The risk of T1D in a sibling of an affected individual is around 6 %, as compared to 0.4 % risk in the background population, which translates to a 15-fold increase in relative risk. A child has a 7 % risk of developing T1D if father is affected and 2 % risk with affected mother. There appears to be a strong genetic component and HLA class II alleles are responsible for up to 30-50 % of genetic T1D risk. HLA alleles contributing to disease susceptibility include HLA DR3, DQB1*0201, and DR4, DQB1*0302 as compared to some associated with disease protection, e. g. HLA DR2, DQB1*0602. Multiple non-HLA loci including insulin, PTPN22, CTLA4, IL2RA and IFIH1 also contribute to disease risk. In fact, with the advent of genome wide association studies (GWAS), more than 50 non-HLA loci associated with T1D susceptibility have been found. Many of these genes have a role in the immune response and may contribute to autoimmunity in general.
Though genetic factors are important, disease concordance in monozygotic twins is only up to 50 % and approximately 90 % of T1D cases lack family history of the condition. This, along with the recent sharp increase in incidence of childhood T1D, suggests that exogenous influence or gene-environment interaction may be important. Furthermore, migrating populations have been shown to have similar risk of developing T1D as people in their adopted geographical area. Over the years, numerous environmental triggers for T1D including viral infections, vitamin D deficiency, cow’s milk consumption, intake of N-nitroso compounds, lack of breast-feeding have been proposed. The ‘hygiene hypothesis’ suggests that reduced exposure to infectious diseases in the west could be contributing to rising incidence of autoimmune diseases including T1D. The role of intestinal microbiomata in facilitating islet autoimmunity is also being explored. Despite numerous studies of environmental influences on T1D, there is still no convincing evidence regarding etiology. The ongoing multicenter, prospective TEDDY (The Environmental Determinants of Diabetes in the Young) study may provide some useful insights.
T1D is caused by cell-mediated autoimmune destruction of pancreatic beta cells in the islets of Langerhans. Gepts, in 1965, noted pancreatic insulitis in recent onset T1D and proposed autoimmunity as a possible mechanism. It was in 1974 that islet cell antibodies (ICA) were discovered which reinforced the role of autoimmunity. ICA and antibodies to glutamic acid decarboxylase (GADA), insulin (IAA), insulinoma - associated protein 2 antigen (IA-2A) and islet antigen zinc transporter-8 (ZnT8A) identify individuals at a high risk of T1D. These autoantibodies can be present in infancy and they often precede T1D by several years. ICA and GADA are detected in 70-80 % of individuals with new-onset T1D where as IAA is more common in younger children with new-onset T1D than in adults.