Type 1 diabetes is a multifactorial disease with both genetic and environmental components. The largest genetic contribution to T1D is determined by genes in the major histocompatibility complex (MHC) located to the short arm of chromosome 6 (IDDM1-HLA, 6p21). Initial associations between T1D and the MHC were described for the HLA class I antigens A1-B8 and B15. With advent of HLA class II serology, closer associations were found with HLA-DR with an increased frequency of DR3 and DR4 and a decreased frequency of DR2 in T1D subjects. At the population level the strongest genetic association with T1D is with HLA-DQ alleles. This is best defined by DNA typing of HLA-DQ1, DQB1, and DRB1. However, due to the strong linkage disequilibrium between these loci it has been very difficult to study the effect of individual HLA-DQ or HLA-DR genes separately. For the individual, susceptibility is best defined by allelic combinations of MHC genes located to all three major regions (classes I, II, and III) called HLA haplotypes. Haplotypes occur because of strong linkage disequilibrium observed in the MHC whereby the combinations of alleles are seen more frequently than would be expected by their individual gene frequencies. An example of a haplotype would be A2, Cw1, B56, TNFa6, DRB1*401, DQA1*0301, DQB1*0302. The haplotypes are likely to relate to functional groups of genes involved in the etiology of T1D. Thus, the critical residues of DR and DQ, accounting for the disease association with T1D, are located in the antigen-binding cleft of the HLA molecule and are likely to influence the binding of antigenic peptides for subsequent presentation to T helper cells. Similarly, polymorphism of the HLA class I molecules are likely to relate to antigen presentation to cytotoxic T cells, and polymorphisms of tumor necrosis factor (TNF) have been associated with differing TNF responses to mitogenic stimulation.

The MHC accounts for approximately 40% of the genetic component to T1D. Evidence from genome scans and candidate gene studies indicates the existence of a large number of putative non-MHC genes contributing to the etiology of T1D, although all of comparatively small effect compared to the MHC. The most reproducible T1D associations have been found with the insulin gene, cytotoxic T lymphocyte antigen 4 gene (CTLA4), and the vitamin D receptor. An association between the insulin gene (located on chromosome 11p15.5; INS), and T1D was described in the 1980s and subsequently confirmed by linkage studies. The INS locus on chromosome 11p15.5 contains a major polymorphism 5' to the transcription site, which is a variable number of tandem repeats (VNTR) region. One functional hypothesis to explain the association between the insulin gene and T1D is that 'hypersecretors' of insulin determined by the disease-associated polymorphism might induce thymic tolerance to insulin, thus providing protection from the autoimmune reaction. A recent study showed association of the T-cell regulatory gene CTLA4 with susceptibility to autoimmune disease, including type 1 diabetes. CTLA4 (gene located on chromosome 2q33) plays an important role in the counter-regulation of CD28 T cell antigen receptor activation of T cells. In the mouse model of T1D, susceptibility was also associated with variation in CTLA4 gene splicing with reduced production of a splice form encoding a molecule lacking the CD80/CD86 ligand-binding domain. There are associations reported between vitamin D receptor gene polymorphisms and type 1 diabetes. The VDR gene is located on chromosome 12q and polymorphisms of the VDR gene may be related to T-cell-mediated autoimmune destruction of 0 cells of pancreas. Vitamin D compounds suppress T cell activation and significantly repress the development of insulitis and diabetes in the nonobese diabetic (NOD) mouse, a mouse model of human type 1 diabetes. Results from other candidate gene studies and a 'total genome' analysis have identified at least another 19 chromosomal regions that may be involved in patho-genesis of the disease. The finding that so many genes are involved in T1D raises the possibility that there are several disease processes that might lead to 0 cell destruction. Furthermore, evidence is still emerging that the genetic susceptibility to T1D is graded both within and among populations.

Diabetes Sustenance

Diabetes Sustenance

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