*1.3.4 Evidence of the role of genetics in diabetes*

The overall risk of T1DM in the general population is 0.4%, but it is higher in relatives of patients. For example, siblings of patients have on average a 6–7% lifetime risk; the risk of T1DM is 1.3–4% in children of a female patient and 6–9% in children of a male patient. While the risk in identical twins with one positive autoantibody reaches up to 60% in some populations and is prone to development of diabetes within three years from detection, accumulated data showed that those with more than two positive autoantibodies will eventually develop diabetes. T1DM in nonidentical twins is similar to that in siblings, which is about 6%.

Over the past 40 years, histocompatibility leukocyte antigen (HLA) regions, on chromosome 6p21, have been the first and largest loci that are linked to T1DM susceptibility, namely, class II HLA DR (especially DR3 and DR4) and DQ (mainly DQ2 and DQ8). These genes are felt to alter type 1 diabetes risk by affecting the ability of these class II molecules to bind to and present β-cell protein peptide fragments to T-cells and therefore to activate an autoimmune reaction. Up to 90% of individuals with type 1 diabetes carry either the DR3/DQ2 halotype, which is associated with glutamic acid decarboxylase autoantibody (GADA), or the DR4/DQ8 haplotype, which is associated with insulin autoantibodies (IAA) (both DQ2 and DQ8 are non-Asp alleles). In contrast, while 20% of the population carries the DQ6.2 alleles (with aspartate at position 57), this allele is rare in individuals with type 1 diabetes, marking this as a dominantly protective allele.
