Comparison of factors associated with total sRAGE and esRAGE in patients with type 2 diabetes

Abstract

Circulating soluble receptor for advanced glycation endproducts (total sRAGE) likely comprises both a secreted isoform lacking a transmembrane domain (esRAGE) and cleavage of RAGE from the cell surface. Which of these sources of sRAGE is more relevant to vascular disease prediction is unclear. We examined whether the determinants of esRAGE and total sRAGE levels differ and whether they have different relationships with coronary heart disease in the type 2 Diabetes patients in Collaborative Atorvastatin Diabetes Study (CARDS). We used a nested case control design sampling incident cases of CVD with available plasma (n=198) in the CARDS trial and randomly selecting three controls per case stratified by treatment. The median follow up was 3.9 years. Serum sRAGE was measured using the R&D Systems Quantikine Immunoassay (specific for the extracellular domain of human RAGE). The assay coefficient of variation was 4.4%. esRAGE was measured using the B-Bridge ELISA CV 6%. Analysis was by Cox regression with adjustment for treatment allocation and relevant covariates. Total and esRAGE were strongly correlated (Spearman's rho =0.88) with a median ratio of total to esRAGE levels of 4.2 (interquartile range 3.7 to 4.8). Higher esRAGE was associated with lower BMI (p<0.001), lower eGFR (p=0.009), higher adiponectin (p<0.001) and white ethnicity (p<0.001). These relationships were similar to those for total sRAGE but these factors explained no more than 10% of the variance in either. esRAGE was an independent predictor of coronary heart disease events (HR=1.5 for a doubling of the esRAGE level, 95% CI: 1.1,2.0 p=0.009 adjusted for age, sex, eGFR, ethnicity, BMI, lipids and treatment allocation). This relationship was slightly weaker than the association of total sRAGE with CHD (p=0.001, difference in log likelihood=-2) and was not independent of total-esRAGE. In conclusion esRAGE is not more informative of vascular risk than total sRAGE and shares similar associations with other risk factors.