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Interleukin-18 levels are not associated with subclinical carotid

atherosclerosis in a community population. The Perth Carotid Ultrasound
Disease Assessment Study (CUDAS)

Article  in  Atherosclerosis · December 2006

DOI: 10.1016/j.atherosclerosis.2005.12.026 · Source: PubMed

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 Atherosclerosis 189 (2006) 414–419

Interleukin-18 levels are not associated with subclinical carotid

atherosclerosis in a community population
The Perth Carotid Ultrasound Disease
Assessment Study (CUDAS)
Caroline M.L. Chapman a , Brendan M. McQuillan b,c , John P. Beilby a,d ,
Peter L. Thompson b,c , Joseph Hung b,c,∗
a Clinical Biochemistry, PathWest, QEII Medical Centre, Perth, WA, Australia
b Sir Charles Gairdner Hospital Campus of the Heart Research Institute of Western Australia, Perth, WA, Australia
c School of Medicine and Pharmacology, University of Western Australia, Perth, WA, Australia
d School of Surgery and Pathology, University of Western Australia, Perth, WA, Australia

Received 29 June 2005; received in revised form 20 December 2005; accepted 22 December 2005
Available online 24 January 2006

Abstract

Interleukin (IL)-18 is a novel proinflammatory cytokine that plays a central role in innate and acquired immunity, making it a likely
inflammatory candidate in atherosclerosis. We investigated whether circulating IL-18 levels were associated with subclinical atherosclerosis
in a community population. Carotid intimal medial thickness (IMT) and carotid plaques were assessed in a cross-sectional study of 1111
randomly selected community subjects, aged 27–77 years. Baseline levels of IL-18, IL-6, high sensitive CRP (hsCRP), fibrinogen and white
cell counts were measured along with conventional cardiovascular risk factors. Men had higher mean IL-18 levels than women (P < 0.0001).
Spearman rank correlations (rs ) showed that IL-18 was weakly correlated with all inflammatory markers in the whole population (rs between
0.11 and 0.23, all P < 0.001). IL-18 was also correlated with conventional risk factors including waist–hip ratio, BMI, blood pressure,
triglycerides, HDL (inversely) and pack-years smoking (rs between 0.18 and 0.39, all P < 0.001) but not with LDL-cholesterol. Independent
predictors of IL-18 concentrations were waist–hip ratio, HDL, IL-6, hsCRP and hypertension. There was a positive univariate association
of IL-18 levels with carotid IMT (P < 0.001) and plaque prevalence (P < 0.001) but no residual association after adjustment for conventional
risk factors (both P > 0.05). In a cross-sectional community population, IL-18 levels were related to traditional risk factors and inflammatory
markers but were not independently associated with subclinical carotid atherosclerosis.
© 2006 Elsevier Ireland Ltd. All rights reserved.

Keywords: Interleukin-18; Inflammation; Atherosclerosis; Carotid arteries; Ultrasound

1. Introduction rotic plaques [1,2]. Studies have shown that markers of

The innate and adaptive immunity via inflammatory medi-
ators plays a fundamental role in the initiation and progres-
sion of atherosclerosis, and the eventual rupture of atheroscle-
∗ Corresponding author at: Sir Charles Gairdner Hospital Unit, School
of Medicine and Pharmacology M503, Verdun Street, Nedlands, WA 6009,
Australia. Tel.: +61 89346 3488; fax: +61 89346 2816.
E-mail address: jhung@cyllene.uwa.edu.au (J. Hung).
inflammation such as high sensitive CRP (hsCRP), inter-
leukin (IL)-6, leucocyte count, and fibrinogen are associated
with future cardiovascular disease [3–5]. However, it is still
unclear whether these markers reflect underlying atheroscle-
rotic burden, an increased tendency for plaque instability and
thrombosis, or both. Determining whether levels of inflam-
matory markers associate with subclinical atherosclerosis
can have important application for clinical and public health
practice [6]. We recently showed that monocyte count is a

