Receptor for advanced glycation end-products (RAGE) provides a link between genetic susceptibility and environmental factors in type 1 diabetes

Abstract

Aims/hypothesis This group of studies examines human genetic susceptibility conferred by the receptor for advanced glycation end-products (RAGE) in type 1 diabetes and investigates how this may interact with a western environment. Methods We analysed the AGER gene, using 13 tag SNPs, in 3,624 Finnish individuals from the FinnDiane study, Kuopio, Finland Diabetologia (2011) 54:1032-1042 DOI 10.1007/s00125-011-2058 followed by AGER associations with a high risk HLA genotype (DR3)-DQA1*05-DQB1*02/DRB1*0401-DQB1*0302 (n=546; HLA-DR3/DR4), matched in healthy newborn infants from the Finnish Type 1 Diabetes Prediction and Prevention (DIPP) Study (n=373) using allelic analysis. We also studied islets and circulating RAGE in NODLt mice. Results The rs2070600 and rs17493811 polymorphisms predicted increased risk of type 1 diabetes, whereas the rs9469089 SNP was related to decreased risk, on a high risk HLA background. Children from the DIPP study also showed a decline in circulating soluble RAGE levels, at seroconversion to positivity for type 1 diabetes-associated autoantibodies. Islet RAGE and circulating soluble RAGE levels in prediabetic NODLt mice decreased over time and were prevented by the AGE lowering therapy alagebrium chloride. Alagebrium chloride also decreased the incidence of autoimmune diabetes and restored islet RAGE levels. Conclusions/interpretation These studies suggest that inherited AGER gene polymorphisms may confer susceptibility to environmental insults. Declining circulating levels of soluble RAGE, before the development of overt diabetes, may also be predictive of clinical disease in children with high to medium risk HLA II backgrounds and this possibility warrants further investigation in a larger cohort.

Decrease in Circulating Concentrations of Soluble Receptors for Advanced Glycation End Products at the Time of Seroconversion to Autoantibody Positivity in Children With Prediabetes

“…In this work, we confirm the results from our previous study in an animal model of autoimmune diabetes and in a smaller group of prediabetic children (10). Since the current samples were derived from a unique prospective collection, we were able to study the variation in the sRAGE concentrations in relation to signs of humoral autoimmunity and compare the results to those of the controls, matched for most of the possible confounding factors.…”

“…It is formed through various pathways and is often used as a marker of AGE accumulation in human studies (5). We have previously identified an association between three polymorphisms of the AGER gene encoding RAGE on a high-risk HLA background (10). We also reported recently in a population-based study that two of the risk-associated AGER polymorphisms also predicted reduced sRAGE concentrations in children with newly diagnosed type 1 diabetes (14).…”

Circulating Concentrations of Soluble Receptor for AGE Are Associated With Age and AGER Gene Polymorphisms in Children With Newly Diagnosed Type 1 Diabetes

“…The strong inverse association between circulating sRAGE concentration and the predisposing minor allele of rs2070600 has been described previously (15,16). The rs2070600 is suggested to play a functional role in the RAGE/ligand interaction (34), and the minor allele was associated with increased risk of type 1 diabetes in a recent study (13). Interestingly, the minor allele of rs9469089, which was associated with decreased risk of type 1 diabetes (13), was associated with higher sRAGE concentration in the current study.…”

“…The AGE-specific receptor gene (AGER) encoding RAGEs is located on the short arm of chromosome 6 within the HLA class III region near the junction with the class II loci, which are the main loci associated with risk for type 1 diabetes (11). Earlier studies have implicated that specific AGER polymorphisms are associated with increased risk of type 1 diabetes (12,13) and complications of diabetes (14). In addition, AGER polymorphisms correlate with the circulating soluble RAGE (sRAGE) concentrations in adult populations (15,16).…”

Circulating soluble RAGE increase after a cerebrovascular event

“…The engagement of AGEs with its receptor promotes activation of nuclear factor-κB (NF-κB) and inflammatory cytokines as well as induction of oxidative stress, leading to vascular damage [16][17][18][19][20].…”