The Functional -374 T/A RAGE Gene Polymorphism Is Associated With Proteinuria and Cardiovascular Disease in Type 1 Diabetic Patients (original) (raw)
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Clinical Chemical Laboratory Medicine, 2007
Background: Polymorphisms of the receptor for advanced glycation end products (RAGE) gene have been associated with diabetes, coronary artery disease (CAD) and inflammatory processes. The-374T)A RAGE gene promoter polymorphism was shown to affect gene transcription. The aim of this study was to evaluate the association of the-374T)A polymorphism with the severity of CAD in patients with or without type 2 diabetes mellitus. Methods: We studied 246 Euro-Brazilians with angiographically defined CAD (stenosis)50%), comprising type 2 diabetic (ns98) and non-diabetic subjects (ns148). Genotyping was performed by PCR-restriction fragment length polymorphism using Tsp509I restriction enzyme. Results: The AA genotype was associated with a significant decrease in CAD severity estimated by the number of diseased vessels (1.43"0.5 vs. 2.49"1.1; ps0.002) and the Duke score (27.3"10.8 vs. 49.3"20.1; ps0.001) only in the group of CAD subjects with type 2 diabetes mellitus. The protective effect of the AA genotype against severity of CAD was not observed in the non-diabetic group. Conclusion: This result confirms that the-374AA genotype of the RAGE gene promoter is a protective factor against the severity of CAD lesions in type 2 diabetic patients.
Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association, 2016
The soluble receptor for advanced glycation end products (sRAGE) has been shown to play an important role in diabetic complications. We conducted genome-wide association study (GWAS) of sRAGE in Asian type 2 diabetes mellitus (T2DM) patient and validated the association in an independent cohort of T2DM. GWAS for sRAGE was performed in 2058 T2DM patients. Associations between single-nucleotide polymorphisms (SNPs) and plasma sRAGE level were analyzed in an additive model using a linear mixed model. To validate the associations, we performed de novo genotyping in an independent cohort (n = 1984). We selected the top SNP for assessment with diabetic kidney disease (DKD). The strongest SNP, rs2070600C>T (P = 1.21 × 10(-52)), was a genotyped, missense SNP located on chromosome 6, corresponding to the RAGE (AGER) gene locus, the gene encoding RAGE. Conditioning analysis on rs2070600 revealed that rs2071288C>T was the top genotyped independent SNP (P = 8.36 × 10(-10)). Both SNPs were...
Gene, 2013
Background and aims: Sustained interaction of advanced glycation end products (AGEs) with their receptor RAGE and subsequent signaling plays an important role in the development of diabetic complications. Genetic variation of RAGE gene may be associated with the development of vascular complications in type 2 diabetes mellitus (T2DM). Objectives: The present study aimed to explore the possible association of RAGE gene polymorphisms namely − 374T/A, − 429T/C and G82S with serum level of AGEs, paraoxonase (PON1) activity and macro-vascular complications (MVC) in Indian type 2 diabetes mellitus patients (T2DM). Methods: A total of 265 diabetic patients, including DM without any complications (n = 135), DM-MVC (n = 130) and 171 healthy individuals were enrolled. Genotyping of RAGE variants were assessed by polymerase chain reaction-restriction fragment length polymorphism. Serum AGEs were estimated by ELISA and fluorometrically. and PON1 activity was assessed spectrophotometrically. Results: Of the three examined SNPs, association of −429T/C polymorphism with MVC in T2DM was observed (OR = 3.001, p = 0.001) in the dominant model. Allele 'A' of −374T/A polymorphism seems to confer better cardiac outcome in T2DM. Patients carrying C allele (−429T/C) and S allele (G82S) had significantly higher AGE levels. −429T/C polymorphism was also found to be associated with low PON1 activity. Interaction analysis revealed that the risk of development of MVC was higher in T2DM patients carrying both a CC genotype of −429T/C polymorphism and a higher level of AGEs (OR = 1.343, p = 0.040). Conclusion: RAGE gene polymorphism has a significant effect on AGE level and PON1 activity in diabetic subjects compared to healthy individuals. Diabetic patients with a CC genotype of −429T/C are prone to develop MVC, more so if AGE levels are high and PON1 activity is low.
