analysis identified five amino acids causally linked to AAA risk. Specifically, increased AAA risk was linked to aspartate (OR: 1.218, P&#xa0;=&#xa0;0.027), glutamate (OR: 1.349, P&#xa0;<&#xa0;0.001), and glycine (OR: 1.147, P&#xa0;=&#xa0;0.040), while proline (OR: 0.856, P&#xa0;=&#xa0;0.005) and tryptophan (OR: 0.871, P&#xa0;=&#xa0;0.048) were associated with reduced risks. The reverse MR analysis revealed no causal effect of AAA on these amino acids. In vivo experiments further showed that proline administration significantly inhibited the development of elastase-induced AAA in mouse models. This study presents new evidence of a causal relationship between plasma amino acids and AAA risk, providing valuable insights into AAA pathogenesis. Additionally, the findings suggest that proline supplementation could be a potential therapeutic strategy for AAA, warranting further translational research.