IL-6 as a Mediator of the Association Between Traditional Risk Factors and Future Myocardial Infarction: A Nested Case-Control Study

Abstract

Objective: Studies elucidating the importance of IL (interleukin)-6 trans-signaling associated with risk of future myocardial infarction (MI) are scarce. Additionally, whether elevation in IL-6 explains part of the association between traditional risk factors and future MI has not been explored. Approach and Results: We conducted a nested case-control study including a total of 584 participants (292 cases and 292 controls) from Västerbotten Intervention Programme and MONICA (Multinational Monitoring of Trends and Determinants in Cardiovascular Disease) cohorts. At baseline, plasma cholesterol levels were measured, and clinical characteristics of participants were collected. In this study, we measured the plasma concentration of IL-6, sIL-6R (soluble IL-6 receptor), and sgp130 (soluble-glycoprotein130). To estimate extent of IL-6 trans-signaling, we estimated plasma concentration of a novel biomarker, the IL-6 binary complex. IL-6 binary complex concentration was significantly elevated in participants who experienced MI compared with those who did not. Univariate analyses showed that a 10-fold increase in IL-6 binary complex was associated with 3.6× higher risk of future MI (95% CI relative risk, 2.0-6.5, P<0.001). Receiver operating characteristics analyses revealed that the predictive performance of IL-6 binary complex (area under the curve, 0.614) was equivalent to that of IL-6 (area under the curve, 0.603). Furthermore, using Process mediation analyses tool, we found statistically significant indirect effect of smoking and hypertension on future MI that is mediated through increased IL-6 binary complex or plasma IL-6. Conclusions: IL-6 and IL-6 binary complex concentration in plasma were significantly associated with future MI. Our data additionally imply that both the elevated plasma IL-6, and the IL-6 binary complex concentration could partly explain, and, thus, might hypothetically be functionally associated with the increased risk of MI in smokers and hypertensive participants.