Promoter methylation cooperates with SNPs to modulate RAGE transcription and alter UC risk.
ABSTRACT: Single-nucleotide polymorphisms (SNPs) located in the promoter region of the receptor for advanced glycation end products (RAGE) gene have been linked to the activity of RAGE. However, contrary to our expectation, we previously detected no correlation between SNPs within the RAGE promoter and ulcerative colitis (UC) risk in a case-control study. Here, we investigated the methylation of the RAGE promoter and analyzed the collective contribution of methylation and SNPs to UC risk. We found that RAGE promoter hypomethylation was more common in UC patients compared to controls (70% vs. 30%, respectively), as determined via bisulfite sequencing PCR (BSP) and methylation-specific PCR (MSP). Furthermore, we investigated the cooperativity of promoter methylation and SNPs and found that either of two SNPs (rs1800624 or rs1800625) and promoter methylation jointly contributed to UC risk (30 UC patients vs. 30 controls, P?
Project description:BACKGROUND Age-related macular degeneration (AMD) is the leading cause of blindness in people aged 65 years and older in developed countries. The pathogenesis of AMD has been linked to mechanisms involving inflammation, oxidative stress, and basal laminar deposit formation between retinal pigment epithelium (RPE) cells and the basal membrane, caused by advanced glycation end products (AGEs). AGEs are implicated in the pathogenesis of AMD through the AGE-and receptor for AGE (RAGE) interaction, which can be altered by polymorphisms of the RAGE gene. We examined RAGE rs1800624 and rs1800625 gene polymorphisms contributing to AMD development. MATERIAL AND METHODS The study enrolled 300 patients with early AMD, 300 patients with exudative AMD, and 800 healthy controls. The genotyping was carried out using the RT-PCR method. RESULTS The analysis of two single nucleotide polymorphisms (SNPs) in the RAGE gene showed that rs1800624 was associated with a 1.6-fold decreased risk for exudative AMD under the dominant model after adjustment for age (OR=0.616; 95% CI: 0.394-0.963; p=0.034) and each copy of allele T at rs1800624 was associated with a 1.4-fold decreased risk for exudative AMD development under the additive model after adjustment for age (OR=0.701; 95% CI: 0.510-0.962; p=0.028). Analysis revealed that the rs1800625 allele G at rs1800625 was associated with a 1.5-fold increased risk for exudative AMD after adjustment for age (OR=1.545; 95% CI: 1.003-2.379; p=0.048). These results suggested that the allele G at rs1800625 was a risk-allele for exudative AMD development. In haplotype analysis, A-G haplotype was significantly more frequently observed in exudative AMD patients compared to healthy controls (3.3% versus 1.4%, p=0.035). CONCLUSIONS We revealed a significant association between RAGE gene rs1800624 and rs1800625 polymorphisms and AMD risk. We considered T allele at rs1800624 to be protective against AMD development, while allele G at rs1800625 was considered to be a marker of poor prognosis in AMD development.
Project description:Objectives: The receptor for advanced glycation end products (RAGE) is an oncogenic trans-membranous receptor expressed in many cells. The aim of this study was to clarify the association between RAGE gene 4 single nucleotide polymorphisms (SNPs) and the risk, invasion, metastasis and overall survival of gastric cancer. Methods and Results: We performed a hospital-based case-control study involving 369 gastric cancer patients and 493 cancer free controls. Four widely-studied SNPs, rs1800625 (T-429C), rs1800624 (T-374A), rs2070600 (Gly82Ser) and rs184003 (G1704T) in RAGE gene, were genotyped by the polymerase chain reaction - ligase detection reaction method. The RAGE gene rs1800625 TT genotype and T allele were significantly associated with a reduced risk of gastric cancer (TT vs. CC: adjusted odds ratio [OR]: 0.72, 95% CI: 0.55-0.95, p=0.021; T vs. C: adjusted OR: 0.67, 95% CI: 0.46-0.97, p=0.032). No hints of significance were detected for the other three SNPs in association with gastric cancer risk. Moreover, rs1800625 and rs184003 were significantly associated with tumor clinical stage (p=0.010 and 0.032, respectively). Survival curves differed significantly between the genotypes of rs1800625. Conclusions: RAGE gene SNP rs1800625 was significantly associated with gastric cancer risk, and rs1800625 and rs184003 were related to tumor clinical stage, indicating that RAGE gene may be a gastric cancer-susceptibility gene.
