Abstract
BackgroundType 1 diabetes (T1D) is a multifactorial autoimmune disorder where interaction and integration of immune response genes along with environmental factors play a role in autoimmune destruction of the insulin producing Pancreatic Beta cells.Methodology/Principal FindingsWe have studied four single nucleotide polymorphisms (FokI site in Exon 2, BsmI and ApaI sites in Intron 8 and TaqI site in exon 9) in the vitamin D receptor (VDR) gene using PCR-RFLP and HLA-DRB1 alleles using PCR and hybridization with sequence specific oligonucleotide probes and studied their interaction using LD based statistics for non-linked loci followed by sequence analysis of the vitamin D response element (VDRE) present in the promoter region of HLA-DRB1*0301. Haplotypes, constructed using SHEsis program for four single nucleotide polymorphisms in the VDR gene, were studied for their interaction with HLA-DRB1 alleles in 233 T1D patients and 191 healthy controls from North India. A significant increase of haplotypes FBAt and fBAT (p<0.02, OR = 1.44 and p<0.002, OR = 3.23 respectively) was observed in the patients. Both the haplotypes FBAt and fBAT were significantly increased in male patients with age at onset less than 18 years; however, fBAT was significantly increased in female patients irrespective of their age at onset. LD based statistics showed significant interaction between the high producer F and T alleles with HLA-DRB1*0301. F and T alleles of VDR have been shown to contribute to VDR mRNA independently. The promoter sequence analysis of HLA-DRB1*0301 showed presence of VDRE involved in higher expression of HLA-DRB1*030, which was confirmed by flow cytometry and real time PCR analysis.Conclusions/SignificanceThese data suggest that the interaction between VDR and HLA alleles is mediated by VDRE present in the promoter region of HLA-DRB1*0301 allele, which may be detrimental for the manifestation of T1D in the absence of 1,25-(OH)2D3 in early childhood due to poor expression of DRB1*0301 in the thymus resulting in autoimmunity.
Highlights
Type 1 diabetes (T1D) is a multifactorial, autoimmune disorder where the insulin producing pancreatic beta cells are destroyed by one’s own immune system
T1D develops as a result of complex interaction of many genetic and environmental factors leading to autoimmune destruction of the insulin producing Pancreatic Beta cells
To further understand the intricate network of genes regulating the immune responses, we have studied the interaction of vitamin D receptor (VDR) polymorphic alleles with predisposing HLA alleles in T1D patients using Linkage Disequilibrium (LD) based statistics between two unlinked loci
Summary
Type 1 diabetes (T1D) is a multifactorial, autoimmune disorder where the insulin producing pancreatic beta cells are destroyed by one’s own immune system. T1D develops as a result of complex interaction of many genetic and environmental factors leading to autoimmune destruction of the insulin producing Pancreatic Beta cells. Low secretor genotype of TNF- a -308 GG along with low secretor genotypes of IFN-c, high secretor genotypes of IL-6, and TGF- b1 were protective This effect of TNF-a high secretor genotype was independent of predisposing HLA-DRB1*0301 [3]. Type 1 diabetes (T1D) is a multifactorial autoimmune disorder where interaction and integration of immune response genes along with environmental factors play a role in autoimmune destruction of the insulin producing Pancreatic Beta cells
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