Serum Levels of Interleukin-18—a Potential Marker of Cardiovascular Death—Could Be Determined by Genetic Predisposition
To the Editor:
Esposito et al1 recently reported that interleukin (IL)-18 and other proinflammatory cytokines are increased by hyperglycemia in subjects with impaired glucose tolerance, suggesting a causal role for hyperglycemia in the immune activation of diabetes. Moreover, they speculated that IL-18 stimulated by stress hyperglycemia could play a role in acute coronary syndromes.
The role of IL-18 in the development of cardiovascular disease was previously identified by a study carried out by Blankenberg et al,2 who found that IL-18 is a strong predictor of cardiovascular death in stable and unstable angina and probably is involved in atherotic plaque destabilization.
It is well known that subjects with type 1 diabetes have a 2- to 4-times increased risk of death from coronary heart disease in comparison with nondiabetic age-matched individuals, and hyperglycemia is believed to be a key risk factor in the development of micro- and macrovascular complications.
In our recent study (Kretowski et al, unpublished data, 2002), we observed that in newly diagnosed subjects with type 1 diabetes, fasting baseline serum levels of IL-18 were increased in comparison with healthy controls, and the degree of these elevations was not dependent on the levels of glycemic control (HbA1C). We have shown that there is an association between type 1 diabetes and G→C polymorphism at position −137 in the promoter of IL-18 gene, suggesting that IL-18 levels in type 1 diabetes could be influenced by genetic predisposition.3 Moreover, we have found that healthy first-degree relatives of diabetic patients (with normal fasting glucose levels and during oral glucose tolerance test), who share diabetic DR3/DR4 and/or DQB1*02/*0302 human leukocyte antigen alleles, have had increased levels of IL-18 independent of their autoimmune status (no difference in subjects with and without GADA, IA-2A autoantibodies). And finally there was a strong positive correlation (r=0.4, P<0.00002) between IL-18 and soluble intercellular adhesion molecule (sICAM-1) in subjects at risk for diabetes but still without glucose level disturbances. Because IL-18 induces ICAM-1 expression on peripheral blood monocytes, and serum levels of sICAM-1 have been suggested as markers of atherosclerosis and coronary heart disease (CHD) deaths,4 we think that the mechanisms of IL-18 influence on CHD still need clarification.
Taken together, our findings suggest that in type 1 diabetes, increased levels of IL-18—a potential marker of atherosclerosis and cardiovascular death—could not only result from acute hyperglycemia but also are related to genetic predisposition. The mechanisms of IL-18’s role in CHD development could also comprise the influence of IL-18 on the sICAM-1 levels.
Esposito K, Nappo F, Marfella R, et al. Inflammatory cytokine concentrations are acutely increased by hyperglycemia in humans: role of oxidative stress. Circulation. 2002; 106: 2067–2072.
Blankenberg S, Tiret L, Bickel C, et al, for the AtheroGene Investigators. Interleukin-18 is a strong predictor of cardiovascular death in stable and unstable angina. Circulation. 2002; 106: 24–30.
Kretowski A, Mironczuk K, Karpinska A, et al. Interleukin 18 promoter polymorphisms in type 1 diabetes. Diabetes. 2002; 51: 3347–3349.
Ballantyne CM, Entman ML. Soluble adhesion molecules and the search for biomarkers for atherosclerosis. Circulation. 2002; 106: 766–767.
On the basis of the association between type 1 diabetes and single nucleotide polymorphisms of the promoter of IL-18 gene at the position 137,1 Kretowski and Kinalska hypothesize that circulating levels of interleukin-18 (IL-18) in serum of diabetic patients may be related to genetic predisposition. This represents an interesting finding that may help in understanding the increased cardiovascular risk in selected patients. Referring to their as yet unpublished data, Kretowski and Kinalska also claim that newly diagnosed type 1 diabetic subjects present higher serum levels of IL-18 than do nondiabetic, healthy control subjects, without relation to glycemic control as assessed by HbA1c. At present, there are insufficient data to determine accurately the relative contribution of the fasting plasma glucose and glycemic oscillations (eg, postprandial glucose) to HbA1c. However, it appears that fasting plasma glucose is somewhat better than postprandial glucose in predicting HbA1c, especially in type 2 diabetes.2
The lack of relation between HbA1c and serum IL-18 levels in type 1 diabetic subjects does not disprove our working hypothesis that IL-18 stimulated by stress hyperglycemia may play a role in acute coronary syndromes through plaque destabilization. A third of all patients with hyperglycemia admitted to an urban general hospital do not have a prior diagnosis of diabetes3; moreover, in patients who have just experienced myocardial infarction, glucose values in excess of 110 to 144 mg/dL (6.1 to 8.0 mmol/L) are associated with a 3-fold increase in mortality (odds ratio, 3.9; 95% confidence interval, 2.9 to 5.4) and a higher risk of heart failure.4 All this strongly suggests that hyperglycemia (not necessarily measured by HbA1c, especially in nondiabetic patients) is associated with adverse outcomes for hospitalized patients with and without diabetes (especially death, disability after acute cardiovascular events, and infections).
The strong correlation Kretowski and Kinalska found between IL-18 and intercellular adhesion molecule (ICAM)-1 in subjects at risk for type 1 diabetes may not be surprising considering the recent evidence that IL-18 signaling evokes ICAM-1 expression in human atheroma in situ.5
In conclusion, genetic predisposition may well be implicated in increased circulating levels of IL-18, at least in selected patients, such as type 1 diabetic patients; on the other hand, the role of acute hyperglycemia as a contributory factor to plaque destabilization in acute coronary syndromes through raised IL-18 concentrations deserves further investigation.
Kretowski A, Mironczuk K, Karpinska A, et al. Interleukin-18 promoter polymorphisms in type 1 diabetes. Diabetes. 2002; 51: 3347–3349.
American Diabetes Association. Postprandial blood glucose. Diabetes Care. 2001; 24: 775–778.
Gerdes N, Sukhova GK, Libby P, et al. Expression of interleukin-18 and functional IL-18 receptor on human vascular endothelial cells, smooth muscle cells, and macrophages: implications for atherogenesis. J Exp Med. 2002; 195: 245–257.