Genetic control of autoimmunity in Type I diabetes and associated disorders

Abstract

Type I (insulin-dependent) diabetes mellitus is a heterogeneous disease with major subdivisions termed Type 1A (immune-mediated) and Type 1B. Immunemediated diabetes is also heterogeneous with ªmono-genicº, oligogenic, and polygenic forms present in humans and in animal models. Single-gene mutations of two transcription factors have been recently identified in rare syndromes of autoimmunity with type 1A diabetes: autoimmune polyendocrine syndrome type 1 (APS-1) and X-linked polyendocrinopathy, immune dysfunction and diarrhoea (XPID). For more common forms of diabetes, susceptibility loci within the major histocompatibility complex and at the insulin locus have been identified. Both DQ* and DR* alleles provide susceptibility and certain alleles dominant protection. In the Diabetes Autoimmunity Study of the Young approximately 50 % of the siblings studied with the highest-risk HLA genotype develop anti-islet autoantibodies by age 3. Insulin could be a crucial autoantigen related to genetic susceptibility. The crystal structure of the high-risk allele, HLA-DQ8, complexed with an insulin peptide has just been reported. Insulin production by macrophage-dendritic cells within the thymus and lymphoid organs could underlie insulin gene polymorphisms influencing the risk of diabetes. Genome-wide scans for linkage in animal models and in humans have not conclusively identified other susceptibility genes though many loci have been implicated. We favour the hypothesis that HLA is a major determinant of susceptibility in animal models and in most families, and that the search for diabetogenes should concentrate on unique families to decrease heterogeneity and favour the eventual discovery of genes influencing risk. [Diabetologia (2002) 45:605±622]

The peptide-binding motif of HLA-DR8 shares important structural features with other type 1 diabetes-associated alleles

“…MHC accounts for approximately 50% of the familiar risk for T1D. 34 The identity of the b57 residue is important both for disease susceptibility and protection: Ala, Ser or Val at b57 defines predisposing alleles such as DQ2, DQ8, I-A g7 and DR8, whereas Asp is found in protective allele DQ6. The structural explanation for the importance of b57 was obtained from the crystal structure of I-A k and I-A d where it was shown that Asp at b57 forms a salt bridge with an Arg at position 76 of the a-chain (homologous to position 79 on the DQa chain).…”

Canine diabetes mellitus: can old dogs teach us new tricks?

“…Susceptibility is linked to HLA DQA and DQB genes, influenced by the DR genes [47]. The observation that certain breeds of dog are predisposed to diabetes suggests that there is also a genetic component to canine diabetes.…”

Children developing type 1 diabetes before 6 years of age have increased linear growth independent of HLA genotypes

“…Genetic factors, mainly HLA DR-DQ genotypes, are strong susceptibility factors [6]. However, among newly diagnosed type 1 diabetes patients only 10 to 15% have a first-degree relative with the disease [7] and the concordance rate between monozygotic twins is low [8,9], underlining the importance of environmental factors.…”