PDF(Pubmed)
Abstract：
N6-methyladenosine (m6A) is essential in the regulation of the immune system, but the role that its single nucleotide polymorphisms (SNPs) play in the pathogenesis of type 1 diabetes (T1D) remains unknown. This study demonstrated the association between genetic variants in m6A regulators and T1D risk based on a case-control study in a Chinese population.
The tagging SNPs in m6A regulators were genotyped in 1005 autoantibody-positive patients with T1D and 1257 controls using the Illumina Human OmniZhongHua-8 platform. Islet-specific autoantibodies were examined by radioimmunoprecipitation in all the patients. The mixed-meal glucose tolerance test was performed on 355 newly diagnosed patients to evaluate their residual islet function. The functional annotations for the identified SNPs were performed in silico. Using 102 samples from a whole-genome expression microarray, key signaling pathways associated with m6A regulators in T1D were comprehendingly evaluated.
Under the additive model, we observed three tag SNPs in the noncoding region of the PRRC2A (rs2260051, rs3130623) and YTHDC2 (rs1862315) gene are associated with T1D risk. Although no association was found between these SNPs and islet function, patients carrying risk variants had a higher positive rate for ZnT8A, GADA, and IA-2A. Further analyses showed that rs2260051[T] was associated with increased expression of PRRC2A mRNA (P = 7.0E-13), and PRRC2A mRNA was significantly higher in peripheral blood mononuclear cell samples from patients with T1D compared to normal samples (P = 0.022). Enrichment analyses indicated that increased PRRC2A expression engages in the most significant hallmarks of cytokine-cytokine receptor interaction, cell adhesion and chemotaxis, and neurotransmitter regulation pathways. The potential role of increased PRRC2A in disrupting immune homeostasis is through the PI3K/AKT pathway and neuro-immune interactions.
This study found intronic variants in PRRC2A and YTHDC2 associated with T1D risk in a Chinese Han population. PRRC2A rs2260051[T] may be implicated in unbalanced immune homeostasis by affecting the expression of PRRC2A mRNA. These findings enriched our understanding of m6A regulators and their intronic SNPs that underlie the pathogenesis of T1D.
The tagging SNPs in m6A regulators were genotyped in 1005 autoantibody-positive patients with T1D and 1257 controls using the Illumina Human OmniZhongHua-8 platform. Islet-specific autoantibodies were examined by radioimmunoprecipitation in all the patients. The mixed-meal glucose tolerance test was performed on 355 newly diagnosed patients to evaluate their residual islet function. The functional annotations for the identified SNPs were performed in silico. Using 102 samples from a whole-genome expression microarray, key signaling pathways associated with m6A regulators in T1D were comprehendingly evaluated.
Under the additive model, we observed three tag SNPs in the noncoding region of the PRRC2A (rs2260051, rs3130623) and YTHDC2 (rs1862315) gene are associated with T1D risk. Although no association was found between these SNPs and islet function, patients carrying risk variants had a higher positive rate for ZnT8A, GADA, and IA-2A. Further analyses showed that rs2260051[T] was associated with increased expression of PRRC2A mRNA (P = 7.0E-13), and PRRC2A mRNA was significantly higher in peripheral blood mononuclear cell samples from patients with T1D compared to normal samples (P = 0.022). Enrichment analyses indicated that increased PRRC2A expression engages in the most significant hallmarks of cytokine-cytokine receptor interaction, cell adhesion and chemotaxis, and neurotransmitter regulation pathways. The potential role of increased PRRC2A in disrupting immune homeostasis is through the PI3K/AKT pathway and neuro-immune interactions.
This study found intronic variants in PRRC2A and YTHDC2 associated with T1D risk in a Chinese Han population. PRRC2A rs2260051[T] may be implicated in unbalanced immune homeostasis by affecting the expression of PRRC2A mRNA. These findings enriched our understanding of m6A regulators and their intronic SNPs that underlie the pathogenesis of T1D.
摘要：
N6-甲基腺苷（m6A）在免疫系统的调节中是必不可少的，但是其单核苷酸多态性（SNP）在1型糖尿病（T1D）发病机制中的作用尚不清楚。这项研究基于中国人群的病例对照研究，证明了m6A调节因子的遗传变异与T1D风险之间的关联。
使用Illumina人OmniZhonghua-8平台,在具有T1D和1257对照的1005种自身抗体阳性患者中对m6A调节因子中的标记SNP进行基因分型。通过放射免疫沉淀检查所有患者的胰岛特异性自身抗体。对355例新诊断患者进行混合餐葡萄糖耐量试验，以评估其胰岛功能。鉴定的SNP的功能注释在计算机模拟中进行。使用来自全基因组表达微阵列的102个样本，对T1D中与m6A调节因子相关的关键信号通路进行了全面评估.
在加法模型下，我们观察到PRRC2A(rs2260051,rs3130623)和YTHDC2(rs1862315)基因非编码区的三个标签SNP与T1D风险相关.尽管这些SNP与胰岛功能之间没有发现关联，携带风险变异的患者对ZnT8A的阳性率更高，GADA,和IA-2A。进一步分析显示rs2260051[T]与PRRC2AmRNA表达增加相关(P=7.0E-13),与正常样本相比，T1D患者外周血单核细胞样本中的PRRC2AmRNA明显更高（P=0.022）。富集分析表明，PRRC2A表达增加参与细胞因子-细胞因子受体相互作用的最重要标志，细胞粘附和趋化性，和神经递质调节途径。增加的PRRC2A在破坏免疫稳态中的潜在作用是通过PI3K/AKT途径和神经免疫相互作用。
本研究发现中国汉族人群中PRRC2A和YTHDC2的内含子变异与T1D风险相关。PRRC2Ars2260051[T]可能通过影响PRRC2AmRNA的表达而参与免疫稳态失衡。这些发现丰富了我们对m6A调节因子及其作为T1D发病机理基础的内含子SNP的理解。
使用Illumina人OmniZhonghua-8平台,在具有T1D和1257对照的1005种自身抗体阳性患者中对m6A调节因子中的标记SNP进行基因分型。通过放射免疫沉淀检查所有患者的胰岛特异性自身抗体。对355例新诊断患者进行混合餐葡萄糖耐量试验，以评估其胰岛功能。鉴定的SNP的功能注释在计算机模拟中进行。使用来自全基因组表达微阵列的102个样本，对T1D中与m6A调节因子相关的关键信号通路进行了全面评估.
在加法模型下，我们观察到PRRC2A(rs2260051,rs3130623)和YTHDC2(rs1862315)基因非编码区的三个标签SNP与T1D风险相关.尽管这些SNP与胰岛功能之间没有发现关联，携带风险变异的患者对ZnT8A的阳性率更高，GADA,和IA-2A。进一步分析显示rs2260051[T]与PRRC2AmRNA表达增加相关(P=7.0E-13),与正常样本相比，T1D患者外周血单核细胞样本中的PRRC2AmRNA明显更高（P=0.022）。富集分析表明，PRRC2A表达增加参与细胞因子-细胞因子受体相互作用的最重要标志，细胞粘附和趋化性，和神经递质调节途径。增加的PRRC2A在破坏免疫稳态中的潜在作用是通过PI3K/AKT途径和神经免疫相互作用。
本研究发现中国汉族人群中PRRC2A和YTHDC2的内含子变异与T1D风险相关。PRRC2Ars2260051[T]可能通过影响PRRC2AmRNA的表达而参与免疫稳态失衡。这些发现丰富了我们对m6A调节因子及其作为T1D发病机理基础的内含子SNP的理解。
