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

Date Published: April 8, 2008

Publisher: Public Library of Science

Author(s): John Danesh, Stephen Kaptoge, Andrea G Mann, Nadeem Sarwar, Angela Wood, Sara B Angleman, Frances Wensley, Julian P. T Higgins, Lucy Lennon, Gudny Eiriksdottir, Ann Rumley, Peter H Whincup, Gordon D. O Lowe, Vilmundur Gudnason, Colin Baigent

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.

Partial Text: As atherosclerosis may be an inflammatory condition [1], there is interest in the relevance of various circulating inflammatory markers to cardiovascular diseases [2]. Inflammatory cascades are propagated by proximal mediators such as interleukin-6 (IL-6), a cytokine produced in various tissues. IL-6 exerts proinflammatory effects including stimulation of the liver to produce positive acute-phase proteins during tissue injury or infection [3–5]. Previous epidemiological studies of coronary heart disease (CHD) and inflammation have focused mainly on “downstream” acute phase reactants (e.g., fibrinogen [6] and C-reactive protein [7]) because they are comparatively stable within individuals over time. By contrast, investigation of IL-6 in CHD has been relatively limited because of its shorter half-life (<2 h) and greater within-person variability. Published prospective studies of IL-6 have yielded divergent odds ratios ranging from 1.0 to 3.0 [8–21]. However, as each report has typically comprised only a few hundred patients with CHD, the estimates involve wide, overlapping confidence intervals (CIs). A recent nonquantitative review [22] reported on published data from five prospective studies of IL-6 and CHD, but it comprised only about one-third of the currently published evidence, and it mixed results of studies involving different vascular outcomes and of different study designs. Even a more comprehensive and consistent review of published reports would not, however, have been able to assess appropriately IL-6–CHD associations, because no individual prospective study to our knowledge has yet made allowances for the cytokine's within-person variability. Owing to fluctuations in IL-6 values over time, comparisons using only baseline values may yield biased estimates of the true association, which can be corrected, for the most part, by using data from paired measurements [23–27] (see Methods). Previous reports on IL-6 levels and CHD have not been able to correct for within-person fluctuations in the levels of this short-acting cytokine, potentially yielding biased estimates. The present study, which made such correction on the basis of paired measurements of IL-6, indicates that long-term average (“usual”) IL-6 levels are about as strongly associated with CHD risk as are some major established risk factors. Increasing IL-6 levels are associated with progressively increasing odds ratios for CHD (i.e., there are continuous, approximately log-linear relationships). There are moderate associations of IL-6 levels with some established risk factors (notably smoking, diabetes, and dyslipidemia) and with several downstream inflammatory markers, consistent with the key role of IL-6 in mediating inflammatory cascades [3–5,41–44]. The current findings do not, of course, establish causality, but they may have implications for understanding disease mechanisms and for further research strategies. Source:


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