0021-9150/$ – see front matter © 2006 Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.atherosclerosis.2005.12.026
 C.M.L. Chapman et al. / Atherosclerosis 189 (2006) 414–419
better independent predictor of subclinical carotid atheroscle-
rosis than hsCRP, IL-6, fibrinogen and total white cell count
in a community population [7]. More research is therefore
required to identify the important inflammatory mediators
involved in atherogenesis.
IL-18 is novel proinflammatory cytokine that appears to
play a central role in innate and acquired immunity, making
it a likely inflammatory candidate in the atherosclerotic pro-
cess [8,9]. IL-18 acts directly as a proinflammatory cytokine
by inducing IL-1␤, IL-8, adhesion molecules, granulocyte-
macrophage colony stimulating factor and tumor necrosis
factor-␣ [10]. IL-18 also promotes (Th1) T lymphocyte differ-
entiation, and stimulates the production of interferon (IFN)-␥
by T cells, natural killer cells and macrophages [11]. IFN-␥
promotes plaque development and instability by stimulating
the expression of adhesion molecules on endothelial cells,
and MHC II complex on macrophages and vascular cells as
well as inhibiting collagen synthesis by smooth muscle cells.
Increased expression of IL-18 has been reported in human
atherosclerotic plaques and related to plaque destabilization
[12]. The introduction of the endogenous inhibitor of IL-18,
the IL-18 binding protein, has been shown to slow the pro-
gression of atherosclerotic plaques and produce a more stable
lesion phenotype in the apoE knockout mice [13].
Epidemiological studies have also suggested that IL-18
levels can predict cardiovascular death in patients with stable
and unstable angina [14] as well as future coronary events
in apparently healthy men [15]. These findings suggest that
IL-18 aggravates existing cardiovascular disease. Whether
levels of IL-18 also associate with early atherosclerosis in
asymptomatic subjects is yet to be investigated.
High-resolution B-mode carotid ultrasonography has been
used for non-invasive detection of subclinical atheroscle-
rosis in large community-based cohorts [7,16,17]. Carotid
intima–medial wall thickness (IMT) and plaque measured in
this way have been shown to correlate with standard cardio-
vascular risk factors, atherosclerosis in other vascular beds
and incident myocardial infarction and strokes [18,19]. In
the present study, we evaluated the independent relation-
ship between the inflammatory marker IL-18 and subclinical
atherosclerosis as assessed by B-mode ultrasound in a cross-
sectional, community-based sample of mostly asymptomatic
subjects from Western Australia.
2. Experimental procedures
2.1. Subjects
The selection criteria and study design of the community-
based Carotid Ultrasound Disease Assessment Study
(CUDAS) have been detailed previously [17,20]. In brief,
this was a random electoral roll sample of 1111 subjects (558
men and 553 women) aged 27–77 years from Perth, Western
Australia. Subjects who had previous carotid artery surgery
were excluded. A self-administered questionnaire was used
415
to record a history of smoking, hypertension, hyperlipidemia,
diabetes, angina pectoris, myocardial infarction (MI), stroke
or a family history of premature-onset MI or stroke by age
55 years in first degree relatives. Anthropomorphic measure-
ments and the lower of two resting blood pressures were
recorded. Written informed consent was obtained from all
study participants. The study protocol was approved by the
Institutional Ethics Committee of the University of Western
Australia.
2.2. Biochemical analysis
A fasting blood sample was obtained from each subject.
Serum IL-18 was measured by a commercially available
ELISA method (MBL Co. Ltd.) as previously described
[15,21]. The within run coefficients of variation were 5.4%
at a mean value of 400 ␮g/L (28 samples); between run coef-
ficients of variation were 8.2% at 298 ␮g/L (9 samples) and
7.8% at 496 ␮g/L (9 samples). Serum IL-6 was measured
using an ELISA (Quantikine HS, R&D Systems) with an
assay range of 0.38–10 ng/L. Serum hsCRP was measured by
a microparticle turbidity assay (Hitachi 917, Roche) with a
range of 0.1–21.0 mg/L. Plasma fibrinogen was measured by
the Clauss method. Monocyte and white cell counts (WCC)
were obtained using standard techniques. Total cholesterol,
HDL cholesterol (HDL) and triglyceride levels were deter-
mined enzymatically with an Hitachi 747 autoanalyzer.
2.3. Carotid ultrasound
Bilateral carotid B-mode ultrasound was performed
by two trained sonographers using a 7.5-MHz annular
phased-array transducer on an Interspec (Apogee) CX 200
ultrasound machine as previously described [17]. The IMT
was defined as the distance between the characteristic echoes
from the lumen–intima and media–adventitia interfaces on
the far wall of the distal common carotid artery measured
over a 1 cm segment length. A thorough search of the
distal common carotid, carotid bulb, and internal and
external carotid arteries was also made to determine the
presence of focal plaque. Plaque was defined as a clearly
identified area of focal increased thickness (≥1 mm) of
the intima–media layer. Three end-diastolic images were
analysed from the right and left distal common arteries at a
site free of any discrete plaque and measurements averaged
to give the mean IMT. Repeat measurements of randomly
selected scans revealed no significant variation in the IMT
measurements.
2.4. Statistical analysis
Outcome variables of the association analyses were
carotid IMT and the presence of carotid plaque. The prin-
cipal explanatory variable was the inflammatory marker IL-
18. Body mass index (BMI), triglycerides, HDL, carotid
IMT, IL-18, IL-6, hsCRP, monocyte count and WCC were
416 C.M.L. Chapman et al. / Atherosclerosis 189 (2006) 414–419

