Lipoprotein(a), Inflammation, and Risk of Coronary Artery Disease and Aortic Valve Stenosis
Niekbachsh Mohammadnia, Linke Li, Daniel Ezzat, Zhi Yu, Vineet K. Raghu, Jennifer L. Halford, Niels P. Riksen, Pradeep Natarajan, Jan H. Cornel, Michael C. Honigberg, Saloua El MessaoudiImportance
Clinical heterogeneity exists among individuals with elevated lipoprotein(a) [Lp(a)] levels. Prior studies suggest that low-grade inflammation may modify this risk, but results remain conflicting.
Objective
To test the hypothesis that inflammatory biomarkers may modify Lp(a)-associated risk for coronary artery disease (CAD) and aortic valve stenosis (AS) in a primary prevention population.
Design, Setting, and Participants
Recruitment occurred between March 2006 through October 2010 among a population-based cohort of UK adults. UK Biobank participants without prevalent CAD or AS who underwent plasma proteomic profiling at study entry were eligible for inclusion. Data were analyzed from June 2025 through April 2026.
Exposures
Lp(a) levels (<125 nmol/L vs ≥125 nmol/L) and inflammatory biomarkers interleukin 1β (IL-1β), IL-18, IL-6, and the neutrophil to lymphocyte ratio (NLR).
Main Outcomes and Measures
The primary outcome was the risk of incident CAD. The secondary outcome was the risk of incident AS.
Results
Among 43 512 UK Biobank participants, 6975 (16.0%) had Lp(a) levels of 125 nmol/L or higher, 24 079 (55.3%) were female, and overall mean (SD) age was 56.5 (8.2) years. Median (Q1-Q3) follow-up was 13.5 (12.7-14.3) years for incident CAD and 13.6 (12.9-14.4) years for incident AS. Multivariable-adjusted Cox proportional hazards models tested the interaction between Lp(a) levels and each inflammatory biomarker in relation to the primary and secondary outcomes. Among inflammatory biomarkers tested, IL-6 demonstrated the strongest association with both incident CAD and AS. IL-6 levels modified Lp(a)-associated risk for incident CAD (hazard ratio [HR] for Lp(a) ≥125 nmol/L vs <125 nmol/L in quartile 4 of IL-6: 1.43; 95% CI, 1.25-1.63 vs in quartile 1 of IL-6: HR, 1.09; 95% CI, 0.85-1.38;
Conclusions and Relevance
In this primary prevention cohort study, Lp(a)-associated risk for incident CAD was modified by IL-6, with lower associated risk observed in the setting of lower inflammatory biomarker levels. These findings identify IL-6 as a biomarker of inflammatory risk that may modify Lp(a)-associated CAD risk.