Triglyceride-rich lipoproteins, low-density lipoproteins, and risk of abdominal aortic aneurysm.

Background: The comparative roles of triglyceride-rich lipoproteins (TRLs) and low-density lipoproteins (LDLs) in abdominal aortic aneurysm (AAA) pathogenesis are unclear. Objectives: To evaluate the putative causal role of TRLs in AAA, quantify the relative effect on AAA risk ("aneurysmogenicity") of TRL vs LDL particles, and prioritize lipid-lowering drug targets for AAA prevention and treatment. Methods: We performed summary-level and individual-level Mendelian randomization (MR) analyses. Genetic variants were selected from 383,983 UK Biobank participants and ranked into 10 sets of variants where set 1 predominantly affected LDL cholesterol (LDL-C) and set 10 predominantly affected TRL cholesterol (TRL-C; and with mixed effects for intermediate variant sets). AAA outcome data were obtained from AAAgen (37,214 cases), FinnGen (4,439 cases), and the VA Million Veteran Program (MVP; 23,848 cases). Multivariable MR was used to assess the independent roles of LDL-C and TRL-C in AAA. For each set of variants, MR or logistic regression was used to estimate AAA odds ratios (ORs) per 10 mg/dL higher apolipoprotein B (apoB). Interaction analyses were conducted between a statin-like LDL-C-lowering variant set (set 3) and a TRL-C-lowering variant set (set 10). Drug-target MR was performed to evaluate lipid-lowering targets relevant to LDL-C- and TRL-C-lowering. Results: Genetically predicted LDL-C and TRL-C concentrations were each associated independently with genetic liability for AAA after mutual adjustment, with 3.0 to 5.5 times stronger associations for TRL-C compared to LDL-C on a per-cholesterol basis. In AAAgen, the AAA OR per 10 mg/dL increased apoB concentrations were 1.10 (95% CI, 1.05-1.14) for variant set 1 (LDL-C-predominant) and 1.89 (95% CI, 1.69-2.11) for variant set 10 (TRL-C-predominant). Using the ratio of log(OR) per 10 mg/dL apoB for set 10 versus set 1 as a conservative estimate of relative aneurysmogenicity, TRLs were approximately 3.2 to 6.9 times more aneurysmogenic than LDLs across the three studies. No evidence of interaction was observed between LDLs and TRLs, indicating additive contribution to AAA risk. Drug-target MR supported strong protective associations for genetically proxied inhibition of TRL-pathway targets, particularly Conclusions: TRLs are at least threefold more aneurysmogenic than LDLs on a per-particle basis. Therapeutic strategies targeting TRL-C -especially via