not normally distributed and therefore log (base e) trans- 3. Results

formed prior to analysis. Geometric means and 95% confi-
dence intervals (1.96 × S.E.M.) are given for these variables.
Outliers of hsCRP and IL-6 (n = 2) and monocyte count
(n = 2) were excluded from analysis as before [7]. Continu-
ous variables were compared using t-tests, or Mann–Whitney
U-test for nonparametric analysis of variables not nor-
mally distributed. Categorical variables were compared by
␹2 -test.
Spearman rank correlations were used to describe the
association of inflammatory markers and conventional risk
factors. Forward and backwards stepwise multiple logistic
regression analysis was used to determine independent pre-
dictors of carotid plaque. Independent predictors of IL-18 and
carotid IMT were determined by generalised linear regres-
sion modelling (GLM). Statistical significance was taken
as P < 0.05. SPSS version 10.1 for windows was used in
analysis.
Analysis was carried out on 557 males and 550 females,
mean age 53.3 ± 12.6 (age range 27–77 years). The char-
acteristics of the population are outlined by sex in Table 1.
Males compared with females had higher IL-18 levels and
monocyte count (both P < 0.0001) and lower fibrinogen lev-
els (P = 0.03). One or more plaques were observed in 22% of
females and 29% of males. A personal history of stroke or
MI was recorded in 8% of the population (5% females and
11% males).
Spearman rank correlations (rs ) showed that IL-18 cor-
related weakly with hsCRP, IL-6, fibrinogen, monocyte and
WCC in this population (rs from 0.11 to 0.23, all P < 0.001)
(Table 2). IL-18 also correlated moderately with conven-
tional risk factors including systolic blood pressure, BMI,
waist–hip ratio, HDL (inversely), triglycerides, and smoking
pack-years (rs from 0.18 to 0.39, all P < 0.001) but not with

Table 1
Characteristics of the CUDAS study population
Variable Females (n = 550) Males (n = 557) P value
Age 53.2 ± 12.7 53.4 ± 12.7 ns
BMIa 25.1 (24.7, 25.4) 26.5 (26.2, 26.8) <0.0001
Waist–hip ratioa 0.77 (0.76, 0.77) 0.90 (0.90, 0.90) <0.0001
Systolic blood pressure (mmHg) 127.1 ± 20.1 129.5 ± 16.8 0.03
HDLa (mmol/L) 1.46 (1.43, 1.49) 1.13 (1.11, 1.15) <0.0001
LDL (mmol/L) 3.56 ± 0.90 3.70 ± 0.87 0.009
Triglyceridesa (mmol/L) 1.01 (0.96, 1.05) 1.28 (1.23, 1.34) <0.0001
Mean IMTa (mm) 0.68 (0.67, 0.69) 0.72 (0.70, 0.73) <0.0001
Interleukin-18a (␮g/L) 266.1 (257.0, 275.5) 340.4 (329.1, 352.0) <0.0001
hsCRPa (mg/L) 1.84 (1.67, 2.02) 1.68 (1.54, 1.84) ns
Interleukin-6a (␮g/L) 3.68 (3.55, 3.82) 3.61 (3.47, 3.76) ns
Fibrinogen (g/L) 2.79 ± 0.68 2.70 ± 0.63 0.03
Monocyte counta (×109 L−1 ) 0.45 (0.44, 0.46) 0.53 (0.52, 0.55) <0.0001
Values are mean ± S.D. ns: non-significant.
a Geometric mean (±95% CI) for skewed variables.

