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 < 0.05). There was no correlation between UC risk and either methylation or SNPs when analyzed separately. This lack of correlation is likely due to promoter methylation repressing gene transcription, whereas SNPs in the RAGE promoter region activate RAGE transcription. We found that variant allele carriers with promoter hypomethylation were at an increased risk for UC (rs1800624, OR = 10, 95% CI: 1.641–60.21, P = 0.009; rs1800625, OR = 4.8, 95% CI: 1.074–21.447, P = 0.039). Furthermore, our data revealed that the RAGE mRNA levels in variant allele carriers with promoter hypomethylation were significantly higher compared to those with promoter hypermethylation (P < 0.05) as well as to those in wild-type allele individuals exhibiting promoter hypomethylation (P < 0.05). We therefore speculate that the methylation status and SNPs present in the RAGE promoter region alter RAGE transcription, thereby impacting UC risk. We also propose that the methylation status and RAGE promoter genotype could jointly serve as clinical biomarkers to assist in UC risk assessment.

The impact of receptor of advanced glycation end‐products polymorphisms on prostate cancer progression and clinicopathological characteristics

“… 58 Besides, the variant of the RAGE rs1800625 SNP was suggested to be associated with the hypomethylation of the promoter region of RAGE and contribute to the ulcerative colitis risk. 59 Furthermore, after we analysed the TCGA database, we found that the RAGE mRNA level was significantly associated with prostate cancer tumorigenesis (Figure 1A ) and pathologic N1 stage development (Figure 1C ). The higher RAGE expression was also observed to be associated with lower overall survival rate in prostate cancer patients (Log Rank p = 0.025, Figure 1D ).…”

Next-Generation Sequencing Profiles of the Methylome and Transcriptome in Peripheral Blood Mononuclear Cells of Rheumatoid Arthritis

“…Furthermore, interaction of genetically associated genes and epigenetically associated genes in RA raised the possibility of cooperation of these two interacting systems to facilitate gene regulation in RA pathogenesis. It is possible that both methylation and genetic alterations were necessary for RA development and altered DNA methylation may be a second hit contributing to penetrance as demonstrated by complex multifactorial traits [27] and supported by past studies of autoimmune diseases [28].…”

Advanced glycation end products regulate the receptor of AGEs epigenetically

“…Diabetes augments the expression of matrix metalloproteinase (MMP)-9 in the skin and its keratinocytes, and a high level of MMP-9 leads to impairments to skin wound healing, in which AGE-induced demethylation of MMP-9 promoter plays a key role ( Perrone et al, 2020 ). On the other hand, the methylation status in the RAGE promoter region exhibits key effects on multiple diseases ( Wang et al, 2019 ). Previous studies also revealed that RAGE promoter methylation status can function as an indicator for the diabetic retinal inflammation and RAGE gene promoters in DR patients, showing a lower methylation rate than that of healthy adults ( Kan et al, 2018 ).…”