Long-Term Interleukin-6 Levels and Subsequent Risk of Coronary Heart Disease: Two New Prospective Studies and a Systematic Review

Abstract

BackgroundThe relevance to coronary heart disease (CHD) of cytokines that govern inflammatory cascades, such as interleukin-6 (IL-6), may be underestimated because such mediators are short acting and prone to fluctuations. We evaluated associations of long-term circulating IL-6 levels with CHD risk (defined as nonfatal myocardial infarction [MI] or fatal CHD) in two population-based cohorts, involving serial measurements to enable correction for within-person variability. We updated a systematic review to put the new findings in context.Methods and FindingsMeasurements were made in samples obtained at baseline from 2,138 patients who had a first-ever nonfatal MI or died of CHD during follow-up, and from 4,267 controls in two cohorts comprising 24,230 participants. Correction for within-person variability was made using data from repeat measurements taken several years apart in several hundred participants. The year-to-year variability of IL-6 values within individuals was relatively high (regression dilution ratios of 0.41, 95% confidence interval [CI] 0.28–0.53, over 4 y, and 0.35, 95% CI 0.23–0.48, over 12 y). Ignoring this variability, we found an odds ratio for CHD, adjusted for several established risk factors, of 1.46 (95% CI 1.29–1.65) per 2 standard deviation (SD) increase of baseline IL-6 values, similar to that for baseline C-reactive protein. After correction for within-person variability, the odds ratio for CHD was 2.14 (95% CI 1.45–3.15) with long-term average (“usual”) IL-6, similar to those for some established risk factors. Increasing IL-6 levels were associated with progressively increasing CHD risk. An updated systematic review of electronic databases and other sources identified 15 relevant previous population-based prospective studies of IL-6 and clinical coronary outcomes (i.e., MI or coronary death). Including the two current studies, the 17 available prospective studies gave a combined odds ratio of 1.61 (95% CI 1.42–1.83) per 2 SD increase in baseline IL-6 (corresponding to an odds ratio of 3.34 [95% CI 2.45–4.56] per 2 SD increase in usual [long-term average] IL-6 levels).ConclusionsLong-term IL-6 levels are associated with CHD risk about as strongly as are some major established risk factors, but causality remains uncertain. These findings highlight the potential relevance of IL-6–mediated pathways to CHD.

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

“…These results are consistent with recent meta-analyses of data from several prospective studies (including Caerphilly) for fibrinogen [6], plasma viscosity [7], leucocyte count [8] and CRP [9,10]. Interleukin-6 (IL-6) is a key pro-inflammatory cytokine which mediates expression of all these "downstream" inflammatory markers [11,12] (Fig. 2).…”

“…2). A recent systematic review of 17 prospective studies showed an overall odds ratio of 1.61 (95%CI 1.42,1.83) for subsequent risk of CHD for a two standard deviation increase in circulating levels of IL-6 [12]. Correction for within-person variability, corresponding to the longterm average IL-6 values increased the odds ratio to 3.34 (95%CI 2.45,4.56).…”

“…Detailed analysis of data from two of these cohorts suggested that IL-6 has comparable associations with subsequent CHD to classical risk factors such as systolic blood pressure and total cholesterol. Hence it has been suggested that IL-6 may play a key role in mediating the associations of "downstream" inflammatory markers (such as CRP) with risk of CHD [12], and possibly also of IS, for which little data are available.…”

Genetic Architecture of the Pro-Inflammatory State in an Extended Twin-Family Design

“…This estimate may derive from unique environmental factors or measurement error, but it may also result from gene-by-environment interactions that may inflate estimates of unique environmental effects. Unravelling the genetics of these pro-inflammatory parameters may greatly contribute to our understanding of the etiology of cardiac disease and major depression as chronic low-grade inflammation has repeatedly been shown to be associated with both (Cesari et al, 2003;Danesh et al, 2004Danesh et al, , 2008Humphries et al, 2007;Packard & Libby, 2008;Libby & Theroux, 2005;O'Brien et al, 2004;Woods et al, 2000;Penninx et al, 2003).…”

Ideal Cardiovascular Health and Incident Cardiovascular Disease: Heterogeneity Across Event Subtypes and Mediating Effect of Blood Biomarkers: The PRIME Study

“…Furthermore, studies on the possible pathways underlying the association between CVH and outcomes are scarce. Inflammatory and hemostatic blood biomarkers such as higher CRP (C‐reactive protein), IL‐6, and fibrinogen have been robustly associated with CHD or stroke and might represent relevant mediating factors to explore 13, 14, 15, 16. So far, only the Framingham study has explored the possible role of blood biomarkers in the associations between ideal CVH and outcomes 17.…”