INTERLEUKIN-18 PROMOTER GENE POLYMORPHISMS
ARE NOT ASSOCIATED WITH MYOCARDIAL INFARCTION
IN TYPE 2 DIABETES IN SLOVENIA
Kariž S1*, Petrovič D2
*Corresponding Author: Stojan Kariž, Department of Internal Medicine, General Hospital Izola, Polje
35, Izola 6310, Slovenia; Tel.: +386-5-660-6480; Fax: +386-660-6305; E-mail: stojan.kariz@siol.net
page: 3
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DISCUSSION
In 495 patients with type 2 diabetes (169 patients
with MI and 326 controls), we found no association
between the –137 (G>C) and –607 (C>A) polymorphisms
in the IL-18 gene promoter region and the occurrence
of MI. The genotype distributions we found
agreed with previously published results from healthy
European Caucasians and from subjects with type 1
diabetes [21].
Type 2 diabetes is a chronic inflammatory disorder
characterized by increased CRP serum levels [22],
which independently increase the risk of cardiovascular
events among these patients [23,24]. Accordingly,
our patients had increased high sensitivity CRP levels,
which was significantly higher in patients with MI. We
also found significantly higher IL-18 levels in diabetic
patients with MI than in those without clinical CAD.
Our results agree with those of previous studies that elevated
IL-18 levels may be associated with acceleration
of atherosclerosis in type 2 diabetic patients [11,25]. It
has been shown that IL-18 is an independent predictor
of cardiovascular events in subjects with metabolic
syndrome and especially in the presence of elevated
fasting glucose, suggesting a synergistic effect of hyperglycemia
and inflammation [26]. Unlike previous
reports [10,27], we found no difference between IL-18
levels in diabetic and in normal patients.
Interleukin-18 is a potent proinflammatory and
proatherogenic cytokine directly associated with development of unstable atherosclerotic plaques [6].
Interleukin-18 induces the expression of interferon-γ
and matrixmetalloproteinases, which may cause plaque
destabilization and rupture [5]. In mouse models,
exogenously-administered IL-18 accelerated the development
of atherosclerotic lesion [28] and increased
plaque size and inflammatory cell content [7]. On
the other hand, the IL-18 binding protein, a natural
antagonist of IL-18, decreased the inflammatory cell
infiltrate and generated a stable plaque phenotype [8].
The IL-18 levels are higher among patients with unstable
angina pectoris and previous MI [9,29,30] and predict cardiovascular death in patients with CAD
[31] and acute coronary events in healthy middle-aged
men [32]. Likewise, serum IL-18 levels are increased
in type 2 diabetic patients [10], and are a strong independent
risk factor for the development of diabetes in
middle-aged men and women [27]. They were also associated
with nephropathy and atherosclerosis in Japanese
patients with type 2 diabetes [25].
Polymorphisms in the promoter region of the IL-18
gene may influence transcriptional activity and thus the
level of the cytokine expression [13]. We found the IL-18
levels to be significantly lower in diabetic patients with the –137 CC genotype compared to those with CG+GG
genotypes. Similarly, a greater capacity to produce IL-
18 by monocytes has been reported in those with the
–137 GG genotype [33], as has higher IL-18 mRNA
levels in those with –607 CC and –137 GG genotypes
compared to persons with other genotypes [13]. Despite
the association between –137 (G>C) polymorphism and
IL-18 serum levels, the polymorphism was not related
to MI in our cohort of diabetic patients. However, in a
recent Chinese study, the –137 GG genotype was linked
to higher IL-18 serum levels and a greater likelihood of
angiographically-proven CAD [16]. Likewise, C allele
carriers of this polymorphism have decreased production
of IL-18 and a lower risk for sudden cardiac death
caused by CAD [15]. The same authors have also demonstrated
that the –137 (G>C) polymorphism modulates
the effect of hypertension on the development and
complications of CAD [34].
The discrepancy between the results of our and
other association studies may be due to differences in
phenotype definition, the variation in the genetic or environmental
background of the populations studied, or
a sample not adequate to detect a modest association
[35]. The negative result may also be due to survival
bias, since we enrolled only patients who survived acute
MI. Since the –137 (G>C) polymorphism has been associated
with sudden cardiac death [15], this could also
have influenced the results of our study. Only a prospective
study could overcome this limitation. In conclusion, the polymorphisms –137 (G>C)
(rs187238) and –607 (C>A) (rs1946518) of the IL-18
gene are not risk factors for MI in patients with type 2
diabetes and cannot be used as genetic markers for MI
in Caucasians with type 2 diabetes. Although the –137
(G>C) polymorphism was related to IL-18 serum levels,
we assume the association is not strong enough to
influence the risk of MI in diabetic patients.
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