Type 1 diabetes (T1D) is an autoimmune disease characterized by progressive destruction of insulin-producing pancreatic beta cells. This multifactorial disease has a strong genetic component associated with the human leukocyte antigens (HLA) and non-HLA regions. In this study, we compared frequencies of HLA-DRB1 alleles and single-nucleotide polymorphisms (SNPs) associated the genes coding for: toll-like receptors (TLRs), tumour necrosis factor (TNF), interleukin-1 (IL-1), interleukin-1 receptor type 1 (IL-1R1), interleukin-1 receptor antagonist (IL-1RN), interleukin-2 (IL-2) and interleukin-12B (IL-12B), between T1D patients and healthy controls. The aim was to identify frequency differences and linkage between these genetic markers in T1D patients and healthy controls. Twelve SNPs were investigated as follows: rs16944 (IL-1B), rs1143634 (IL-1B), rs1800587 (IL-1A), rs2069762 (IL-2), rs3212227 (IL-12B), rs2234650 (IL-1R1), rs315952 (IL-1RN), rs3804099 (TLR2), rs4986790 (TLR4), rs4986791 (TLR4), rs1800629 (TNF) and rs361525 (TNF). TaqMan genotype assay method was used for SNPs genotyping. HLA-DRB1* genes were typed by Sequence Specific Oligonucleotide Probe (SSOP). SPSS and SNPStats programs were used for the statistical analysis. Significant differences between T1D and control groups were found for the dominant model of rs361525 and rs1800629A:rs361525G genotypes for TNF. Increased frequencies of DRB1*03 and DRB1*04 and decreased frequencies of DRB1*07, DRB1*11 and DRB1*13 and DRB1*15 were observed in T1D patients compared with controls. However, the genotype, DRB1*07 with rs1800629A/G was associated with T1D. We have confirmed that DRB1*03 and DRB1*04 are associated with increased risk and DRB1*07, DRB1*11 and DRB1*13 and DRB1*15 with decreased risk of T1D. Also, the dominant model of rs361525A, and the rs1800629G:361525A genotype were associated with increased risk. The simultaneous presence of DRB1*07 and rs1800629A/G genotypes in 23 out of 27 DRB1*07 positive T1D patients implied that islet cell peptide processing may have been biased towards autoimmunity by upregulation of TNF associated intronic SNPs.

中文翻译：

---

肿瘤坏死因子和人类白细胞抗原基因单核苷酸多态性与1型糖尿病的相关性

1 型糖尿病 (T1D) 是一种自身免疫性疾病，其特征是产生胰岛素的胰腺 β 细胞进行性破坏。这种多因素疾病具有与人类白细胞抗原 (HLA) 和非 HLA 区域相关的强烈遗传成分。在这项研究中，我们比较了 HLA-DRB1 等位基因和与编码基因相关的单核苷酸多态性 (SNP) 的频率：toll 样受体 (TLR)、肿瘤坏死因子 (TNF)、白细胞介素-1 (IL-1)、白细胞介素 1 受体 1 型 (IL-1R1)、白介素 1 受体拮抗剂 (IL-1RN)、白介素 2 (IL-2) 和白介素 12B (IL-12B)，在 T1D 患者和健康对照之间。目的是确定 T1D 患者和健康对照中这些遗传标记之间的频率差异和联系。如下研究了 12 个 SNP：rs16944 (IL-1B)、rs1143634 (IL-1B)、rs1800587 (IL-1A), rs2069762 (IL-2), rs3212227 (IL-12B), rs2234650 (IL-1R1), rs315952 (IL-1RN), rs3804099 (TLR9​​86),79rs7rs (TLR9​​86),79rs4TLR1 rs1800629 (TNF) 和 rs361525 (TNF)。TaqMan 基因型检测方法用于 SNP 基因分型。HLA-DRB1* 基因通过序列特异性寡核苷酸探针 (SSOP) 进行分型。SPSS和SNPStats程序用于统计分析。在 rs361525 和 rs1800629A:rs361525G TNF 基因型的优势模型中发现 T1D 和对照组之间存在显着差异。与对照组相比，在 T1D 患者中观察到 DRB1*03 和 DRB1*04 频率增加，DRB1*07、DRB1*11 和 DRB1*13 和 DRB1*15 频率降低。然而，带有 rs1800629A/G 的基因型 DRB1*07 与 T1D 相关。我们已经确认 DRB1*03 和 DRB1*04 与风险增加相关，而 DRB1*07、DRB1*11 和 DRB1*13 和 DRB1*15 与 T1D 风险降低相关。此外，rs361525A 的主导模型和 rs1800629G:361525A 基因型与风险增加有关。在 27 名 DRB1*07 阳性 T1D 患者中的 23 名中同时存在 DRB1*07 和 rs1800629A/G 基因型，这表明胰岛细胞肽加工可能因 TNF 相关内含子 SNP 的上调而偏向于自身免疫。