PeerJ, 2016
Background: Chronic kidney disease (CKD) is a condition associated with progressive loss of kidney function and kidney damage. The two common causes of CKD are diabetes mellitus and hypertension. Other causes of CKD also include polycystic kidney disease, obstructive uropathy and primary glomerulonephritis. The receptor for advanced glycation end-products (RAGE) is a multi-ligand cell surface receptor of the immunoglobulin superfamily and it has been associated with kidney disease in both non-diabetic and diabetic patients. Presently, data on the association between RAGE polymorphisms and CKD in the Malaysian population is limited, while numerous studies have reported associations of RAGE polymorphisms with diabetic complications in other populations. The present study aims to explore the possibility of using RAGE polymorphisms as candidate markers of CKD in Malaysian population by using association analysis. Methods: A total of 102 non-diabetic CKD patients, 204 diabetic CKD patients and 345 healthy controls were enrolled in the study. DNA isolated from blood samples were subjected to genotyping of RAGE G82S,-374T/A,-429T/C, 1704G/T and 2184A/G polymorphisms using real-time polymerase chain reaction (PCR). The 63-bp deletion, a polymorphism in the RAGE gene promoter, was genotyped using conventional PCR method and visualized using agarose gel electrophoresis. The collective frequencies of genotypes with at least one copy of the minor alleles of the four polymorphisms were compared between the non-diabetic CKD patients, diabetic CKD patients and healthy controls. Results: After adjustment of age, gender and ethnic groups in binary logistic regression analysis, the G82S CT + TT genotypes were associated with non-diabetic CKD patients when compared with diabetic CKD patients (p = 0.015, OR = 1.896, 95% CI = 1.132-3.176). After further adjustment of CKD comorbidities, the G82S CT + TT genotypes were still associated with non-diabetic CKD patients when compared with diabetic CKD patients (p = 0.011, OR = 2.024, 95% CI = 1.178-3.476). However, it cannot be suggested that G82S polymorphism was associated with CKD in non-diabetic patients in this study. This is because there were no significant differences in the frequencies of G82S CT + TT genotypes between non-diabetic CKD patients and healthy controls. In addition, the RAGE-374T/A, How to cite this article Wong et al. (2016), Association of the receptor for advanced glycation end-products (RAGE) gene polymorphisms in Malaysian patients with chronic kidney disease. PeerJ 4:e1908;
Bulletin of Egyptian Society for Physiological Sciences
The binding of advanced glycation end-products (AGEs) to their receptor (RAGE) may play an important role in the development of diabetic retinopathy (DR). Recently, endogenous secretory RAGE (esRAGE) has been identified as an alternative splicing form of RAGE able to capture AGEs, and exerts protection against AGEs-induced endothelial cell injury. A Gly82Ser polymorphism in exon 3 of RAGE gene was identified and thought to have an effect on the functions of its protein. This study was planned to investigate the frequency of the Gly82Ser polymorphism in RAGE gene and the role of esRAGE as a biological marker for DR in type2 diabetes and its association with the severity of DR. Thirty-five patients with type2 diabetes were recruited into the study. They were subclassified into 15 patients with no clinically apparent retinopathy (No DR), 12 patients with nonproliferative DR (NPDR), and 8 patients with proliferative DR (PDR). Twenty, age matched, healthy subjects were included as controls. Serum esRAGE level was measured by enzyme-linked immunosorbent assay. Genotype frequencies of Gly82Ser polymorphism were studied by polymerase chain reaction amplification and restriction fragment length polymorphism analysis using AluI enzyme. The results showed no significant difference between serum esRAGE levels in both controls and diabetic patients with No DR (P = 0.15). Among the diabetic subjects, there was a significant decrease of serum esRAGE levels between patients with No DR and patients with NPDR (P = 0.008) and a more significant decrease between diabetic patients with No DR and patients with PDR (P = 0.001). The low serum esRAGE diabetic patients had higher risk to develop DR than those with high serum esRAGE level (odds ratio = 4.7, 95% confidence interval = 1.07-20.65, P = 0.02). There were no significant differences in genotyping frequencies or allele frequencies between controls and diabetic patients with No DR, or patient with DR (P<0.05). In conclusion, serum esRAGE level showed a significant association with the severity of DR and, hence, it could be used as a prognostic tool to predict the development and progression of DR. esRAGE could be a novel and potential protective factor for DR. Gly82Ser polymorphisms in RAGE gene are not associated with the susceptibility of type 2 diabetes, or with the development of DR in type 2 diabetic subjects.
Glycation and diabetes: The RAGE connection
2002
The hyperglycaemic state seen in diabetes mellitus is associated with the development of diabetes-specific microvascular complications and accelerated macrovascular disease. Evidence implicates the formation and subsequent effects of advanced glycation endproducts (AGEs) as a contributing cause.
Atherosclerosis, 2005
The receptor for advanced glycation end-products (RAGE) is expressed to enhance degrees in human atherosclerotic plaques and colocalizes with inflammatory and pro-oxidant mediators in the vulnerable regions of the plaque. Previous studies highlighted a number of variants in the gene encoding the receptor, including a Gly to Ser substitution at amino acid 82 within the ligand-binding domain of RAGE. The Ser82 allele enhanced ligand-binding affinity and increased ligand-stimulated generation of inflammatory mediators in transfected cells and human monocytes compared to the common RAGE Gly82 allele. Thus it was logical to test the hypothesis that increased prevalence of the Gly82Ser polymorphism was associated with cardiovascular events in the Framingham offspring study (n = 1632). Our analyses revealed that the Gly82Ser RAGE polymorphism did not demonstrate any association with the incidence of cardiovascular disease in diabetic or non-diabetic subjects (Gly82 96%, Ser82 4%). Analysis of specific manifestations of cardiovascular disease, including coronary heart disease (CHD), cardiovascular disease (CVD), myocardial infarction (MI) and ischemic disease (ISD) revealed no association with RAGE genotype. Further studies are required on other more prevalent genetic variants of RAGE and cardiovascular disease.