Table 2
Spearman rank correlations of interleukin-18 and other inflammatory variables against standard cardiovascular risk factors and carotid IMT in the whole
population
IL-18 hsCRP IL-6 Fibrinogen Monocytes WCC
hsCRP 0.23† – – – – –
IL-6 0.21† 0.49† – – – –
Fibrinogen 0.11† 0.50† 0.40† – – –
Monocytes 0.15† 0.14† 0.20† 0.08* – –
WCC 0.15† 0.27† 0.27† 0.19† 0.55† –
Age 0.12† 0.20† 0.34† 0.34† 0.06* 0.04
Systolic BP 0.18† 0.23† 0.27† 0.25† 0.08* 0.07*
Waist–hip ratio 0.39† 0.19† 0.14† 0.07* 0.28† 0.14†
BMI 0.26† 0.39† 0.26† 0.21† 0.13† 0.13†
LDL 0.07* 0.10* 0.07 0.14† 0.02 −0.02
HDL −0.31† −0.15† −0.10* −0.09* −0.18† −0.17†
Triglycerides 0.26† 0.25† 0.20† 0.15† 0.18† 0.26†
Smoking (pack-years) 0.19† 0.16† 0.17† 0.07* 0.24† 0.23†
IMT 0.17† 0.21† 0.30† 0.26† 0.12† 0.09*
* P < 0.05.
† P < 0.001.
 C.M.L. Chapman et al. / Atherosclerosis 189 (2006) 414–419 417

Table 3
Age adjusted mean levels of inflammatory markers for categorical risk factors
IL-18 (␮g/L) hsCRP (mg/L) IL-6 (␮g/L) Fibrinogen (g/L) Monocytes (×109 L−1 )
Hypertension
No 291.8 (283.4, 300.4) 1.65 (1.53, 1.78) 3.54 (3.44, 3.65) 2.73 (2.69, 2.78) 0.48 (0.47, 0.49)
Yes 327.7 (311.4, 344.8) 2.18 (1.91, 2.49) 4.00 (3.79, 4.22) 2.77 (2.70, 2.85) 0.51 (0.49, 0.53)
P value <0.0001 <0.0001 <0.0001 ns 0.02
Smoking
Never 283.2 (273.4, 292.9) 1.57 (1.44, 1.72) 3.52 (3.39, 3.65) 2.76 (2.70, 2.81) 0.46 (0.45, 0.47)
Ever 319.3 (308.3, 330.6) 1.99 (1.81, 2.17) 3.80 (3.66, 3.94) 2.73 (2.68, 2.79) 0.52 (0.51, 0.53)
P value <0.0001 <0.0001 0.003 ns <0.0001
Obesity
BMI <30 292.4 (284.3, 300.4) 1.57 (1.47, 1.68) 3.52 (3.42, 3.61) 2.71 (2.67, 2.75) 0.49 (0.48, 0.49)
BMI ≥30 342.7 (322.8, 363.9) 3.13 (2.68, 3.64) 4.41 (4.14, 4.69) 2.91 (2.82, 3.00) 0.51 (0.49, 0.53)
P value <0.0001 <0.0001 <0.0001 <0.0001 0.04
Plaque
No 296.5 (287.7, 305.8) 1.76 (1.63, 1.90) 3.60 (3.48, 3.71) 2.75 (2.70, 2.79) 0.48 (0.47, 0.49)
Yes 311.1 (295.0, 328.3) 1.79 (1.56, 2.07) 3.82 (3.61, 4.05) 2.74 (2.66, 2.83) 0.53 (0.51, 0.55)
P value ns ns 0.08 ns <0.0001
History of MI and/or stroke
No 299.5 (291. 8, 307.7) 1.73 (1.61, 1.84) 3.61 (3.51, 3.71) 2.74 (2.70, 2.78) 0.49 (0.48, 0.50)
Yes 309.5 (283.2, 338.3) 2.36 (1.86, 2.99) 4.27 (3.87, 4.69) 2.81 (2.67, 2.95) 0.54 (0.51, 0.58)
P value ns 0.01 0.001 ns 0.003
Data are geometric means ±95% confidence intervals adjusted for age. ns: non-significant; MI: myocardial infarction.

