Triglyceride-rich lipoproteins, low-density lipoproteins, and risk of abdominal aortic aneurysm
This article has been Reviewed by the following groups
Discuss this preprint
Start a discussion What are Sciety discussions?Listed in
- Evaluated articles (PREreview)
Abstract
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 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 around 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 APOC3 and LPL, with AAA risk. Conclusions TRLs are at least threefold more aneurysmogenic than LDLs on a per-particle basis. Therapeutic strategies targeting TRL-C especially via APOC3 and LPL-should be prioritized for AAA prevention and treatment.
Article activity feed
-
This Zenodo record is a permanently preserved version of a PREreview. You can view the complete PREreview at https://prereview.org/reviews/21833219.
This manuscript presents a robust and clinically relevant genetic investigation into the comparative roles of triglyceride-rich lipoproteins (TRLs) and low-density lipoproteins (LDLs) in the pathogenesis of abdominal aortic aneurysm (AAA). Given the current absence of approved pharmacological agents to attenuate AAA progression or prevent rupture, the identification of actionable causal pathways remains highly critical. Utilizing summary- and individual-level Mendelian randomization (MR) across three extensive cohorts — AAAgen, FinnGen, and the VA Million Veteran Program — the authors provide evidence that both lipid fractions independently contribute to AAA liability.
The primary novelty …
This Zenodo record is a permanently preserved version of a PREreview. You can view the complete PREreview at https://prereview.org/reviews/21833219.
This manuscript presents a robust and clinically relevant genetic investigation into the comparative roles of triglyceride-rich lipoproteins (TRLs) and low-density lipoproteins (LDLs) in the pathogenesis of abdominal aortic aneurysm (AAA). Given the current absence of approved pharmacological agents to attenuate AAA progression or prevent rupture, the identification of actionable causal pathways remains highly critical. Utilizing summary- and individual-level Mendelian randomization (MR) across three extensive cohorts — AAAgen, FinnGen, and the VA Million Veteran Program — the authors provide evidence that both lipid fractions independently contribute to AAA liability.
The primary novelty and methodological strength of this study reside in its stratification strategy, which partitioned 1,357 genetic variants into ten distinct sets to directly compare the pathogenic effect on a per-particle basis (termed "aneurysmogenicity") of TRL versus LDL. The finding that TRL particles exhibit an estimated 3- to 7-fold higher association with AAA risk than LDL particles represents a substantial shift in the understanding of vascular lipidomics. Furthermore, the drug-target MR analysis provides translational evidence for prioritizing TRL-lowering pathways, specifically targeting APOC3 and LPL, in AAA prevention and management strategies.
The researchers are commended for their transparent and candid acknowledgment of inherent limitations, including lifelong exposure assumptions, the calculation of TRL-C, potential residual pleiotropy, and the need for broader ancestral validation. Crucially, as the authors note, AAA phenotyping and outcomes can vary across different healthcare systems. Since the utilized MR frameworks primarily reflect the risk of incident AAA, a next step for future clinical translation will be to explicitly differentiate whether these TRL-related pathways drive the initial development of the disease or directly accelerate the aneurysm growth rate over time. Addressing this mechanistic distinction will be essential to determine whether TRL-targeted therapies should be deployed as primary preventive measures or as interventions to halt active disease progression. By directly confronting these methodological caveats, the manuscript provides a well-validated, actionable foundation for future clinical studies on AAA prevention and management.
This is a cross-post of a peer review originally submitted via ScienceOpen. The original publication with its metadata can be found at: https://doi.org/10.14293/s2199-1006.1.sor-uncat.asjyj2.v1.rqgfnk
Competing interests
The author declares that they have no competing interests.
Use of Artificial Intelligence (AI)
The author declares that they did not use generative AI to come up with new ideas for their review.
-