Project description:Hepatocellular carcinoma (HCC) is a common malignancy of the liver, whose heterogeneous incidence reflects genetic variations among individuals in the main risk factors. The receptor for advanced glycosylation endproducts (RAGE) is a multiligand receptor and known to be implicated in various pathogenic conditions, such as diabetes, inflammatory disorder, Alzheimer disease, and cancer. In this study, the impact of RAGE gene polymorphisms on the susceptibility to hepatocarcinogenesis was explored. Four single-nucleotide polymorphisms (SNPs), rs184003 (1704G?>?T), rs1800624 (-374T?>?A), rs1800625 (-429T?>?C), and rs2070600 (Gly82Ser), as well as 1 gene polymorphism of RAGE gene, a 63?bp deletion allele (-407 to -345) were analyzed between 300 cancer-free subjects and 265 HCC cases. We detected a significant association of rs1800625 with the increased risk of HCC (odds ratio [OR], 2.565; 95% confidence interval [CI], 1.492-4.409 and adjusted odds ratio [AOR], 2.568; 95% CI, 1.418-4.653). However, patients who possess at least 1 polymorphic allele of rs1800625 are less prone to develop late-stage (stage III/IV, OR, 0.502; 95% CI, 0.243-1.037; P?=?0.059 and AOR, 0.461; 95% CI, 0.219-0.970; P?=?0.041) and large-size tumors (OR, 0.398; 95% CI, 0.183-0.864; P?=?0.017 and AOR, 0.351; 95% CI, 0.157-0.781; P?=?0.010). Furthermore, individuals bearing specific haplotypes of 4 RAGE SNPs tested are more inclined to have HCC. In conclusion, our data suggest a correlation of RAGE gene polymorphism rs1800625 with the early stage of liver tumorigenesis and implicate its protective role in the progression of HCC.
Project description:Abstract The receptor for advanced glycation end products (RAGE) overexpression was suggested to be associated with prostate cancer development and poor prognosis. In this study, we focused on the correlations between the clinicopathological characteristics and susceptibility of prostate cancer and RAGE single‐nucleotide polymorphisms (SNPs). In 579 prostate cancer patients, the RAGE SNPs rs1800625, rs1800624, rs2070600 and rs184003 in patients with or without grade group upgrade were analysed with real‐time polymerase chain reaction. The results demonstrated that the prostate cancer patients who carried the RAGE SNPs rs2070600 ‘GA’ genotypic variants were significantly associated with lower risk to develop grade group upgrade. Moreover, patients with the RAGE rs1800625 ‘TC + CC’ genotypic variants were associated with higher risk of perineural invasion. In 343 prostate cancer patients who carried the RAGE rs1800625 ‘TC + CC’ genotype without grade group upgrade were correlated with higher risk of biochemical recurrence and perineural invasion. In the analysis of TCGA database, significant differences of the RAGE mRNA level were found between the normal controls and prostate cancer patients (p < 0.0001), and the pathologic stage N1 and N0 patients (p = 0.0027). The prostate cancer patients with high RAGE expression were associated with lower overall survival rate (p = 0.025). In conclusion, our results have revealed that the RAGE SNPs rs2070600 and rs1800625 were associated with the grade group upgrade of prostate cancer and clinical status. The RAGE polymorphisms may provide as a pivotal predictor to evaluate prostate cancer disease progression and prognosis.
Project description:Oral squamous cell carcinoma is a common neoplasm that is known to be causally associated with genetic factors and environmental carcinogens. The receptor for advanced glycosylation endproducts (RAGE) is a transmembrane protein of the immunoglobulin superfamily with broad specificity for multiple ligands, and it has been shown to play vital roles in several pathophysiologic processes, including diabetes, Alzheimer disease, renal disease, cardiovascular disease, and cancer. The present study aimed to assess the influences of RAGE gene polymorphisms, combined with environmental carcinogens on the predisposition to oral tumorigenesis. Five polymorphisms of the RAGE gene-including -374T>A (rs1800624), -429T>C (rs1800625), 1704G>T (rs184003), Gly82Ser (rs2070600), and a 63-bp deletion allele (-407 to -345)-were examined from 592 controls and 618 patients with oral cancer. We found that individuals carrying the polymorphic allele of rs1800625 are more susceptible to oral cancer (odds ratio [OR], 1.899; 95% confidence interval [CI], 1.355 to 2.661; adjusted OR [AOR], 2.053; 95% CI, 1.269 to 3.345) after adjustment for age, sex, betel nut chewing, and tobacco consumption. Moreover, we observed a significant association of rs1800625 variants with late-stage tumors (stage III/IV, OR, 1.736; 95% CI, 1.126 to 2.677; AOR, 1.771; 95% CI, 1.101 to 2.851) and large-size tumors (>2 cm in the greatest dimension; OR, 1.644; 95% CI, 1.083 to 2.493; AOR, 1.728; 95% CI, 1.089 to 2.741). Based on behavioral exposure of environmental carcinogens, the presence of 4 RAGE single-nucleotide polymorphisms (SNPs), combined with betel quid chewing and/or tobacco use, greatly augmented the risk of oral cancer. In addition, carriers of particular haplotypes of the 4 RAGE SNPs examined are more prone to develop oral cancer. These results indicate an involvement of RAGE SNP rs1800625 in the development of oral squamous cell carcinoma and implicate the interaction between RAGE gene polymorphisms and environmental mutagens as a predisposing factor of oral carcinogenesis.
