Association of RAGE gene polymorphism with circulating AGEs level and paraoxonase activity in relation to macro-vascular complications in Indian type 2 diabetes mellitus patients (original) (raw)
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Diabetes Research and Clinical Practice, 2014
The study was designed to evaluate the association of À374T/A and À429T/C polymorphism in the promoter region and Gly82Ser polymorphism in exon 3 region of RAGE gene with diabetic vascular complications in Indian population. Methods: We screened 603 subjects which includes 176 healthy controls, 140 type 2 diabetes mellitus (T2DM) subjects without any vascular complications (DM), 152 T2DM subjects with microvascular complications (DM-micro) and 135 T2DM subjects with macrovascular complications (DM-macro) for À374T/A, À429T/C and Gly82Ser polymorphisms of RAGE gene. DNA isolated from the enrolled subjects were genotyped by PCR-RFLP. Logistic regression analysis was used to evaluate the association of single nucleotide polymorphisms (SNPs). Results: The À429 T/C and Gly82Ser RAGE polymorphisms were found to be significantly associated with the development of macrovascular and microvascular complications, respectively, in T2DM subjects while À374A allele showed reduced risk towards the development of macrovascular complications. Further, À429T/C, À374T/A and Gly82Ser haplotype analysis revealed association of CTG haplotype with development of macrovascular complications while haplotype TAG was observed to be significantly protective towards development of macrovascular complications in T2DM subjects (OR = 0.617, p = 0.0202). Conclusions: Our data indicates significant association of RAGE SNPs and haplotypes with vascular complications in North Indian T2DM subjects.
Diabetes, 2003
The hyperglycemic milieu in diabetes results in the formation of advanced glycation end products (AGEs) that predominantly act through specific receptors, particularly the receptor for AGEs (RAGE). Two functional polymorphisms in the promoter of the RAGE gene (؊429 T/C and ؊374 T/A) and one in the AGE binding domain in exon 3 (G82S) were studied in 996 Finnish type 1 diabetic patients. In patients with poor metabolic control (HbA 1c >9.5%), the AA genotype of the ؊374 T/A polymorphism was more common in those with a normal albumin excretion rate than in those with proteinuria (30 vs. 10%, P ؍ 0.01). We observed less coronary heart disease (6 vs. 14%, P < 0.05), acute myocardial infarction (2 vs. 14%, P ؍ 0.01), and peripheral vascular disease (2 vs. 14%, P < 0.05) in patients with the AA genotype of the ؊374 T/A polymorphism than in those with the TT ؉ TA genotype. Thus, the association between the RAGE ؊374 T/A homozygous AA genotype and cardiovascular disease as well as albumin excretion in type 1 diabetic patients with poor metabolic control suggests a gene-environment interaction in the development of diabetic nephropathy and cardiovascular complications. Diabetes 52:891-894, 2003
RAGE polymorphisms and the heritability of insulin resistance: the Leeds family study
Diabetes & vascular disease research : official journal of the International Society of Diabetes and Vascular Disease, 2005
A ctivation of the receptor for advanced glycation endproducts (RAGE) leads to a cascade of pro-inflammatory and pro-coagulant responses which are important in the pathogenesis of the vascular complications of diabetes mellitus. It is known that pro-inflammatory mechanisms underpin the development of type 2 diabetes. Our hypothesis is that RAGE may be involved in the evolution of insulin resistance in addition to mediating glucotoxic complications of diabetes mellitus.
The Journal of Clinical Endocrinology & Metabolism, 2009
The receptor for advanced glycation end products (RAGE)-ligand interaction has been linked to vascular complications. The family of soluble forms of RAGE (sRAGE) consists of splice variants and proteolytically cleaved and shed forms of RAGE. sRAGE may be a reflection of cellbound RAGE. Because genetic variation in the RAGE gene may be associated with individual differences in sRAGE concentration and outcome, we investigated whether RAGE single-nucleotide polymorphisms (SNPs) were associated with circulating levels of sRAGE.
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.
Diabetes, 2001
Interactions between advanced glycation end products (AGEs) and the receptor for AGE (RAGE) are implicated in the vascular complications in diabetes. We have identified eight novel polymorphisms, of which the ؊1420 (GGT)n, ؊1393 G/T, ؊1390 G/T, and ؊1202 G/A were in the overlapping PBX2 3 untranslated region (UTR), and the ؊429 T/C (66.5% TT, 33.5% TC/CC), ؊407 to -345 deletion (99% I, 1% I/D, 0% D), ؊374 T/A (66.4% TT, 33.6% TA/AA), and ؉20 T/A were in the RAGE promoter. To evaluate the effects on transcriptional activity, we measured chloramphenicol acetyl transferase (CAT) reporter gene expression, driven by variants of the -738 to ؉49 RAGE gene fragment containing the four polymorphisms identified close to the transcriptional start site. The -429 C, ؊374 A, and 63-bp deletion alleles resulted in a mean increase of CAT expression of twofold (P < 0.0001), threefold (P < 0.001), and fourfold (P < 0.05), respectively, with the -374 T and A alleles yielding highly differential binding of nuclear protein extract from both monocyte-and hepatocyte-derived cell lines. The prevalence of the functional polymorphisms were investigated in subjects with type 2 diabetes (106 with and 109 without retinopathy), with the -429 C allele showing an increase in the retinopathy group (P < 0.05). These data suggest that the polymorphisms involved in differences in RAGE gene regulation may influence the pathogenesis of diabetic vascular complications. Diabetes 50:1505-1511, 2001
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.
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...