Association of -308 TNF-α promoter polymorphism with type 1 diabetes in North Indians

Tumour necrosis factor alpha (TNF-α) is a pleiotropic cytokine with a potent immunomodulatory activity. In humans, TNF-α gene is located on chromosome 6p21.31 in the region of highly polymorphic human leucocyte antigen (HLA) gene complex, hence the genetic variability of TNF-α has been widely implicated in the altered expression of the gene leading to different inflammatory conditions and autoimmune diseases including type 1 diabetes. We assessed the association of TNF-α promoter polymorphisms at -308 and -238 sites with type 1 diabetes and correlated it with TNF-α production in the serum and by the lipopolysaccharide-activated peripheral blood mononuclear cells in North Indian subjects. Genotyping was performed on 130 patients and 133 normal subjects by polymerase chain reaction-restriction fragment length polymorphism analysis using NcoI and BglII restriction endonucleases. The frequency of A allele and AG genotype at -308 site was significantly higher in patients with type 1 diabetes than that of the controls (Pc = 0.000248 and 0.000438, respectively) while no significant difference was observed at -238 site between the two groups. The frequency of A allele at -238 site was very rare (<2%) among the patients and was absent in the control group. The AG genotype at -308 site was associated with relatively higher production of TNF-α in the peripheral blood (P < 0.001), as well as by the peripheral blood mononuclear cells both at the basal level (P < 0.05) and after stimulation with lipopolysaccharide as compared to the -308 GG genotype. The results of the present study suggest that higher frequency of A allele at the -308 promoter site may be related to higher expression of TNF-α gene consequently leading to increased susceptibility to type 1 diabetes in North Indians. © 2006 The Authors.