Increased serum levels of interleukin 1 receptor antagonist (IL-1ra) levels precede the onset of coronary heart disease: results from the MONICA/KORA Augsburg study

Aims: Interleukin-1β (IL-1β) represents a key proinflammatory cytokine in the development of atherosclerosis and coronary heart disease (CHD). The activity of IL-1β is counter-regulated by interleukin-1 receptor antagonist (IL-1ra), an endogenous inhibitor. Data on the relevance of circulating IL-1ra levels for cardiovascular risk are scarce and inconsistent. Therefore, this study aimed (i) to examine the association between serum IL-1ra and incident CHD in the general population and (ii) to test whether this association is explained by other inflammation-related biomarkers. Methods: This case-cohort study uses data from the population-based MONICA/KORA Augsburg cohort. During a follow-up time of 16.0 ± 5.8 years, 803 cases and 1942 non-cases were observed for the combined CHD endpoint (non-fatal myocardial infarction and coronary death before the age of 75 years). Associations between IL-1ra and incidence of CHD were assessed using Cox regression adapted for cases-cohort analyses. Results: Cases had higher IL-1ra serum levels than non-cases (geometric means [antilog of SE] 338.81 [1.02] vs. 352.59 [1.01] pg/ml; p < 0.001). The hazard ratio (95% CI) for incident CHD was 1.15 (1.02; 1.30) per standard deviation of log-transformed IL-1ra serum levels after adjustment for age, sex, anthropometric, metabolic and lifestyle factors (p = 0.022). The excess risk for CHD was attenuated by ≥10% after additional adjustment for high-sensitivity C-reactive protein, IL-6, myeloperoxidase or soluble adhesion molecules. Conclusion: Serum IL-1ra levels are positively associated with increased risk of CHD. This association may at least partially reflect a counter-regulation to subclinical inflammation, endothelial activation and oxidative stress.