Promoter methylation cooperates with SNPs to modulate RAGE transcription and alter UC risk
Promoter methylation cooperates with SNPs to modulate RAGE transcription and alter UC risk
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启动子甲基化与 SNP 协同调节 RAGE 转录并改变 UC 风险
DOI：
10.1016/j.bbrep.2018.11.001
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发表时间：
2019-03-01
影响因子：
2.7
通讯作者：
Zhang, Lingli
中科院分区：
文献类型：
--
作者：
Wang, Jiafeng;Zhen, Yan;Zhang, Lingli
位于晚期糖基化终末产物受体（Receptor for Advanced Glycation End Products，RECEPTOR）基因启动子区的单核苷酸多态性（Single-nucleotide polymorphism，SNPs）与RECEPTOR的活性相关。然而，与我们的预期相反，我们先前在病例对照研究中未检测到SNP与溃疡性结肠炎（UC）风险之间的相关性。在这里，我们研究了UC启动子的甲基化，并分析了甲基化和SNP对UC风险的共同贡献。我们发现，UC患者中，与对照组相比（分别为70%和30%），如通过亚硫酸氢盐测序PCR（BSP）和甲基化特异性PCR（MSP）确定的那样，UC患者中的p53启动子低甲基化更常见。此外，我们研究了启动子甲基化和SNPs的协同性，发现两个SNPs（rs 1800624或rs 1800625）和启动子甲基化中的任何一个都有助于UC风险（30例UC患者vs. 30例对照，P < 0.05）。当分别分析时，UC风险与甲基化或SNP之间没有相关性。这种相关性的缺乏可能是由于启动子甲基化抑制基因转录，而SNP的启动子区域激活转录。我们发现启动子低甲基化的变异等位基因携带者发生UC的风险增加（rs 1800624，OR = 10，95% CI：1.641-60.21，P = 0.009; rs 1800625，OR = 4.8，95% CI：1.074-21.447，P = 0.039）。此外，我们的数据显示，启动子低甲基化的变异等位基因携带者的mRNA水平显着高于启动子高甲基化（P < 0.05），以及那些在野生型等位基因个体表现出启动子低甲基化（P < 0.05）。因此，我们推测，甲基化状态和SNPs存在于p53启动子区域改变p53转录，从而影响UC的风险。我们还建议，甲基化状态和基因型共同作为临床生物标志物，以协助UC的风险评估。
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.