The association between the -374T/A polymorphism of the receptor for advanced glycation endproducts gene and blood pressure and arterial stiffness is modified by glucose metabolism status: the Hoorn and CoDAM studies.

OBJECTIVES

Receptor for advanced glycation endproducts (RAGE)-ligand interaction may lead to vascular complications. Genetic variation in RAGE has been shown to alter expression, activity of RAGE or both. We, therefore, investigated whether RAGE single-nucleotide polymorphisms (SNPs) and haplotypes were associated with vascular disease.

METHODS

Nine tag SNPs that cover the common RAGE gene variation were genotyped in 1291 individuals from two Dutch population-based cohort studies, aged 64.5 +/- 8.6 years, with normal glucose metabolism (44%), impaired glucose metabolism (23%) or type 2 diabetes mellitus (33%). We used multiple regression analyses to compare prevalent cardiovascular disease and markers of atherosclerosis, blood pressure and arterial stiffness across genotypes, and examine effect modification by glucose metabolism status.

RESULTS

In unstratified analyses, no consistent associations between RAGE SNPs and prevalent cardiovascular disease and markers of atherosclerosis were found. However, the AA genotype of SNP rs1800624 (-374T/A) was consistently associated with lower SBP [-5.0 mmHg (95% confidence interval -10.4 to 0.3)] and DBP [-4.2 (-7.2 to -1.3)], pulse pressure [-0.8 (-5.0 to 3.4)] as well as with less arterial stiffness [-0.56 SD (-1.04 to -0.09)] in individuals with normal glucose metabolism, but with higher SBP [6.2 (0.9-11.5)], DBP [2.1 (-0.7 to 5.0)] and pulse pressure [4.1 (-0.2 to 8.4)] in individuals with impaired glucose metabolism or type 2 diabetes mellitus (P for interaction <or=0.05 in all analyses). Similar results were found for a haplotype that includes the -374A allele.

CONCLUSION

In individuals with normal glucose metabolism, the -374A allele of the RAGE gene is protectively associated with blood pressure and arterial stiffness, whereas in individuals with impaired glucose metabolism or type 2 diabetes mellitus, it is adversely associated with these variables.