IL-6 Modifies Coronary Artery Disease Risk Associated with Elevated Lipoprotein(a), UK Biobank Study Finds
核心洞察
A UK Biobank study of 43,512 participants found that IL-6 levels significantly modify the risk of incident coronary artery disease (搜索) associated with elevated lipoprotein(a).
Individuals with elevated Lp(a) (≥125 nmol/L) in the highest IL-6 quartile had a 43% increased CAD risk (HR, 1.43; 95% CI, 1.25-1.63), while those in the lowest IL-6 quartile showed no significant increase (HR, 1.09; 95% CI, 0.85-1.38; P for interaction = 0.008).
The findings support IL-6 as an actionable inflammatory biomarker that may help identify patients with elevated Lp(a) who could benefit from targeted preventive strategies.
A large primary prevention cohort study published in JAMA Cardiology has demonstrated that interleukin-6 (IL-6) levels significantly modify the risk of incident coronary artery disease (搜索) (CAD) conferred by elevated lipoprotein(a) [Lp(a)], underscoring the critical interplay between lipid profiles and systemic inflammation in cardiovascular risk assessment.
The study, conducted by Mohammadnia and colleagues using the UK Biobank dataset, analyzed 43,512 participants without prior coronary artery disease (搜索) or aortic valve stenosis (搜索) who underwent comprehensive plasma proteomics profiling. Among this cohort, 6,975 individuals (16.0%) had elevated Lp(a) levels of 125 nmol/L or greater. The mean age was 56.5 years (SD, 8.2), and 55.3% of participants were female. Recruitment occurred between March 2006 and October 2010, with analysis conducted from June 2025 to April 2026.
IL-6 Emerges as the Key Inflammatory Modifier
Among the inflammatory biomarkers assessed—interleukin-1β, interleukin-18, interleukin-6, and neutrophil-to-lymphocyte ratio—IL-6 demonstrated the strongest association with both CAD and aortic valve stenosis (搜索) outcomes. Using a multivariable-adjusted Cox proportional hazard model, the researchers found that IL-6 concentrations substantially influenced Lp(a)-mediated CAD risk.
In participants with Lp(a) levels of 125 nmol/L or greater who were in the highest IL-6 quartile (quartile 4), the hazard ratio for incident CAD was 1.43 (95% CI, 1.25-1.63). By contrast, those with similarly elevated Lp(a) but in the lowest IL-6 quartile (quartile 1) showed a markedly attenuated and non-significant hazard ratio of 1.09 (95% CI, 0.85-1.38). The interaction between Lp(a) and IL-6 was statistically significant (P = 0.008).
Over a median follow-up of 13.5 years (quartiles 1-3: 12.7-14.3) for incident CAD and 13.6 years (12.9-14.4) for incident aortic valve stenosis (搜索), these findings suggest that lower levels of systemic inflammation, as reflected by IL-6, may substantially mitigate the atherogenic risk posed by elevated Lp(a).
No Modification of Aortic Valve Stenosis (搜索) Risk
Notably, none of the inflammatory biomarkers assessed modified the risk of incident aortic valve stenosis (搜索) associated with elevated Lp(a). While the interaction between Lp(a) and neutrophil-to-lymphocyte ratio yielded a P value for interaction of 0.02, this association was considered only suggestive and did not remain statistically significant after correction for multiple testing.
Clinical Implications and the Evolving Role of IL-6
These results align with a growing body of evidence positioning IL-6 as a central mediator in the atherogenic inflammatory cascade. IL-6 sits downstream of the NLRP3 inflammasome and IL-1β and upstream of hepatic CRP production, promoting atherogenesis through endothelial activation, monocyte recruitment, lipoprotein oxidation, and release of prothrombotic mediators.
The findings carry particular relevance given the expanding therapeutic landscape targeting the IL-6 pathway. Ziltivekimab, a human monoclonal antibody targeting the IL-6 ligand, is currently being evaluated in the phase 3 ZEUS cardiovascular outcomes trial, which has randomized 6,376 patients with ASCVD, chronic kidney disease, and hs-CRP ≥2 mg/L. Additional ongoing trials include ARTEMIS in post-acute MI patients, HERMES and ATHENA in heart failure populations, and studies of other IL-6-directed agents such as pacibekitug and clazakizumab.
The study authors concluded that IL-6 represents "a highly actionable marker of inflammatory risk that may modify the risk for coronary artery disease (搜索) posed by lipoprotein(a)," reinforcing the principle that lipid levels must be assessed together with inflammatory markers in modern cardiovascular medicine. These findings may help identify patients with elevated Lp(a) who could derive the greatest benefit from targeted anti-inflammatory preventive strategies.