The Gly82Ser polymorphism in the receptor for advanced glycation end products is associated with increased risk for coronary events in the general population

Abstract

Abstract Background/Introduction Activation of the receptor for advanced glycation end products (RAGE) by AGEs and various immune mediators has pro-inflammatory and pro-atherogenic effects. RAGE also exists in a soluble form, sRAGE, that acts as a decoy receptor for RAGE ligands. Low plasma sRAGE has previously been found to be associated with a higher risk for major adverse coronary events (MACE) in the population. Purpose The purpose of our study was to examine the causality of the association, by exploring whether genetic variants that influence sRAGE are associated with atherosclerosis progression and incident MACE and mortality in the population. Methods We performed a genome-wide association study (GWAS) in 4192 individuals from a randomly selected subgroup of a population-based cohort. Subsequently, we explored the associations between the identified single nucleotide polymorphims (SNPs) associated with plasma sRAGE levels, baseline intima media thickness (IMT) and IMT progression in the common carotid artery during a median follow-up of 16.5 years. Further, we analyzed the prospective relationships between the sRAGE-associated SNPs, incident MACE and mortality in the entire population-based cohort of 29245 individuals. The median follow-up time from baseline was 21.2 years for MACE and 21.6 years for total mortality (time to event or end of follow-up). Results We found the minor alleles of two single nucleotide polymorphisms (SNPs), rs2070600 and rs204993, to be independently associated with lower plasma sRAGE. While rs204993 is a silent intronic mutation, rs2070600 is known to cause a Gly82Ser polymorphism in the ligand binding domain, enhancing RAGE propensity for activation. In Cox regression analyses, we found an association between the minor T (vs. C) allele of rs2070600 and increased risk for first-time MACE [HR 1.12 (1.02–1.23); P=0.023]. The association was independent of traditional cardiovascular risk factors, blood pressure-lowering medication and lipid-lowering medication at baseline. rs204993 was not associated with MACE. Neither SNP was associated with carotid IMT at baseline or with IMT progression. We did not identify any relationships with total mortality. Conclusions We demonstrate for the first time an independent link between a genetic RAGE determinant and the risk for MACE in the population. Despite both identified SNPs being associated with lower sRAGE levels, only the functional rs2070600 mutation was associated with MACE, suggesting that the link is probably due to the enhancement of RAGE function rather than to the sRAGE lowering effect. Funding Acknowledgement Type of funding source: Public Institution(s). Main funding source(s): This study was supported by grants from the Swedish Research Council and the Swedish Heart and Lung foundation.