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

John Danesh1* , Stephen Kaptoge1 , Andrea G. Mann1, Nadeem Sarwar1, Angela Wood1, Sara B. Angleman1, Frances Wensley1, Julian P. T. Higgins2, Lucy Lennon3, Gudny Eiriksdottir4,5, Ann Rumley6, Peter H. Whincup7, Gordon D. O. Lowe6, Vilmundur Gudnason4,5 1 Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom, 2 Medical Research Council Biostatistics Unit and Public Health Genetics Unit, Cambridge, United Kingdom, 3 Department of Primary Care and Population Sciences, Royal Free University College London Medical School, London, United Kingdom, 4 Icelandic Heart Association, Kopavogur, Iceland, 5 University of Iceland, Kopavogur, Iceland, 6 Division of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, Scotland, United Kingdom, 7 Division of Community Health Sciences, St George's, University of London, London, United Kingdom

Background

The 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 Findings

Measurements 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).

Conclusions

Long-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.

Funding:

This study was supported by programme and project grants from the British Heart Foundation (to JD, PHW, GDOL, and VG) and by the Raymond and Beverly Sackler Research Award in the Medical Sciences (to JD). SA is supported by a National Institutes of Health-Cambridge fellowship and her doctoral studies are cosupervised by T. Harris at the National Institute on Aging. Aspects of the study were supported by an unrestricted educational grant from GlaxoSmithKline (to JD). The funding bodies had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.

Competing Interests: The authors have declared that no competing interests exist.

Academic Editor: Colin Baigent, University of Oxford, United Kingdom

Citation:Danesh J, Kaptoge S, Mann AG, Sarwar N, Wood A, et al. (2008) Long-Term Interleukin-6 Levels and Subsequent Risk of Coronary Heart Disease: Two New Prospective Studies and a Systematic Review. PLoS Med 5(4): e78 doi:10.1371/journal.pmed.0050078

Received: September 6, 2007

Accepted: February 18, 2008

Published: April 8, 2008

Copyright: © 2008 Danesh et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abbreviations: BRHS, British Regional Heart Study; CHD, coronary heart disease; CI, confidence interval; ECG, electrocardiogram; IL-6, interleukin-6; MI, myocardial infarction; SD, standard deviation

* To whom correspondence should be addressed. E-mail: john.danesh@phpc.cam.ac.uk

These authors contributed equally to this work.