Osteoprotegerin is associated with reduced risk of abdominal aortic aneurysm and the role of vascular calcification: insights from Mendelian randomization approach.

BACKGROUND AND AIMS Studies have suggested that osteoprotegerin (OPG) is implicated in modulating vascular calcification and is associated with the risk of aneurysms, but the causal relationships among them remain unclear. This Mendelian randomization (MR) study aims to investigate the causal effects of OPG on aneurysm risk and to explore the role of vascular calcification.

METHODS AND RESULTS Genetic variants associated with OPG levels from three independent studies were used as instrumental variables. A single-variable MR analysis was conducted to investigate the impact of OPG levels on vascular calcification and aneurysm, including abdominal aortic aneurysm (AAA, N = 39,221), thoracic aortic aneurysm (TAA, N = 19,646), and intracranial aneurysm (IA, N = 79,429). Furthermore, multivariable MR (MVMR) was applied to assess the mediating role of vascular calcification in the association between OPG levels and aneurysm. Pooled results showed that genetically predicted higher OPG levels were linked to a reduced risk of AAA (odds ratio [OR] = 0.943, 95%CI = 0.906-0.982, P = 0.004), but not TAA and IA. In addition, genetically predicted OPG levels were associated with decreased coronary artery calcification (β = -0.101, 95%CI = -0.197 to -0.004, P = 0.040). MVMR analysis showed that the inverse relationship between OPG levels and AAA disappeared after adjusting for abdominal aortic calcification (OR = 0.959, 95%CI = 0.905-1.016, P = 0.152).

CONCLUSION Our findings provide novel insights into the protective effect of OPG in AAA, which may be dependent on inhibiting vascular calcification. These findings highlight OPG as a potential biomarker and therapeutic target for aneurysm management.