Abstract Body: Background Recent work has highlighted the importance of apoB-associated lipoproteins in the pathogenesis of abdominal aortic aneurysms. The relative aneurysmogenic roles of the constituent triglyceride-rich and low-density lipoproteins in abdominal aortic aneurysm (AAA) remain unclear.
Objectives To evaluate the causal role of TRL in AAA, quantify the relative aneurysmogenicity of TRL - and LDL-predominant particles, and prioritize lipid lowering targets for AAA.
Methods We performed summary-level and individual-level Mendelian randomization (MR) analyses. Genetic variants were selected from up to 383,983 UK Biobank participants and grouped into 10 clusters defined by increasing TRL-cholesterol (TRL-C) to LDL-cholesterol (LDL-C) ratios. Summary AAA outcome data were obtained from AAAgen (37,214 cases), FinnGen (4,439 cases). Individual-level analyses were performed in the VA Million Veteran Program (MVP; 23,848 cases). Multivariable MR was used to assess the independent roles of TRL-C and LDL-C in AAA. For each cluster, MR and logistic regression were used to estimate AAA odds ratios (ORs) per 10 mg/dL higher apolipoprotein B (apoB). Interaction analyses were conducted between a statin-like LDL-lowering cluster (cluster 3) and a TRL-lowering cluster (cluster 10). Drug-target MR was performed to evaluate TRL- and LDL-lowering drug targets.
Results Genetically predicted LDL-C and TRL-C were independently associated with genetic liability to AAA after mutual adjustment, with stronger associations for TRL-C on an apoB-equivalent basis. In AAAgen, the AAA OR per 10 mg/dL higher apoB was 1.10 (95% CI, 1.05-1.14) for cluster 1 (LDL-predominant) and 1.89 (95% CI, 1.69-2.11) for cluster 10 (TRL-predominant). Using the ratio of log(OR) for cluster 10 versus cluster 1 as a conservative estimate of relative aneurysmogenicity, TRL-predominant particles were approximately 3.2 to 6.9 times more aneurysmogenic than LDL-predominant particles. No evidence of interaction was observed between the predominantly LDL-C and predominantly TRL-C clusters. Drug-target MR supported stronger protective associations for genetically proxied inhibition of TRL-C pathway targets, particularly APOC3 and LPL, with AAA risk.
Conclusions TRL-predominant particles are at least threefold more aneurysmogenic than LDL-predominant particles on a per-particle basis. Therapeutic strategies targeting TRL—especially via APOC3 and LPL—should be prioritized for AAA prevention and treatment.