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

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.