Association analysis of 374T/A (rs1800624) receptor for advanced glycation end-products (RAGE) gene polymorphism with diabetic retinopathy in Pakistani patients.

OBJECTIVES: to determine the relationship of 374T/A (rs1800624) polymorphism in the gene encoding RAGE with Type-2 diabetes mellitus (T2DM), diabetic retinopathy (DR) and serum soluble RAGE (sRAGE) level in Pakistani patients. METHODS: A case-control study, conducted from January 2017 to December 2018, involving 150 healthy controls (HC), 150 T2DM patients with no retinopathy (DNR) and 150 DR patients diagnosed by coloured fundus photography. Tetra-primer amplification refractory mutation system - polymerase chain reaction (T-ARMS-PCR) was used for genotyping. Serum sRAGE levels were measured by enzyme-linked immunosorbent assays (ELIZA). RESULTS: The frequency of TT, TA and AA genotypes of rs1800624 polymorphism were: 92.7%, 6%, 1.3% in HC, 80%, 17.3%, 2.7% in DNR and 76.7%, 19.3%, 4.3% in DR groups. Heterozygous TA genotype and mutant A allele showed significant association with diabetes and DR vs HC. In dominant model, mutant allele showed significant association with DNR and DR vs HC. No significant association of rs1800624 was detected with DR and its sub-groups, non-proliferative DR (NPDR) and proliferative DR (PDR) vs DNR. Dividing NPDR into mild, moderate and severe, heterozygous TA genotype showed significant association with moderate and severe NPDR vs DNR. In DNR and DR groups, TA genotype was significantly associated with raised sRAGE. CONCLUSION: rs1800624 RAGE gene polymorphism might be a risk factor for T2DM and NPDR in Pakistani patients. Raised sRAGE levels have a positive correlation with PDR and are associated with heterozygosity of rs1800624 polymorphism in DNR and DR groups.

G82S polymorphism of receptor for advanced glycation end products gene and serum soluble RAGE levels in mild cognitive impairment and dementia of Alzheimer's type patients in Turkish population.

Alzheimer's disease (AD) is a chronic, neurodegenaration resulting in progressive cognitive decline leading to dementia. Mild cognitive impairment (MCI) is also a clinical definition of cognitive decline without functional impairment. Receptor for advanced glycation end products (RAGE) is one of the neuronal membrane receptors that binds amyloid beta peptide (Aß) triggering Aß-related pathologic signalling mechanisms. Soluble RAGE (sRAGE) is the soluble isoform of RAGE and it collects peripheral Aß by acting as a sink, prevents both RAGE-AGE interaction and transfer of Aß into brain. In this study, an association was investigated in Turkish cohorts of patients with dementia with Alzheimer's Type (DAT) and MCI patients by measuring serum sRAGE levels and by genotyping G82S polymorphism and comparing them to healthy control (HC) subjects. Although the serum sRAGE levels showed a decreasing manner among the groups, these differences were not statistically significant (p = 0.2). This is the first study for Turkish population.

The potential effect of garlic extract and curcumin nanoparticles against complication accompanied with experimentally induced diabetes in rats.

BACKGROUND: Modified herbal medicines implicate the combination of several therapeutic practices of native systems of medicine that may extend many earlier generations, which frequently afford valuable therapeutic benefits. PURPOSE: In this study, the role of nano-curcumin and aged garlic extract (AGE) as two modified phytomedicines on alleviating both of advanced glycation end products (AGEPs) and oxidative stress (OS) in streptozotocin (STZ) induced diabetic rats were investigated during this study. METHOD: Nano-curcumin and AGE suspension were orally administrated at a dose of 300, 500 mg/kg body weight respectively. Serum glucose, insulin, total cholesterol, triglycerides and myocardial enzyme activities including creatine kinase-isoenzyme (CK-MB), lactate dehydrogenase (LDH) and aspartate aminotransferase (AST) were determined biochemically, while quantitative real-time polymerase chain reaction (qRT-PCR)-test had been used to determine relative of manganese-superoxide dismutase (Mn-SOD) and receptor for advanced glycation end products (RAGE) gene expressions in the heart tissue of rats. Structure of rat's heart tissue was examined by histopathological analysis (H&E). RESULTS: AGE increased the body weight and insulin concentration, while, it decreased serum glucose concentration, CK-MB, and LDH enzyme activities in comparing with the diabetic group. In addition, total cholesterol, triglycerides, and AST didn't show any significant changes in serum values of AGE compared to diabetic rats. Nano-curcumin suspension decreased the serum levels of triglycerides, CK- MB, LDH, and AST. While, there were non-significant changes in the body weight, glucose, insulin, and total cholesterol level of the same group compared with the STZ- untreated induced diabetic rats. The transcript quantity of manganese-superoxide dismutase gene (Mn-SOD) was highly accumulated (3.25 and 3.87-fold) in the heart tissue sample of the induced diabetic rats in response to both nano-Curcumin and AGE suspension respectively. While AGE was the most potent treatment where it caused down regulation of the receptor for advanced glycation end products gene (RAGE) expression (1.79-fold). Results of histopathological analyses under the light microscope showed restoring the structural integrity of the myocytes towards normalization in diabetic hearts treated with each of nano-curcumin and AGE suspension compared with the untreated diabetic heart samples. CONCLUSION: Nano-curcumin and AGE suspension have a great therapeutic potential in the treatment of DCM, Diabetic cardiomyopathy, by attenuating cardiac inflammation, myocardial fibrosis, and programmed myocardial cell deaths through inhibiting OS and AGEPs accumulation in diabetic heart tissue. Furthermore, the hypoglycemic antioxidant properties of AGE resulted in more potent therapeutic effect than nano-curcumin in the treatment of diabetic hearts.

