Association and interaction of the TNF‐alpha gene with other pro‐ and anti‐inflammatory cytokine genes and HLA genes in patients with type 1 diabetes from North India

Abstract

Type 1 diabetes (T1D) is a multifactorial autoimmune disorder where major histocompatibility complex (MHC) genes and the insulin‐linked polymorphic region have been shown to play major roles. We report here an integrated effect of tumor necrosis factor (TNF) α with other cytokine genes. The TNF‐α−308 GA and AA (high secretor) polymorphisms were significantly increased in the patients with T1D (n = 235) [P < 7 × 10⁻⁶, odds ratio (OR) = 3.04, 95% confidence interval (CI) = 1.8–5.3] compared with the controls (n= 128). The variants of interferon‐γ (IFN‐γ) (A⁺⁸⁷⁴T), interleukin (IL)‐6 (G⁻¹⁷⁴C), IL‐10 (A⁻¹⁰⁸²G, T⁻⁸¹⁹C, C⁻⁵⁹²A) and transforming growth factor (TGF) β1 (T^cdn10C, G^cdn25C) did not show a significant difference between patients and controls. However, simultaneous presence of TNF‐α−308 GA+AA along with both high and low secretor genotypes of IFN‐γ (P < 0.003) was significantly increased in patients. Simultaneous presence of TNF‐α−308 GA + AA along with high secretor genotypes of IL‐6 (P < 0.0001, OR = 2.61, 95% CI = 1.5–4.56), IL‐10 (P < 0.0001, OR = 4.26, 95% CI = 1.9–10.1) and TGF‐β1 (P < 0.00004, OR = 2.8, 95% CI = 1.6–4.86) was also significantly increased in patients with T1D. Low secretor genotype of TNF‐α−308 GG along with low secretor genotypes of IFN‐γ (P < 0.001, OR = 0.465, 95% CI = 0.28–0.77), high secretor genotypes of IL‐6 (P < 0.000004, OR = 0.76, 95% CI = 0.227–0.621) and TGF‐β1 (P < 0.000006, OR = 0.336, 95% CI = 0.198–0.568) was protective. The TNF‐α−308 G allele was in linkage disequilibrium (LD) with the human leukocyte antigen (HLA)‐B*0801‐DRB1*0301 haplotype, while TNF‐α−308 A allele was in LD with the HLA‐B*5001‐DRB1*0301 and B*5801‐DRB1*0301 haplotypes, suggesting that the effect of TNF‐α−308 A allele is not because of its being in LD with any HLA alleles, but because of its functional role and its integrated effect with other cytokines.