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Genetic susceptibility to type 1 diabetes is most closely associated with HLA genes that lie within the major histocompatibility complex (MHC) region on the short arm of chromosome 6. HLAs are cell surface glycoproteins that show extreme variability through polymorphisms in the genes that code for them. Both high‐ and low‐risk HLA haplotypes have been identified. HLA DR4–DQ8 and DR3–DQ2 confer high risk: the odds ratios for developing type 1 diabetes are 8–11 and 3.6 respectively for each, and 16 for both. 90% of Europid people with type 1 diabetes carry one or the other, and 30% carry both, compared to just 2% in the general population. Siblings sharing the exact DR3–DQ2 and DR4–DQ8 haplotypes with the proband have a >85% risk of developing diabetes before the age of 15 years. HLA DR3 and DR4 susceptibility haplotypes account for around 50% of the heritability of type 1 diabetes. Protective alleles include DQB1*0602, DQA1*0102 and DRB1*1501. DQB1*0602 is present in around 20% of the non‐Hispanic white population but only 2% of people with type 1 diabetes. HLA susceptibility and protective haplotypes differ across ethnic groups. In African–Americans, the DR3 haplotype versions are very similar to those seen in non‐Hispanic white populations, yet are protective, whereas the DR7 haplotype which is protective in non‐Hispanic whites confers susceptibility.

Class II HLAs (HLA–D) play a key role in presenting foreign and self‐antigens to T‐helper lymphocytes and therefore in initiating the autoimmune process. Polymorphisms in the DR and DQ genes will encode for different amino acids in the peptide binding pockets of the HLA molecules. This affects the binding affinity and range of peptides that are presented to T cells, including potential autoantigens derived from the β cell. This is a likely critical step in ‘arming’ T lymphocytes, which initiate the immune attack against the β cells. Class I HLA alleles (A, B and C) also modify risk for type 1 diabetes but much less so than class II and usually in interaction. Class I/peptide antigen complexes play a role in CD8 T cell mediated cytotoxicity.

The current understanding of the events leading to β cell damage is as follows: Insulitis represents activation of CD4 and CD8 lymphocytes, CD 68 macrophages, and CD 20 B cells. CD 4 cell activation is related to HLA Class II protein expression, whilst CD 8 cells are related to HLA Class I; both are involved in initiation of insulitis and β cell loss, whereas CD 20 B cells appear to determine progression, and high or low expression results in fast or slow development of symptomatic type 1 diabetes.

Over 50 other regions of the human genome have been identified as being associated with type 1 diabetes using the candidate gene and genome‐wide scanning (GWAS) approaches, and together these explain around 80% of heritability. Some of the major genetic polymorphisms and their likely role in Type 1 diabetes are shown in Table 6.2. Combination of the HLA susceptibility genes and PTPN22 and UBASH3A polymorphisms improved the predictability of developing type 1 diabetes by age 15 years to 45%, compared to only 3% in children who had the other combined genotypes. Prospective studies have shown that different genetic polymorphisms affect different stages of the disease process; DR3–DQ2 and DR4–DQ8 together with PTPN22 and UBASH3A seem to influence the development of autoantibodies, whereas INS, UBASH3A and IFIH1 impact upon the progression to symptomatic diabetes.

Table 6.2 Main non‐ HLA polymorphisms that have been used in predictive modelling, and their possible role in type 1 diabetes. PTNP22 polymorphisms are shared with other autoimmune diseases such as rheumatoid arthritis and inflammatory bowel disease.

Genetic polymorphism	Possible impact
Insulin gene (INS)	Affects amount of insulin mRNA in thymus and influences immune tolerance
Protein tyrosine phosphatase non‐receptor type 22 (PTPN22)	Promotes survival of auroreactive T cells in thymus and functional effects on circulating effector and regulator T cells and B cells
Cytotoxic T lymphocyte associated protein (CTLA‐4)	Negative regulator of cytotoxic T cells Target for Abatacept therapy
Interleukin‐2 receptor subunit α (IL2RA)	Affects sensititvity to IL2
Protein tyrosine phosphatase non‐receptor type 2 (PTPN2)	β cell apoptosis after interaction with interferon
Interferon induced helicase (IFIH1)	Binds to virus RNA and moderates interferon mediated viral response
Basic leucine zipper transcription factor 2 (BACH2)	Regulates apoptotic pathways in β cells in conjunction with PTNP2
Ubiquitin associated and SH3 domain‐containing protein A (UBASH3A)	Downregulates Nfκβ signaling pathway in response to T cell stimulation decreasing IL‐2 gene expression
erb‐b2 receptor tyrosine kinase 3 (ERBB3)	Uncertain role in diabetes. Encodes a member of the epidermal growth factor receptor family receptor tyrosine kinase

Intriguingly, there seems to be cross‐talk with the type 2 diabetes susceptibility gene transcription factor 7 like‐2 (TCF7L2). People with type 1 diabetes and only a single autoantibody, or who do not have HLA susceptibility haplotypes, are more likely to have the genetic variant TCF7L2 associated with type 2 diabetes, even though its overall frequency in people with type 1 diabetes is not increased.

The genetics of type 1 diabetes are obviously complex and polygenic. The interaction with environmental factors (see below) which results in an orchestrated T cell mediated and B cell facilitated autoimmune destruction of β cells is likely mediated by a range of different mechanisms, some of which will be more prominent in different individuals, and some of which will operate in sequence or together at different stages in the evolution of type 1 diabetes. It is also worth noting that the majority of those who carry genetic polymorphisms that predispose them to developing type 1 diabetes never do so.