RAGE polymorphisms and oxidative stress levels in Hashimoto's thyroiditis.

BACKGROUND: Polymorphisms of the receptor for advanced glycation end products (RAGE) gene have been studied in various autoimmune disorders, but not in Hashimoto's thyroiditis. Also, increased oxidative stress has been described in patients with Hashimoto's thyroiditis. The aim of this study was to investigate the possible role of two common RAGE polymorphisms (-429T>C, -374T>A) in Hashimoto's thyroiditis; in parallel, we studied oxidative stress levels. MATERIALS AND METHODS: A total of 300 consecutive euthyroid women were examined and classified into three groups: Hashimoto's thyroiditis with treatment (n = 96), Hashimoto's thyroiditis without treatment (n = 109) and controls (n = 95). For a rough evaluation of oxidative stress, total lipid peroxide levels in serum were measured. The -429T>C AluI and -374T>A MfeI polymorphisms of RAGE were studied in genomic DNA. RESULTS: Significant association of the RAGE system with Hashimoto's thyroiditis was found only with regard to the prevalence of the -429T>C, but not with -374T>A polymorphism. The levels of oxidative stress were significantly elevated in Hashimoto's thyroiditis patients under treatment. Further analysis demonstrated that an oxidative stress cut-off value of 590 µmol/L is associated with an increased risk of progression of Hashimoto's thyroiditis from euthyroidism to hypothyroidism; this risk is further increased in carriers of the RAGE -429T>C polymorphism. CONCLUSIONS: Our findings indicate that both examined risk factors may be implicated in the occurrence of Hashimoto's thyroiditis, but this covers only a fraction of the pathophysiology of the disease.

Genetic variants in the receptor for advanced glycation end products (RAGE) gene were associated with circulating soluble RAGE level but not with renal function among Asians with type 2 diabetes: a genome-wide association study.

BACKGROUND: 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. METHODS: 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). RESULTS: 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 strongly and dose-dependently correlated with sRAGE level (TT = 399.6 pg/mL, CT = 737.0 pg/mL and CC = 967.0 pg/mL, P < 0.001 for rs2070600; TT = 687.9 pg/mL, CT = 737.6 pg/mL and CC = 904.7 pg/mL, P < 0.001 for rs2072188). Both SNPs were robustly replicated in the independent cohort, especially among Chinese patients (P = 9.02 × 10-72 for rs2070600; P = 1.13 × 10-9 for rs2071288). Log-transformed sRAGE was associated with DKD after adjustment for age, gender and ethnicity in pooled cohorts [odds ratio 2.536 (95% confidence interval 1.864-3.450), P < 0.001]. However, we did not observe any significant association between rs2070600 and DKD. CONCLUSIONS: Common variants in RAGE are strongly associated with plasma sRAGE level, which is associated with DKD. However, we did not find a causal link between sRAGE and renal function by Mendelian randomization.

Short-term effects of dietary advanced glycation end products in rats.

Dietary advanced glycation end products (AGE) formed during heating of food have gained interest as potential nutritional toxins with adverse effects on inflammation and glucose metabolism. In the present study, we investigated the short-term effects of high and low molecular weight (HMW and LMW) dietary AGE on insulin sensitivity, expression of the receptor for AGE (RAGE), the AGE receptor 1 (AGER1) and TNF-α, F2-isoprostaglandins, body composition and food intake. For 2 weeks, thirty-six Sprague-Dawley rats were fed a diet containing 20% milk powder with different proportions of this being given as heated milk powder (0, 40 or 100%), either native (HMW) or hydrolysed (LMW). Gene expression of RAGE and AGER1 in whole blood increased in the group receiving a high AGE LMW diet, which also had the highest urinary excretion of the AGE, methylglyoxal-derived hydroimidazolone 1 (MG-H1). Urinary excretion of N ε-carboxymethyl-lysine increased with increasing proportion of heat-treated milk powder in the HMW and LMW diets but was unrelated to gene expression. There was no difference in insulin sensitivity, F2-isoprostaglandins, food intake, water intake, body weight or body composition between the groups. In conclusion, RAGE and AGER1 expression can be influenced by a high AGE diet after only 2 weeks in proportion to MG-H1 excretion. No other short-term effects were observed.

Polymorphisms in three genes are associated with hemorrhagic stroke.

