Genome-Wide Identification of N6-Methyladenosine Associated SNPs as Potential Functional Variants for Type 1 Diabetes.
Genome-Wide Identification of N6-Methyladenosine Associated SNPs as Potential Functional Variants for Type 1 Diabetes.
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N6-甲基腺苷相关 SNP 的全基因组鉴定作为 1 型糖尿病的潜在功能变异
DOI：
10.3389/fendo.2022.913345
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发表时间：
2022
影响因子：
5.2
通讯作者：
Yang, Tao
中科院分区：
文献类型：
--
作者：
Chen, Yang;Shen, Min;Ji, Chen;Huang, Yanqian;Shi, Yun;Ji, Li;Qin, Yao;Gu, Yong;Fu, Qi;Chen, Heng;Xu, Kuanfeng;Yang, Tao
关键词：
N6-甲基腺苷（m6 A）在免疫系统的调节中是必不可少的，但其单核苷酸多态性（SNP）在1型糖尿病（T1 D）发病机制中的作用仍然未知。本研究基于中国人群的病例对照研究，证明了m6 A调节因子的遗传变异与T1 D风险之间的相关性。使用Illumina Human OmniZhongHua-8平台，在1005名自身抗体阳性T1 D患者和1257名对照中对m6 A调节因子中的标签SNP进行基因分型。所有患者均采用放射免疫沉淀法检测胰岛特异性自身抗体。对355例初诊患者进行混合餐葡萄糖耐量试验，评价其残余胰岛功能。对鉴定的SNP的功能注释在计算机中进行。使用来自全基因组表达微阵列的102个样品，对T1 D中与m6 A调节剂相关的关键信号通路进行了深入评估。在加性模型下，我们观察到PRRC 2A（rs 2260051，rs3130623）和YTHDC 2（rs 1862315）基因非编码区的三个标签SNP与T1 D风险相关。虽然这些SNPs与胰岛功能之间没有关联，但携带风险变体的患者对ZnT 8A，GADA和IA-2A的阳性率较高。进一步分析显示rs 2260051 [T]与PRRC 2A mRNA表达增加相关（P = 7.0E-13），与正常样本相比，T1 D患者外周血单核细胞样本中PRRC 2A mRNA显著更高（P = 0.022）。富集分析表明，PRRC 2A表达增加参与了最重要的标志，包括精氨酸-细胞因子受体相互作用、细胞粘附和趋化性以及神经递质调节途径。增加的PRRC 2A在破坏免疫稳态中的潜在作用是通过PI 3 K/AKT途径和神经免疫相互作用。这项研究发现PRRC 2A和YTHDC 2的内含子变异与中国汉族人群中的T1 D风险相关。PRRC 2A rs 2260051 [T]可能通过影响PRRC 2A mRNA的表达而参与不平衡的免疫稳态。这些发现丰富了我们对m6 A调节子及其内含子SNP的理解，这些SNP是T1 D发病机制的基础。
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.
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影响因子：
3.7
作者：
Goudey B;Abraham G;Kikianty E;Wang Q;Rawlinson D;Shi F;Haviv I;Stern L;Kowalczyk A;Inouye M
通讯作者：
Inouye M
影响因子：
16.2
作者：
Chiang JL;Kirkman MS;Laffel LM;Peters AL;Type 1 Diabetes Sourcebook Authors
通讯作者：
Type 1 Diabetes Sourcebook Authors
影响因子：
14.9
作者：
Ritchie ME;Phipson B;Wu D;Hu Y;Law CW;Shi W;Smyth GK
通讯作者：
Smyth GK
影响因子：
64.5
作者：
Manning BD;Toker A
通讯作者：
Toker A
影响因子：
13.8
作者：
Lee DF;Walsh MJ;Aguiló F
通讯作者：
Aguiló F