Genetic Variants of the Receptor for Advanced Glycation End-products in Susceptibility to Type 2 Diabetes Mellitus in Primary Hypertensive Patients

Diabetes mellitus is frequently comorbid with hypertension, which is approximately twice as common as diabetes mellitus in China. We designed a case-control association study to inspect the susceptibility of the receptor for advanced glycation end-products (RAGE) gene 6 variants to type 2 diabetes mellitus (T2DM) in 2199 patients with primary hypertension (1252 diabetic cases and 947 nondiabetic controls). The genotypes/alleles of −429T > C and 82Gly > Ser variants differed significantly between the two groups, and their associations with T2DM were significant after Bonferroni correction. Two variants, −374T > A and I/D, showed only marginal associations with T2DM. Haplotype analysis of above 4 significant variants indicated that a low-penetrance haplotype simultaneously bearing −429C and 82Ser alleles was overrepresented in cases relative to controls (4.75% vs. 1.72%, P < 0.001). Moreover, the predictive capability of 6 variants was significantly superior to available risk factors, with better goodness-of-fit. A predictive nomogram of 4 baseline risk factors and 2 variants of statistical significance was structured, with a good predictive accuracy (C-index = 0.761, P < 0.001). Taken together, our findings highlighted a contributory role of the RAGE gene, especially its two functional variants −429T > C and 82Gly > Ser, in susceptibility to T2DM in primary hypertensive patients, which may aid early detection and risk assessment for high-risk individuals.