Abstract Body: Introduction: The association between type 2 diabetes (T2D) and abdominal aortic aneurysm (AAA) remains unclear in observational studies. As T2D is pathophysiologically heterogeneous—encompassing insulin resistance and β-cell dysfunction—these mechanisms may have opposing effects on vascular remodeling. We therefore investigated whether AAA risk differs across distinct mechanistic pathways of T2D.
Methods: We performed two-sample Mendelian randomization with genetic instruments selected from the T2DGGI (242,283 individuals with T2D; 1,569,730 without) and summary-level outcome data from the AAAgen (37,214 cases and 997,456 controls) consortia in Europeans. Predefined clusters of T2D-associated genetic variants that represent independent mechanistic pathways were tested in relation to genetic liability to AAA. To independently assess mechanism-specific effects we tested the effects of genetically proxied glycemic (fasting glucose, 2-hour glucose, hemoglobin A1c) and insulin resistance (fasting insulin, insulin sensitivity, triglyceride-to-HDL ratio, body mass index, waist-to-hip ratio) traits on genetic liability to AAA. The inverse variance weighted (IVW) method was used as the primary analysis and supplemented by other methods, including MR-Egger regression, as sensitivity analyses.
Results: Estimates of the association between genetic liability to T2D and genetic liability to AAA did not exclude the null (OR 1.00, 95%CI 0.96–1.05) in the primary analysis; however, this null association was not consistently observed in the sensitivity analyses (Figure 1), suggesting the possibility of pleiotropy. Cluster-specific analyses revealed that variants within beta cell dysfunction clusters were inversely associated with AAA, whereas those within the obesity and lipodystrophy clusters were associated with higher risk of AAA (Figure 2). Independently, genetically proxied glycemic traits were associated with lower genetic liability to AAA, whereas genetically proxied insulin resistance related traits demonstrated consistently increased AAA risk (Figure 3).
Conclusions: Type 2 diabetes shows mechanism-specific heterogeneity in abdominal aortic aneurysm (AAA) risk. Genetic liability driven by hyperglycemia and β-cell dysfunction appears protective, whereas liability reflecting insulin resistance and adiposity is associated with higher AAA risk.