title: Long-term interleukin-6 levels and subsequent risk of coronary heart disease: two new prospective studies and a systematic review.
abstract: 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.
authors.affiliation: Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom. john.danesh@phpc.cam.ac.uk
authors.forename: John
authors.initials: J
authors.lastname: Danesh
authors.forename: Stephen
authors.initials: S
authors.lastname: Kaptoge
authors.forename: Andrea G
authors.initials: AG
authors.lastname: Mann
authors.forename: Nadeem
authors.initials: N
authors.lastname: Sarwar
authors.forename: Angela
authors.initials: A
authors.lastname: Wood
authors.forename: Sara B
authors.initials: SB
authors.lastname: Angleman
authors.forename: Frances
authors.initials: F
authors.lastname: Wensley
authors.forename: Julian P T
authors.initials: JP
authors.lastname: Higgins
authors.forename: Lucy
authors.initials: L
authors.lastname: Lennon
authors.forename: Gudny
authors.initials: G
authors.lastname: Eiriksdottir
authors.forename: Ann
authors.initials: A
authors.lastname: Rumley
authors.forename: Peter H
authors.initials: PH
authors.lastname: Whincup
authors.forename: Gordon D O
authors.initials: GD
authors.lastname: Lowe
authors.forename: Vilmundur
authors.initials: V
authors.lastname: Gudnason
mesh_terms: 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
chemical_list: D015850:Interleukin-6