Comparative associations of LDL-C, Lp(a), hsCRP, and IL-6 with cardiovascular risk: Insights from the UK Biobank and MESA

INTRODUCTION: Low-density lipoprotein-cholesterol (LDL-C) is a well-established causal risk factor for atherosclerosis and remains the cornerstone of primary prevention. Lipoprotein(a) [Lp(a)] and high-sensitivity C-reactive protein (hsCRP) are considered risk-enhancing factors in current guidelines. Interleukin-6 (IL-6), a pro-inflammatory cytokine upstream of CRP, has recently emerged as a potential therapeutic target. We sought to compare the longitudinal associations of LDL-C, Lp(a), hsCRP, and IL-6, both individually and in relation to one another, with atherosclerotic cardiovascular disease (ASCVD) events in two large, contemporary primary prevention cohorts. METHODS: Participants with baseline measurements of LDL-C, Lp(a), hsCRP, and IL-6 from the United Kingdom (UK) Biobank and the Multi-Ethnic Study of Atherosclerosis (MESA) were included in this study. The primary endpoint was incident ASCVD (defined as composite of myocardial infarction, stroke, or cardiovascular death). Cox proportional hazards models were used to calculate hazard ratios across biomarker quartiles, adjusting for traditional risk factors and other biomarkers. RESULTS: The mean age (SD) was 56.8 (8.1) years in UK Biobank and 62.2 (10.2) years in MESA. In fully adjusted models including all covariates, the HRs for ASCVD comparing top vs bottom quartiles in UK Biobank were: LDL-C 1.10 (95% CI: 0.97-1.25), Lp(a) 1.15 (1.03-1.29), hsCRP 1.19 (1.04-1.37), and IL-6 1.67 (1.44-1.93). In MESA, corresponding HRs were: LDL-C 1.26 (1.02-1.56), Lp(a) 1.23 (0.99-1.53), hsCRP 1.13 (0.88-1.44), and IL-6 1.60 (1.24-2.07). CONCLUSION: In two large primary prevention cohorts, IL-6 demonstrated the strongest association with ASCVD, independent of LDL-C, Lp(a), and hsCRP when mutually adjusted. These data suggest that IL-6 may be a key driver of ASCVD, with potential implications for risk prediction and therapeutic targeting for prevention of ASCVD.