The principal novel observation of the present study is that lower levels of sRAGE are independently associated with a greater prevalence of coronary atherosclerosis, demonstrated in a large probability-based population study. These associations remained statistically significant after multivariable adjustment and were evident in the overall population as well as across several key subgroups. Because of small sample sizes in some subsets, validation of the findings in additional studies is needed in key subgroups, including those with diabetes.
Our observations are concordant with the limited data investigating the relationship between circulating sRAGE and atherosclerosis (8
). In a small cohort of nondiabetic Italian men, Falcone et al. (8
) demonstrated that subjects with angiographic coronary artery disease had lower levels of sRAGE than age-matched control subjects without coronary artery disease. Also, Koyama et al. (9
) showed that sRAGE was inversely associated with carotid intima-medial thickness. Although both studies are provocative, they are limited by small sample sizes and the discrete populations studied. These reports coupled with the present results provide compelling support for a possible link between sRAGE and atherosclerosis.
Indeed, our observations lend validation to prior experimental observations supporting the plausible contribution of sRAGE to the development and progression of atherosclerosis (3
). These concordant observations are promising and should prompt further evaluation of the sRAGE/RAGE pathway to better understand the pathobiology and to explore the potential of this pathway as a novel target for the prevention and treatment of vascular disease. The cross-sectional design of our study allows only a demonstration of association, and conclusions cannot be drawn regarding causality. However, evidence from several elegant animal studies demonstrates that exogenous administration of sRAGE suppresses the progression of atherosclerosis (3
). Therefore, either exogenous administration of sRAGE or therapies that amplify endogenous sRAGE levels may offer an attractive pathway to treat or prevent vascular disease (12
). Future investigation into sRAGE modulation as a therapeutic modality is needed.
In summary, within a large multiethnic population, we observed an independent and graded association between lower sRAGE levels and coronary atherosclerosis; therefore, sRAGE could prove to be a useful biomarker for the prediction of atherosclerosis and cardiovascular disease risk. External validation of our data in other populations, especially in cohorts with cardiovascular outcomes, is crucial. With the data from prior basic science experiments and our hypothesis-generating data, sRAGE appears to hold promise not only as a biomarker for atherosclerosis prediction but also as a potential therapeutic target for the treatment and prevention of atherosclerosis and should be investigated further.