BACKGROUND: Multiligand receptor for advanced glycation end products (RAGE), osteoprotegerin, and Golgb1 genes may be implicated in atherosclerosis and vascular diseases. Single nucleotide polymorphisms (SNPs) rs1035798 in RAGE gene, rs2073617 and rs2073618 in TNFRSF11B, and rs3732410 in Golgb1 will be investigated on whether there is an association with hemorrhagic stroke (HS) in Chinese population. METHODS: A total of 600 subjects including 199 HS patients and 401 controls were assayed. These samples were divided into two groups: the ≤50 year and >50 year groups. Genotyping of SNPs was determined using the SEQUENOM MassARRAY matrix-assisted laser desorption ionization-time-of-flight-mass spectrometry. The association between genotype and HS risk was evaluated by computing the odds ratio (OR) and 95% confidence interval (CI) with multivariate unconditional logistic regression analyses. RESULTS: Our data showed that in the ≤50 year group, the rs1035798 major allele homozygote C/C in RAGE gene was associated with an increased risk of HS, while Golgb1 rs3732410 minor allele homozygote G/G was associated with a decreased risk of HS. In the >50 year group, the major allele homozygote G/G of rs2073618 was found to be associated with an increased risk of HS. CONCLUSIONS: The polymorphisms rs1035798 of RAGE gene, rs2073618 of TNFRSF11B, and rs3732410 of Golgb1 might be involved in the risk of HS at different stage of ages.

Receptor for advanced glycation end products (RAGE) gene polymorphism and cardiovascular disease in end-stage renal disease patients.

BACKGROUND/OBJECTIVES: Receptor for advanced glycation end products (RAGE) contributes to the pathogenesis of vascular and inflammatory diseases. We investigated whether the functional polymorphism in the promoter region of the RAGE gene (-374 T/A) influences development of cardiovascular disease in the end-stage renal disease (ESRD) patients. METHODS: The cohorts of 1866 ESRD patients and 1143 healthy subjects were genotyped by polymerase chain reaction (PCR) for the RAGE variant rs1800624. RESULTS: The genotype and allele frequencies did not differ significantly between ESRD patients and controls. There was no significant difference in the genotype distribution when patients with CVD were compared to those without it (p for A allele = 0.62). After stratifying CVD patients according to CVD clinical phenotype, the ESRD patients with stroke had a lower frequency of A allele than patients without CVD (0.12 vs. 0.21, p = 0.027). To confirm this finding, we genotyped 163 patients with ischemic stroke but without renal disease. In this group, the AA/TA genotypes were also significantly associated with lower risk of stroke (OR 0.46, p = 0.0002). CONCLUSION: Our data suggest that the presence of the A allele of -374 T/A polymorphism in the RAGE gene has a protective effect against stroke.

Functional promoter polymorphisms of the receptor for advanced glycation end products in children and adolescents with type 1 diabetes.

RAGE promoter polymorphisms are associated with increases in RAGE expression. A case-control association study was conducted involving a Euro-Brazilian population of children and adolescents with type 1 diabetes (n = 90) and healthy controls (n = 105), which were matched by sex and age. Genotyping by PCR-RFLP the -429T>C (rs1800625), -374T>A (rs1800624), and 63 bp deletion/insertion (-407 to -345 bp) showed no significant differences (P > 0.05) between the groups.

Association of RAGE gene polymorphism with vascular complications in Indian type 2 diabetes mellitus patients.

AIMS: The study was designed to evaluate the association of -374T/A and -429T/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 -374T/A, -429T/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 -429 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 -374A allele showed reduced risk towards the development of macrovascular complications. Further, -429T/C, -374T/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.

Association of RAGE gene polymorphisms with sporadic Parkinson's disease in Chinese Han population.

Previous studies have corroborated receptor for advanced glycation end-products (RAGE) ablation had a protective effect on nigral dopaminergic neurons in the MPTP model of Parkinson's disease (PD). Genetic variation of RAGE gene may be associated with the development of onset of sporadic PD. The present study aimed to explore the possible association of RAGE gene polymorphisms namely -374T/A,-429T/C, and G82S with PD. A total of 285 PD patients and 285 healthy-matched individuals in Chinese Han population were enrolled. Genotype analyses were performed using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Only the -429T/C polymorphism denoted a significant difference between PD patients and controls (P=0.015) of the three examined single nucleotide polymorphisms (SNPs). Our data also revealed that -429C allele carriers seem to have a decreased risk of PD (OR=0.617, P=0.007). Moreover, there were significant differences in genotype distribution in female PD group and its healthy-matched control subgroup (P=0.014), as well as between late-onset PD (LOPD) and the controls subgroup (P=0.016). However, for -374T/A and 82GS polymorphisms, there was no significant difference in the genotype and allele frequencies between PD patients and the controls, as well as gender- and age-related differences. Our present findings indicate that the RAGE -429T/C polymorphism may be associated with the susceptibility of PD and the CC genotype of -429T/C may be a protective factor for PD in Chinese Han population.