Fasting blood soluble RAGE may be causally implicated in impaired glucose metabolism in Chinese patients with primary hypertension

We prepared to investigate the association of four well-defined polymorphisms in the receptor for advanced glycation end-products (RAGE) gene with the changes of fasting blood soluble RAGE (sRAGE) and endogenous secretory RAGE (esRAGE) and the risk for impaired glucose metabolism (IGM) in 1704 patients with primary hypertension, aiming to infer possible causality between sRAGE/esRAGE and IGM. This was a hospital-based case-control study, including 848 patients coexisting with IGM (the case group) and 856 patients with normal glucose tolerance (the control group). Fasting blood sRAGE and esRAGE concentrations were measured in 300 cases and 300 controls. There were significant differences in the genotypes/alleles of T-429C (rs1800625) and T-374A (rs1800624) polymorphisms between the case and control groups after Bonferroni correction (P < 0.05/8). Adjusted estimates of above two polymorphisms for IGM risk were remarkably significant, especially under the recessive model (odd ratio [OR], 95% confidence interval [CI], P: 3.57, 1.95-5.18, 0.002 for T-429C and 3.49, 1.42-8.58, 0.007 for T-374A). Mean sRAGE and esRAGE concentrations were significantly higher in controls than in cases (P < 0.001). Participants with the rs1800625 -429CC and -429TC genotypes had significantly lower sRAGE (417.3 and 473.6 vs. 502.3 pg/mL, P < 0.01) and esRAGE (230.1 and 298.0 vs. 340.4 pg/mL, P < 0.05) concentrations than those with the -429TT genotype in primary hypertensive patients with IGM. Further Mendelian randomization analysis revealed that per 100 pg/mL reduction in fasting blood sRAGE and esRAGE was causally associated with 2.40-fold (95% CI: 1.46-3.94) and 2.65-fold (95% CI: 1.24-5.13) increased IGM risk, respectively. Our findings collectively demonstrate that fasting blood sRAGE and esRAGE may be causally implicated in IGM in primary hypertensive patients.