Total Soluble and Endogenous Secretory Receptor for Advanced Glycation End Products as Predictive Biomarkers of Coronary Heart Disease Risk in Patients With Type 2 Diabetes: An Analysis From the CARDS Trial

Medical Research Institute, University of Dundee, Dundee, U.K.
Diabetes (Impact Factor: 8.1). 07/2011; 60(9):2379-85. DOI: 10.2337/db11-0291
Source: PubMed


Circulating levels of soluble receptor for advanced glycation end products (sRAGE) likely comprise both a secreted isoform (esRAGE) and wild-type RAGE cleaved from the cell membrane. Both sRAGE and esRAGE have been proposed as biomarkers of cardiovascular disease (CVD), but prospective data are limited. We examined the relationship of sRAGE and esRAGE to incident coronary heart disease (CHD) and stroke in type 2 diabetic patients followed for 3.9 years in a trial of atorvastatin: the Collaborative Atorvastatin Diabetes Study (CARDS).
We used a nested case-control design sampling all incident cases of CVD with available plasma and randomly selecting three control subjects, who were free of CVD throughout follow-up, per case. Analysis was by Cox regression with adjustment for treatment allocation and relevant covariates.
sRAGE and esRAGE were strongly correlated (ρ = 0.88) and were both higher in those with lower BMI (P < 0.001), higher adiponectin (P < 0.001), lower estimated glomerular filtration rate (P = 0.009), and white ethnicity (P < 0.001). Both sRAGE and esRAGE were associated with incident CHD events, independently of treatment allocation and the above factors; hazard ratio (HR) = 1.74 (95% CI 1.25-2.41; P = 0.002) for a doubling of the sRAGE level; HR = 1.45 (1.11-1.89; P = 0.006) for a doubling of the esRAGE level. There was no significant association with stroke; HR for sRAGE = 0.66 (0.38-1.14). Atorvastatin, 10 mg daily, did not alter sRAGE.
Higher levels of sRAGE and esRAGE are associated with incident CHD but not stroke in type 2 diabetes.

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    • "Colhoun et al. investigated the relationship of sRAGE to incident coronary heart disease (CHD) in patients with type 2 diabetes [28]. The patients were followed for 3.9 years, and it was demonstrated that sRAGE concentration were positively associated with incident CHD in type 2 diabetes [28]. Similar results have been obtained among type 1 diabetes [29,30] and elderly women [31]. "
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    ABSTRACT: Although several studies showed that decreased soluble receptor for advanced glycation end products (sRAGE) is associated with metabolic syndrome (MetS), inflammation level has not been considered, even though ligand-RAGE interaction induces inflammation. The objective of the study was to determine the association between sRAGE and MetS among Japanese adult in a cross-sectional survey, taking the level of low grade inflammation into consideration. Serum soluble RAGE (sRAGE) were measured in 712 men and 176 women aged 30-83 years with serum C-reactive protein (hsCRP) concentration below 3 mg/L. MetS was defined using the criteria of the American Heart Association Scientific Statements of 2009. After multivariable adjustment, among men, higher sRAGE levels were associated with lower odds of MetS as well as central obesity and elevated blood pressure. Comparing the extreme tertiles of sRAGE, odds ratios (95% confidence interval) were 0.58 (0.36-0.95; P for trend = 0.001) for MetS; 0.41 (0.25-0.52; P for trend < 0.001) for central obesity; and 0.45 (0.29-0.70; P for trend < 0.001) for elevated blood pressure. Moreover, participants were categorized according to their median hsCRP and sRAGE values. Men in the higher hsCRP/higher sRAGE category had a 40% lower odds ratio for MetS than those in the higher hsCRP/lower sRAGE category (P = 0.031). Among women, there was no association between sRAGE levels and the prevalence of MetS. Higher circulating RAGE concentrations were associated with lower prevalence of MetS and its components among Japanese men.
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    • "Numerous kinase-regulated pathways also undergo co-activation with AGE receptor induction, including mitogen-activated protein kinases [96]. AGE-modified proteins have been detected within myocardial fibers [97,98] and the numbers of such proteins have been shown to correlate with the severity of coronary heart disease [99]. A strong relationship between cardiac disease and overall AGE levels has been demonstrated, with elevated AGE content correlating with poor outcome as shown by adverse cardiac events in patients after cardiac surgery [100]. "
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    • "Our finding of substantially lower sRAGE levels in blacks compared with whites suggests that racial differences in sRAGE are an important area for further investigation. Previous studies also have reported significantly lower levels of sRAGE in blacks compared with whites (14,22,49). Nonetheless, owing to small numbers of events in the subgroup of black participants in our study, we were unable to rigorously evaluate potential effect modification by race on the association of sRAGE with long-term outcomes. "
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    ABSTRACT: Advanced glycation end products (AGEs) and their receptors are strongly implicated in the development of diabetic complications. When stimulated by AGEs, the receptors for AGEs (RAGE) induce inflammation and are thought to fuel disease progression. Soluble circulating RAGE (sRAGE) may counteract the detrimental effects of RAGE. We measured sRAGE in stored plasma from a random sample of 1201 participants in the ARIC Study who were ages 47-68, had normal kidney function, and no history of cardiovascular disease. In cross-sectional analyses, black race, male gender, higher body mass index, and higher C-reactive protein were independently associated with low sRAGE. The racial difference was striking, with blacks ∼3 times more likely to have low sRAGE as compared to whites even after adjustment. During approximately 18 years of follow-up there were 192 incident coronary heart disease events, 53 ischemic strokes, 213 deaths and 253 cases of diabetes (among the 1057 people without diabetes at baseline). In multivariable Cox models comparing risk in the first quartile to the fourth quartile of baseline sRAGE, low levels of sRAGE were significantly associated with risk of diabetes (HR 1.64, 95%CI 1.10 to 2.44), coronary heart disease (HR 1.82, 95%CI 1.17 to 2.84) and mortality (HR 1.72, 95%CI 1.11 to 2.64), but not ischemic stroke (HR 0.78, 95%CI 0.34 to 1.79). In conclusion, we found that low levels of sRAGE were a marker of future chronic disease risk and mortality in the community and may represent an inflammatory state. Racial differences in sRAGE deserve further examination.
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