Project description:Clinical and experimental data have shown that the receptor for advanced glycation end products (RAGE) is implicated in the pathogenesis of respiratory disorders. In this study, we genotyped five widely-evaluated variants in RAGE gene, aiming to assess their association with the risk for chronic obstructive pulmonary disease (COPD) and asthma in northern Han Chinese. Genotypes were determined in 105 COPD patients, 242 asthma patients and 527 controls. In single-locus analysis, there was significant difference in the genotype distributions of rs1800624 between COPD patients and controls (p=0.022), and the genotype and allele distributions of rs1800625 differed significantly (p=0.040 and 0.016) between asthma patients and controls. Haplotype analysis revealed that haplotype T-A-G-T (allele order: rs1800625, rs1800624, rs2070600, rs184003) was significantly associated with a reduced COPD risk (OR=0.32, 95% CI: 0.06-0.60), and haplotype T-A-A-G was significantly associated with a reduced asthma risk (OR=0.19, 95% CI: 0.04-0.96). Further haplotype-phenotype analysis showed that high- and low-density lipoprotein cholesterol and blood urea nitrogen were significant mediators for COPD (psim=0.041, 0.043 and 0.030, respectively), and total cholesterol was a significant mediator for asthma (psim=0.009). Taken together, our findings indicate that RAGE gene is a promising candidate for COPD and asthma, and importantly both disorders are genetically heterogeneous.
Project description:We aimed to evaluate the association of four common polymorphisms (rs1800625, rs1800624, rs2070600, and rs184003) in receptor for advanced glycation end products (RAGE) gene to evaluate their epistatic influence on breast cancer risk in northeastern Han Chinese. This is a hospital-based case-control study involving 509 histologically-proven breast cancer patients and 504 cancer-free controls. The genotype and allele distributions of rs184003 differed significantly between patients and controls, even after the Bonferroni correction. Individuals carrying the rs184003 T allele exhibited 1.62-fold increased risk of breast cancer (odds ratio (OR) = 1.62; 95% confidence interval (95% CI): 1.26-2.08; P < 0.001) after adjusting for confounders. The frequency of haplotype T-T-G-T (alleles in order of rs1800625, rs1800624, rs2070600, and rs184003) was remarkably higher in patients than in controls (Simulated P = 0.001), and this haplotype was significantly associated with a 1.43-fold (95% CI: 1.01-2.01; P = 0.041) increase in adjusted risk of breast cancer. Further analysis indicated that there was synergistic interaction between rs184003 and rs2070600, whereas their joint information gain value was relatively small (0.27%). Taken together, although there was no suggestive evidence for the presence of epistasis in RAGE gene, our findings clearly demonstrate that rs184003 might play a predominant role in the development of breast cancer.
Project description:Breast cancer constitutes an enormous burden in China. A strong familial clustering of breast cancer suggests a genetic component in its carcinogenesis. To examine the genetic predisposition of high mobility group box-1/receptor for advanced glycation end products (HMGB1/RAGE) pathway to breast cancer, we genotyped six well-defined polymorphisms in this pathway among 524 breast cancer patients and 518 cancer-free controls from Heilongjiang province, China. There were no deviations from Hardy-Weinberg equilibrium for all polymorphisms. In single-locus analysis, the frequency of rs1800624 polymorphism mutant A allele in RAGE gene was significantly higher in patients than in controls (24.52% versus 19.50%, P = 0.006), with the carriers of rs1800624-A allele being 1.51 times more likely to develop breast cancer relative to those with rs1800624-GG genotype after adjustment (95% confidence interval or CI: 1.17-1.94, P = 0.001). In HMGB1 gene, haplotype analysis did not reveal any significance, while in RAGE gene, haplotypes C-T-A and C-A-G (alleles in order of rs1800625, rs18006024, rs2070600) were significantly associated with an increased risk of breast cancer (adjusted OR = 2.72 and 10.35; 95% CI: 1.20-6.18 and 1.58-67.80; P = 0.017 and 0.015 respectively). In further genetic score analysis, per unit and quartile increments of unfavourable alleles were significantly associated with an increased risk of breast cancer after adjustment (odds ratio or OR = 1.20 and 1.26; 95% CI: 1.09-1.32 and 1.12-1.42; P < 0.001 and <0.001 respectively). Our findings altogether demonstrate a significant association between RAGE gene rs1800624 polymorphism and breast cancer risk, and more importantly a cumulative impact of multiple risk associated polymorphisms in HMGB1/RAGE pathway on breast carcinogenesis.
