Long-term interleukin-6 levels and subsequent risk of coronary heart disease: two new prospective studies and a systematic review.
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.


RESULTS
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.
Danesh
John
J
Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom. john.danesh@phpc.cam.ac.uk
Kaptoge
Stephen
S
Mann
Andrea G
AG
Sarwar
Nadeem
N
Wood
Angela
A
Angleman
Sara B
SB
Wensley
Frances
F
Higgins
Julian P T
JP
Lennon
Lucy
L
Eiriksdottir
Gudny
G
Rumley
Ann
A
Whincup
Peter H
PH
Lowe
Gordon D O
GD
Gudnason
Vilmundur
V
D015331:Cohort Studies; D003327:Coronary Disease / Q000175:diagnosis / Q000209:etiology* / Q000276:immunology; D005260:Female; D006801:Humans; D007249:Inflammation; D015850:Interleukin-6 / Q000097:blood*; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D012307:Risk Factors
D015850:Interleukin-6