LDL-cholesterol (Table 2). IL-18 had a weak positive associ-
ation with age (rs = 0.12, P < 0.001) and mean IMT (rs = 0.17,
P < 0.001). Similar trend associations were seen in males and
females (data not shown).
As with other inflammatory markers, age-adjusted IL-18
levels were higher in subjects with hypertension, or who were
current/ex-smokers or were obese (Table 3, all P < 0.0001).
IL-18 levels were also higher in subjects with carotid plaques
compared to those without, 322.1 (306.3, 338.8) and 292.7
(284.3, 301.2) ␮g/L, respectively (P = 0.001). However, once
adjusted for age no significant difference was observed
(Table 3). Subjects who had a personal history of myocardial
infarction or stroke did not have significantly higher IL-18
levels than those without disease (Table 3). However other
inflammatory markers were significantly raised in subjects
with vascular disease (Table 3).
Multivariate analysis showed that waist–hip ratio
(β = 0.265, P < 0.0001), HDL (β = −0.146, P < 0.0001),
hsCRP (β = 0.105, P = 0.002), IL-6 (β = 0.082, P = 0.01) and
hypertension (β = 0.073, P = 0.01) were independent predic-
tors of IL-18 levels in the whole population. These variables
explained ≈20% of the variance in levels of IL-18.
Multivariate regression analysis showed that mean carotid
IMT (adjusted for age, sex, systolic blood pressure, waist–hip
ratio, LDL, smoking and family history of premature MI)
did not associate with increasing tertiles of IL-18 (Table 4,
P > 0.05). There was also no significant association when
IL-18 was entered into the model as a continuous variable
(P > 0.05). In a stepwise analysis IL-18 was significantly
associated with carotid IMT when adjusted for age and sex
(P = 0.04), but on addition of systolic blood pressure signifi-
cance was no longer reached.
Multivariate modelling (adjusted for age, LDL, smoking,
and history of hypertension, stroke or MI) indicated that the
odds of having a carotid plaque did not differ between tertiles
of IL-18 (Table 4, P > 0.05). There was also no linear associ-
ation of IL-18 with carotid plaque (P > 0.05). No interaction
effects on IMT or presence carotid plaque were observed
between IL-18, standard cardiovascular risk factors or other
inflammatory markers.