Project description:<h4>Background</h4>Lung cancer is the leading cause of cancer mortality in China. Given the ubiquitous nature of gene-to-gene interaction in lung carcinogenesis, we sought to evaluate five common polymorphisms from advanced glycosylation end product-specific receptor (RAGE) and apurinic/apyrimidinic endonuclease 1 (APE1) genes in association with lung cancer among Han Chinese.<h4>Methods and results</h4>819 patients with lung cancer and 803 cancer-free controls were recruited from Qiqihar city. Genotypes of five examined polymorphisms (RAGE gene: rs1800625, rs1800624, rs2070600; APE1 gene: rs1760944, rs1130409) were determined by ligase detection reaction method. Data were analyzed by R software and multifactor dimensionality reduction (MDR). Hardy-Weinberg equilibrium was satisfied for all five polymorphisms. Overall differences in the genotype and allele distributions were significant for rs1800625 (Pgenotype<0.0005; Pallele<0.0005), rs2070600 (Pgenotype?=?0.005; Pallele?=?0.004) and rs1130409 (Pgenotype?=?0.009; Pallele?=?0.004) polymorphisms. Haplotype C-A-A (alleles in order of rs1800625, rs1800624 and rs2070600) of RAGE gene was overrepresented in patients, and conferred a 2.1-fold increased risk of lung cancer (95% confidence interval: 1.52-2.91), independent of confounding factors. Further application of MDR method to five examined polymorphisms identified the overall best interaction model including rs2070600 and rs1130409 polymorphisms. This model had a maximal testing accuracy of 64.63% and a maximal cross-validation consistency of 9 out of 10 at the significant level of 0.006.<h4>Conclusions</h4>Our findings demonstrated a potential interactive contribution of RAGE and APE1 genes to the pathogenesis of lung cancer among Han Chinese. Further studies are warranted to confirm or refute these findings.
Project description:<h4>Background</h4>Growing evidence indicates that advanced glycation end-product receptor (RAGE) might play a contributory role in the pathogenesis of coronary artery disease (CAD). To shed some light from a genetic perspective, we sought to investigate the interactive association of RAGE gene four common polymorphisms (rs1800625 or T-429C, rs1800624 or T-374A, rs2070600 or Gly82Ser, and rs184003 or G1704A) with the risk of developing CAD in a large northeastern Han Chinese population.<h4>Methodology/principal findings</h4>This was a hospital-based case-control study incorporating 1142 patients diagnosed with CAD and 1106 age- and gender-matched controls. All individuals were angiographically confirmed. Risk estimates were expressed as odds ratio (OR) and 95% confidence interval (CI). Overall there were significant differences in the genotype and allele distributions of rs1800625 and rs184003, even after the Bonferroni correction. Logistic regression analyses indicated that rs1800625 and rs184003 were associated with significant risk of CAD under both additive (OR?=?1.20 and 1.23; 95% CI: 1.06-1.37 and 1.06-1.42; P?=?0.006 and 0.008) and recessive (OR?=?1.75 and 2.39; 95% CI: 1.28-2.40 and 1.47-3.87; P<0.001 and <0.001) models after adjusting for confounders. In haplotype analyses, haplotypes C-T-G-G and T-A-G-T (alleles in order of rs1800625, rs1800624, rs2070600 and rs184003), overrepresented in patients, were associated with 52% (95% CI: 1.19-1.87; P?=?0.0052) and 63% (95% CI: 1.14-2.34; P?=?0.0075) significant increases in adjusted risk for CAD. Further interactive analyses identified an overall best multifactor dimensionality reduction (MDR) model including rs1800625 and rs184003. This model had a maximal testing accuracy of 0.6856 and a cross-validation consistency of 10 out of 10 (P?=?0.0016). The validity of this model was substantiated by classical Logistic regression analysis.<h4>Conclusions</h4>Our findings provided strong evidence for the potentially contributory roles of RAGE multiple genetic polymorphisms, especially in the context of locus-to-locus interaction, in the pathogenesis of CAD among northeastern Han Chinese.