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

Key words human leukocyte antigen B; human leukocyte antigen-DRB1; interferon-g; interleukin-6; interleukin-10; single nucleotide polymorphisms; transforming growth factorb; tumor necrosis factor-a; type 1 diabetes AbstractType 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) a with other cytokine genes. The TNF-a 2308 GA and AA (high secretor) polymorphisms were significantly increased in the patients with T1D (n ¼ 235) [P < 7 Â 10 C) did not show a significant difference between patients and controls. However, simultaneous presence of TNFa 2308 GA1AA along with both high and low secretor genotypes of IFN-g (P < 0.003) was significantly increased in patients. Simultaneous presence of TNF-a 2308 GA 1 AA along with high secretor genotypes of IL-6 (P < 0.0001, OR ¼ 2.61, 95% CI ¼ 1.5-4.56), IL-10 (P < 0.0001, OR ¼ 4.26, 95% CI ¼ 1.9-10.1) and TGFb1 (P < 0.00004, OR ¼ 2.8, 95% CI ¼ 1.6-4.86) was also significantly increased in patients with T1D. Low secretor genotype of TNF-a 2308 GG along with low secretor genotypes of IFN-g (P < 0.001, OR ¼ 0.465, 95% CI ¼ 0.28-0.77), high secretor genotypes of IL-6 (P < 0.000004, OR ¼ 0.76, 95% CI ¼ 0.227-0.621) and TGF-b1 (P < 0.000006, OR ¼ 0.336, 95% CI ¼ 0.198-0.568) was protective. The TNF-a 2308 G allele was in linkage disequilibrium (LD) with the human leukocyte antigen (HLA)-B*0801-DRB1*0301 haplotype, while TNF-a 2308 A allele was in LD with the HLA-B*5001-DRB1*0301 and B*5801-DRB1*0301 haplotypes, suggesting that the effect of TNF-a 2308 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.

Family-based analysis of tumor necrosis factor and lymphotoxin-α tag polymorphisms with type 1 diabetes in the population of South Croatia

“…LTA lies next to TNF, and several studies have combined TNF/LTA SNPs and analyzed them with respect to T1DM. A significant increase in TNF −308 allele A and G/A and A/A genotypes was found in North Indian T1DM cases [17,19]. Similarly, an increase in the prevalence of the TNF −308 A allele was reported in Hungarian diabetic patients [20].…”

“…A functional support for independent effects may be explained by transcription rate enhancement of TNF gene by TNF promoter −308 and −238 SNPs, functional control of TNF promoter SNPs on LTA expression and expression of other nearby genes [34,35,[37][38][39]. An integrated role of TNF and other inflammatory cytokines in the destruction of pancreatic beta cells [19] provides further argument for a TNF/LTA T1DM effect.…”

“…However, several other studies found an independent effect of TNF/LTA with T1DM [17][18][19][20]. TNF involvement in the destruction of pancreatic β-cells [10,11] and multiple inflammatory activities of TNF and LTA cytokines make them plausible targets for revealing molecular susceptibility to T1DM.…”

“…According to Makhatadze there is a localization of TNF and LTA genes within the HLA complex, as shown in Figure 1 [8]. Two TNF gene promoter single nucleotide polymorphisms (SNPs), G-238A (rs361525) and G-308A (rs1800629), have frequently been studied [6,[16][17][18][19][20][21][22]. However, inconsistencies in SNP designation through various LTA gene studies makes difficult to distinguish and differentiate investigated SNPs [6,7,18,22].…”

“…However, inconsistencies in SNP designation through various LTA gene studies makes difficult to distinguish and differentiate investigated SNPs [6,7,18,22]. Studies in North Indian, Hungarian, Bahraini, and Moroccan populations observed associations of TNF -308 SNP and TNF/LTA haplotypes with T1DM independently of HLA loci [17][18][19][20]22]. On the other hand, TNF/LTA T1DM associations in Chinese, Caucasian, and Polish populations were explained by dependence on HLA alleles [6,16,21].…”