Table 4
Multivariate analysis of interleukin-18 with carotid atherosclerosis
Interleukin-18 Adjusted mean P valueb Subjects with carotid Odds ratio (95% CI) P valuec
(␮g/L) IMT (mm)a plaque, n (%) for carotid plaque
Tertiles
1 ≤250.06 0.70 (0.69, 0.71) Reference 84 (24.3) Reference
2 250.07–356.66 0.70 (0.69, 0.71) >0.05 91 (26.4) 0.94 (0.62, 1.44) >0.05
3 ≥356.67 0.70 (0.69, 0.71) >0.05 103 (29.9) 0.87 (0.57, 1.32) >0.05
a Data is adjusted geometric means and 95% confidence intervals.
b Multivariate linear regression analysis of carotid IMT adjusted for age, sex, systolic BP, waist–hip ratio, LDL, smoking (pack-years) and family history of
MI.
c Logistic regression analysis for carotid plaque adjusted for age, LDL, smoking (pack-years) and history of hypertension, stroke and MI.
418 C.M.L. Chapman et al. / Atherosclerosis 189 (2006) 414–419
4. Discussion
In this cross-sectional community study we have shown
that serum IL-18 levels are not independently associated
with subclinical carotid atherosclerosis in predominantly
healthy subjects. Although the role of IL-18 in atherogen-
esis is not fully understood, IL-18 is an important candi-
date marker due to its pleiotropic proinflammatory effects
and regulatory role in the innate and acquired immune
response. Our study is the first broad based community
study investigating the association of IL-18 with subclinical
atherosclerosis.
A proatherogenic role for IL-18 is supported by several
sources of evidence [8,9]. Ex vivo studies have shown that
IL-18 is expressed in human atherosclerotic lesions, with
unstable plaques having significantly higher levels of IL-18
mRNA [12]. Other experimental studies have shown that IL-
18 is directly involved in atherosclerotic plaque progression
and vulnerability through proinflammatory effects and stim-
ulation of IFN-␥ production [13,22,23]. Indeed it has recently
been shown that IL-18 over-expression decreased intimal
collagen content in ApoE null mice, leading to increased
instability of plaques [24].
Epidemiological studies have also suggested a role for
IL-18 in cardiovascular disease. Cardiovascular death was
predicted by circulating IL-18 levels in patients with stable
and unstable angina [14]. A recent study showed that baseline
plasma levels of IL-18 can predict future coronary events after
a 5 years follow-up in apparently healthy middle aged men
[15].
Thus IL-18 appears to participate in progression of
atherosclerosis and may predispose to plaque instability and
acute coronary events. Our principal finding that IL-18 levels
are not a multivariate predictor of subclinical atherosclerosis
does not definitely exclude a role for IL-18 in early stages of
disease. However, it does indicate that the circulating IL-18
levels are not a useful risk marker for subclinical atheroscle-
rosis. This is consistent with our previous finding that levels
of inflammatory markers, hsCRP and IL-6, also did not inde-
pendently associate with subclinical carotid atherosclerosis
in this community population [7].
A recent paper by Yamagami et al. [25] showed a posi-
tive association of IL-18 with carotid IMT in 366 hospital
patients who had undergone a carotid examination, but who
did not have a history of ischaemic heart disease, stroke or
arteriosclerosis obliterans. This association remained after
controlling for traditional risk factors (P < 0.001). The sub-
jects in this study were not from the broader community, as
in our study, were older, and exhibited a higher prevalence
of atherosclerotic risk factors. Moreover their mean maximal
IMT was higher than the mean IMT in our subjects (0.99 mm
versus 0.70 mm) suggesting the association of IL-18 levels
is with more advanced carotid atherosclerosis than displayed
in our community subjects.
IL-18 correlates modestly with other inflammatory mark-
ers hsCRP, IL-6, fibrinogen and WCC in this population.
The large prospective PRIME study of European males
aged 50–59 years also found a weak correlation of IL-
18 concentrations with CRP and IL-6 but not with fib-
rinogen [15]. We found that IL-6 and hsCRP were both
independent predictors of IL-18 concentration. This sup-
ports the idea that proinflammatory mediators such as IL-6
and hsCRP can induce IL-18 gene expression, creating a
positive feedback loop that promotes a persistent inflam-
matory state possibly contributing to disease progression
[9,26].
In our study, there was also a significant albeit modest
association of IL-18 levels with all the conventional risk fac-
tors except for LDL-cholesterol. By contrast, in the PRIME
study IL-18 concentrations did not associate with hyperten-
sion, smoking, BMI, or triglycerides [15]. Differences from
our study is likely to be explained by the fact that the PRIME
study was limited to men aged 50–59 years whereas our
study included a broad cross-sectional population of men
and women aged from 27 to 77 years. In our study, waist–hip
ratio, HDL, and hypertension history were also multivariate
predictors of IL-18 levels. Waist–hip ratio is a good indicator
of central obesity. We have previously shown that IL-18 lev-
els associate particularly with central obesity and metabolic
syndrome traits [21]. Whilst it is not known if adipose tissue
is a source of IL-18, a previous study has shown that IL-18
levels are elevated in obese women and levels are decreased
by weight loss [27]. That HDL was found to be a independent
(negative) predictor of IL-18 concentration is also interesting
and supports the proposed anti-inflammatory roles of HDL
[28].
We acknowledge that limitations of the present study exist.
IL-18 levels were measured once on serum stored at −80 ◦ C
from the date of collection. Although freeze thawing of the
sample has been minimised we cannot rule out some pro-
tein degradation, although no time dependent degradation
of IL-18 throughout the course of the study was observed.
Also the IL-18 population mean is similar to other pub-
lished studies [15]. As this study is cross-sectional in design,
our findings reflect only the association of IL-18 levels with
prevalent rather than incident atherosclerosis. Our findings do
not exclude a role for IL-18 in more advanced atherosclerotic
disease or in plaque vulnerability as suggested by previous
studies.
In conclusion, in this cross-sectional community popula-
tion, serum levels of IL-18 were related to traditional risk
factors and other inflammatory markers but were not inde-
pendently associated with subclinical carotid atherosclerosis.
The potential role IL-18 in atherosclerosis needs further elu-
cidation.
Acknowledgements
This study was supported by grant-in-aid from the
National Health and Medical Research Council (211980) and
HeartSearch, Perth, Western Australia (C.C. and J.B.)
 C.M.L. Chapman et al. / Atherosclerosis 189 (2006) 414–419
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