HLA-DRB1 基因和 HLA CIITA 的表达动态决定了 T2DM 的易感性。
HLA-DRB1 genes and the expression dynamics of HLA CIITA determine the susceptibility to T2DM.
机构信息
Department of Immunology, School of Biological Sciences, Madurai, Tamil Nadu, 625021, India.
Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, 79430, USA.
出版信息
Immunogenetics. 2021 Aug;73(4):291-305. doi: 10.1007/s00251-021-01212-x. Epub 2021 Mar 22.
Type 2 diabetes mellitus (T2DM) is a disease with polygenic inheritance. The expression of major histocompatibility complex class II genes are regulated by several trans-activators. We have studied the expression of HLA-DRB1, RFX, CIITA-P1, PIV transactivators, immunophenotyping of cells, SNPs in CIITA-168 (A/G) and IFN-γ + 874 (T/A) in T2DM patients and controls (n = 201 each). We observed increased frequencies of DRB103, DRB104 and DRB107 and decreased frequencies of DRB110, DRB114, and DRB115 alleles among patients. Significant up-regulations of HLA-DRB1 genes were observed in patients (p < 0.0001). Down-regulated expressions were documented in DRB103-homo (p < 0.002) and DRB104-homo (p < 0.009) patients. No significant differences were observed for CIITA-P1 expression except DRB104-pooled (p < 0.0113). The CIITA-PIV was up-regulated in overall (p < 0.0001), DRB103-pooled (p < 0.0006), DRB103-hetero (p < 0.0006) and DRB103-homo (p < 0.001) T2DM patients. However, significant down-regulations were documented for DRB104-pooled (p < 0.040), DRB104-hetero (p < 0.060), and DRB104-homo (p < 0.027) combinations. Further, significant down-regulations of RFX5 were observed in overall (p < 0.0006), DRB104-pooled (p < 0.0022), and DRB104-hetero (p < 0.0004) combinations. Immunophenotyping studies revealed significant increase of CD45 CD14, CD19, CD14 and CD8 cells and elevated level of expression of IFN-γ (p < 0.0001) in patients. A significant increase of TT (p < 3.35 × 10) and decrease of TA (p < 4.57 × 10) genotypes of IFN-γ + 874 (T/A) and an increase of GG (p < 0.001) and decrease of AG (p < 8.24 × 10) genotypes of CIITA-168 A/G SNPs were observed. The combinatorial analysis revealed susceptible associations for DRB103 + AA, *03 + AG, *03 + GG and 04 + GG and protective associations for DRB110 + AG, *10 + GG, *15 + AG, and *14 + GG combinations. Thus, the present study corroborated the effect of differential expressions of promoters of risk alleles in the pathogenesis of T2DM.
2 型糖尿病（T2DM）是一种具有多基因遗传的疾病。主要组织相容性复合体 II 类基因的表达受几种转录激活子调控。我们研究了 HLA-DRB1、RFX、CIITA-P1、PIV 转录激活子、细胞免疫表型、CIITA-168（A/G）和 IFN-γ+874（T/A）中的 SNPs 在 T2DM 患者和对照组（n=201）中的表达。我们观察到患者中 DRB103、DRB104 和 DRB107 等位基因的频率增加，而 DRB110、DRB114 和 DRB115 等位基因的频率降低。患者中 HLA-DRB1 基因的显著上调（p<0.0001）。在 DRB103-homo（p<0.002）和 DRB104-homo（p<0.009）患者中观察到下调表达。CIITA-P1 表达除 DRB104-池（p<0.0113）外，无显著差异。CIITA-PIV 在总体（p<0.0001）、DRB103-池（p<0.0006）、DRB103-杂合（p<0.0006）和 DRB103-纯合（p<0.001）T2DM 患者中上调。然而，在 DRB104-池（p<0.040）、DRB104-杂合（p<0.060）和 DRB104-纯合（p<0.027）组合中观察到显著下调。此外，在总体（p<0.0006）、DRB104-池（p<0.0022）和 DRB104-杂合（p<0.0004）组合中观察到 RFX5 的显著下调。免疫表型研究显示，患者中 CD45 CD14、CD19、CD14 和 CD8 细胞显著增加，IFN-γ 的表达水平升高（p<0.0001）。IFN-γ+874（T/A）的 TT（p<3.35×10）基因型增加和 TA（p<4.57×10）基因型减少以及 CIITA-168 A/G SNPs 的 GG（p<0.001）基因型增加和 AG（p<8.24×10）基因型减少均有统计学意义。组合分析显示，DRB103+AA、03+AG、03+GG 和04+GG 存在易感关联，而 DRB110+AG、*10+GG、15+AG 和14+GG 组合存在保护关联。因此，本研究证实了风险等位基因启动子的差异表达在 T2DM 发病机制中的作用。
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