The associations of interleukin-6 (IL-6) and downstream inflammatory markers with risk of cardiovascular disease: The Caerphilly Study

Abstract Objectives Interleukin-6 (IL-6) is a key pro-inflammatory cytokine which mediates expression of several ‘downstream’ inflammatory markers and may play a role in atherothrombosis. However, it is not yet known whether IL-6 plays a role in mediating the associations of each marker with risk of coronary heart disease (CHD) or ischaemic stroke (IS). Methods and results We examined the role of IL-6 and several “downstream” markers of inflammation (leucocyte counts, plasma and serum viscosity, fibrinogen, C-reactive protein, α1-antitrypsin and α2-macroglobulin) with risk of subsequent CHD, IS, and a combined endpoint (CHD/IS) in a population of British men. 2208 men aged 45–64 years were followed for a median of 13.4 years and 486 men had experienced a cardiovascular event. In age-adjusted analyses, most inflammatory markers were significantly associated with risk of CHD or CHD/IS, but for IS associations were weaker. On multivariable analyses, including conventional risk factors, associations of serum viscosity, α2-macroglobulin and leucocyte count became non-significant for CHD and CHD/IS, while no inflammatory marker retained a significant association with risk of IS. In contrast, IL-6 retained a significant association with CHD and CHD/IS and, after adjustment for IL-6, hazard ratios for downstream inflammatory markers were attenuated to non-significance. Conclusions These findings suggest that IL-6 may play a role in mediating the associations of circulating inflammatory markers with risk of CHD in men. Further studies are required to assess whether this is also the case for risk of IS, and for CHD/IS in women.