Pathology and Clinical Laboratory Management Department, 37849King Fahad Medical City, Riyadh, Saudi Arabia.
Obesity, Endocrine and Metabolism Center, 37849King Fahad Medical City, Riyadh, Saudi Arabia.
Int J Immunopathol Pharmacol. 2022 Jan-Dec;36:3946320221090330. doi: 10.1177/03946320221090330.
Type 1 diabetes mellitus (T1DM) is characterized by autoimmune destruction of insulin-producing pancreatic beta (β-) cells. Previous studies suggested an imbalance between and pro- and anti-inflammatory cytokines exacerbates T1DM development.
We aimed to test the hypothesis that patients with T1DM carry a higher frequency of regulatory genes associated with low levels of the anti-inflammatory cytokines interleukin-4 (IL-4), its receptor (IL-4R), and interleukin-10 (IL-10).
Accordingly, we compared frequencies of five different single nucleotide polymorphisms (SNPs) in T1DM patients and healthy controls who had been typed for HLA-DRB1, HLA-DQA1, and HLA-DQB1 genes.
The frequencies of rs2070874 (IL-4) alleles C and T differed between T1DM patients and controls (p = 0.0065), as did their codominant (p = 0.026) and recessive (p = 0.015) models. Increased frequencies were observed in T1DM patients for HLA alleles: DRB103 (pc < 0.0013), DRB104 (p = 0.0169), DQA103 (p = 0.0222), DQA105 (p < 0.0006), DQB102 (p = 0.0005), and DQB106 (p < 0.0005). And lower frequencies were observed for: DRB107 (p = 0.0078), DRB111 (p = 0.0013), DRB113 (p < 0.0364), DRB115 (p < 0.0013), DQA101 (p < 0.0006), and DQA102 (p = 0.0348). Certain DRB1: DQA1: DQB1 haplotypes showed greater frequencies, including, 03:05:02 (p < 0.0001) and 04:03:03 (p = 0.0017), whereas others showed lower frequencies, including, 07:02:02 (p = 0.0032), 11:05:03 (p = 0.0007), and 15:01:06 (p = 0.0002). Stratification for the above HLA haplotypes with rs2070874 C/C exhibited no significant differences between T1DM patients overall and controls. However, when stratified for the vulnerable HLA haplotype (03:05:02/04:03:03), young patients in whom T1DM began at ≤13 years had a higher frequency of the SNP (rs2070874 C/C); a gene associated with low IL-4 production (p < 0.024).
This study suggests that possession of the rs2070874 C/C genotype, which is associated with low production of IL-4, increases the risk of T1DM in young individuals carrying vulnerable HLA alleles/haplotypes.
1 型糖尿病（T1DM）的特征是胰岛β（β）细胞的自身免疫破坏。先前的研究表明，促炎细胞因子和抗炎细胞因子之间的失衡会加剧 T1DM 的发展。
我们旨在检验以下假设，即 T1DM 患者携带与抗炎细胞因子白细胞介素 4（IL-4）、其受体（IL-4R）和白细胞介素 10（IL-10）水平较低相关的调节基因的频率更高。
因此，我们比较了 T1DM 患者和已对 HLA-DRB1、HLA-DQA1 和 HLA-DQB1 基因进行分型的健康对照者中五种不同单核苷酸多态性（SNP）的频率。
T1DM 患者和对照组之间的 rs2070874（IL-4）等位基因 C 和 T 的频率不同（p = 0.0065），其共显性（p = 0.026）和隐性（p = 0.015）模型也不同。T1DM 患者 HLA 等位基因的频率增加：DRB103（pc < 0.0013），DRB104（p = 0.0169），DQA103（p = 0.0222），DQA105（p < 0.0006），DQB102（p = 0.0005）和 DQB106（p < 0.0005）。而 HLA 等位基因频率降低：DRB107（p = 0.0078），DRB111（p = 0.0013），DRB113（p < 0.0364），DRB115（p < 0.0013），DQA101（p < 0.0006）和 DQA102（p = 0.0348）。某些 DRB1：DQA1：DQB1 单体型的频率更高，包括 03：05：02（p < 0.0001）和 04：03：03（p = 0.0017），而其他单体型的频率较低，包括 07：02：02（p = 0.0032），11：05：03（p = 0.0007）和 15：01：06（p = 0.0002）。在 T1DM 患者和对照组中，rs2070874 C/C 与上述 HLA 单体型分层无显著差异。然而，当按脆弱 HLA 单体型（03：05：02/04：03：03）分层时，T1DM 发病年龄≤13 岁的年轻患者的 SNP（rs2070874 C/C）频率更高；这是一种与 IL-4 产量低相关的基因（p < 0.024）。
本研究表明，携带与低 IL-4 产生相关的 rs2070874 C/C 基因型会增加携带脆弱 HLA 等位基因/单体型的年轻个体发生 T1DM 的风险。
