Lipoprotein(a), interleukin-6 and cardiovascular risk in a primary prevention setting

BACKGROUND AND AIM: Both lipoprotein(a) Lp(a) and inflammation are independent causal risk factors for atherosclerotic cardiovascular disease (ASCVD). While previous studies have indicated that subclinical inflammation may influence the relationship between Lp(a) and cardiovascular risk, findings remain inconsistent. We investigated whether interleukin-6 (IL-6), an upstream cytokine, modifies the association between Lp(a) and cardiovascular risk in primary prevention. METHODS: We included UK Biobank participants free of ASCVD at baseline with plasma measurements of Lp(a) and IL-6. Participants were categorized by Lp(a) and IL-6 according to median splits and on the continuous scale using restricted cubic spline models. Primary endpoint was major adverse cardiovascular events (MACE), defined as coronary artery disease or ischemic stroke. Cox proportional hazards models estimated hazard ratios (HR) and 95% confidence intervals (CI). RESULTS: In total, 34,092 individuals were included. During a median follow-up of 13.6 years, 3166 individuals experienced a MACE. Among individuals with IL-6 above the median, elevated Lp(a) was associated with increased MACE risk (HR 1.17 95% CI 1.07-1.28) versus below median Lp(a). In contrast, no significant association was observed between above median Lp(a) levels and MACE risk in individuals with IL-6 below the median (P for interaction = 0.008). Spline-based models indicated a non-linear Lp(a) risk gradient by IL-6 strata with risk increase at lower Lp(a) levels among individuals with above median IL-6. CONCLUSIONS: In this large primary prevention cohort, we found that IL-6 modifies Lp(a)-associated cardiovascular risk.