Association of single‐nucleotide polymorphisms in tumour necrosis factor and human leukocyte antigens genes with type 1 diabetes

Abstract

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.

Single nucleotide polymorphism rs 2070874 at Interleukin-4 is associated with increased risk of type 1 diabetes mellitus independently of human leukocyte antigens

“…Within the context of the simplistic paradigm whereby autoimmune diseases are facilitated by an imbalance between anti-inflammatory (IL-4, IL-10, IL-13) and proinflammatory cytokines (TNF-α, IFN-γ) low levels of the former and high levels of the latter facilitate T1DM onset (Moudgil and Chouby 2011) 39 . Both our former finding (Osman et al 2021), 37 that T1DM was associated with high TNF producer genes (rs361525), and current findings of low IL-4 producer genes are consistent with this model.…”

“…Of 180 patients with T1DM, 90 (50%) were females (aged 3-28) and 90 (50%) were males (aged [16][17][18][19][20][21][22][23][24][25][26][27][28][29][30]. The age of onset of T1DM was below 13 years in 142 (78.9%) and above 13 in 34 (18.1%) patients.…”

“…15 Multiple research studies, including our own, have investigated associations between single nucleotide polymorphisms (SNPs) linked to regulatory or structural regions of cytokine genes and T1DM. [18][19][20][21] Depending on their location within the genome, SNPs are flags highlighting possible differences in the expression, function, and/or production of cytokines within T1DM phenotypes. For example, the IL-4 SNP rs2070874 is located in the 5 0untranslated region of exon one of the IL-4 gene and, as such, could regulate the levels of cytokine production.…”

Interleukin-18 cytokine in immunity, inflammation, and autoimmunity: Biological role in induction, regulation, and treatment

“…Comprising of six exons and five introns, the IL-18 gene is located on chromosome 11q22.2-q22.3 ( 152 ). Several IL-18 polymorphisms have been identified, however the genetic relationship between single nucleotide polymorphisms (SNPs) at positions-137, -607 in IL-18 gene promoter and T1D have been of interest and is widely reported in previous studies ( 153 ). Conversely, other studies failed to show any association between T1D and these SNPs.…”

Exploring Interleukin Levels in Type 1 Diabetes and Periodontitis: A Review with a Focus on Childhood

“…More research is needed to understand the role of IL2RA gene variants in the development of vascular complications in people with T1DM; however, recent findings suggest that IL2RA gene variants may be a target for the development of new treatments for these complications, and could confer risk alleles for T1DM among the Emirati population [27]. In a study published in 2021, Osman A. E. and colleagues [23] investigated the levels of ILs in patients with T1DM and healthy controls. They found that the levels of IL-1A/B, IL-2, and IL-12 were significantly higher in patients with T1DM in contrast to healthy controls.…”