nterleukin 18 and coronary heart disease : Prospective study and systematic eview

Aim: Previous studies suggest that circulating levels of interleukin-18 (IL-18) may be prospectively related to risk of coronary heart disease (CHD) in the general population. We report new data from the largest prospective study to date, which are combined with data from all published prospective studies in a meta-analysis. Methods: We measured baseline IL-18 levels in stored serum samples of subjects from a case–control study nested within a prospective study of 5661 men aged 40–59 years recruited from general practices in 18 British towns in 1978–1980 and followed-up for up to 16 years (median time to event 8.4 years) for fatal CHD and non-fatal myocardial infarction (595 cases, 1238 controls). Results: IL-18 concentrations were strongly related to cigarette smoking, triglyceride, HDL-cholesterol (inversely) and to circulating levels of several inflammatory and haemostatic markers. Men in the top third of baseline IL-18 levels had an age-adjusted odds ratio (OR) for CHD of 1.55 (95% CI 1.21, 1.98) compared with those in the lowest third; this was reduced to 1.30 (95% CI 0.99, 1.69) after additional adjustment for vascular risk factors and 1.12 (95% CI 0.84, 1.49) after further adjustment for CRP and IL-6. In meta-analyses of CVD, associations (or effect sizes) were consistent between studies; RRs were 1.63 (95% CI 1.46, 1.82) after age adjustment, 1.39 (95% CI 1.24, 1.55) after additional risk factor adjustment and 1.34 (95% CI 1.17, 1.54) after additional adjustment for inflammatory markers. Conclusions: Circulating IL-18 is prospectively and independently associated with CVD risk. Atherosclerosis includes an important inflammatory compoent [1]; a substantial body of evidence demonstrates prospective ssociations between circulating acute-phase reactant proteins particularly C-reactive protein [CRP] and fibrinogen) and coronary eart disease (CHD) risk [2,3]. More recently, growing evidence uggests that levels of circulating pro-inflammatory cytokines, paricularly interleukin-6 (IL-6), are prospectively related to CHD risk ∗ Corresponding author. Tel. : +44 2078302239; fax: +44 2077941224. E-mail addresses: B.jefferis@ucl.ac.uk (B.J.M.H. Jefferis), O.papacosta@ucl.ac.uk O. Papacosta), c.owen@sgul.ac. u (C.G. Owen), G.wannamethee@ucl.ac.uk S.G. Wannamethee), s.humphries@ucl.ac.uk (S.E. Humphries), arkw@georgeinstitute.org. au (M. Woodward), l.lennon@ucl.ac.uk (L.T. Lennon), . thomson@ucl.ac.uk (A. Thomson), P.welsh@clinmed.gla. ac.uk (P. Welsh), r4a@clinmed.gla. ac.uk (A. Rumley), Gdlowe@clinmed.gla. ac.uk (G.D.O. Lowe), . whincup@sgul.ac.uk (P.H. Whincup). 021-9150 © 2011 Elsevier Ireland Ltd. oi:10.1016/j.atherosclerosis. 2011.03. 015 Open access under CC BY-NC-ND license. © 2011 Elsevier Ireland Ltd. [4]. However, evidence about the influence of circulating levels of other pro-inflammatory cytokines is more limited. Interleukin-18 (IL-18) is a pleiotropic proinflammatory cytokine which plays an important role in the inflammatory cascade [5]. Some evidence suggests that its expression may be related to atherosclerotic plaque progression and vulnerability [6,7]. Circulating concentrations of IL-18 have been prospectively related to vascular events in patients with stable and unstable angina [8] or pre-existing CHD [9,10] and, more recently in nested case–control studies carried out within a population-based studies of healthy adults [11–14]. In order to clarify the strength and independence of this relationship further, we report here on the relationship Open access under CC BY-NC-ND license. between IL-18 and CHD risk in a large prospective study with considerably more events than in previous studies: a nested case–control study of middle-aged British men, nested within a large prospective study (the British Regional Heart Study), in which