Type I (insulin-dependent) diabetic multiplex families: mode of genetic transmission

HLA genotypes have been analyzed in 120 classic type I (insulin-dependent) diabetic sib pairs with an age of onset below 16 yr reported to the British Diabetic Association register (1972--78). By this age, siblings of diabetic children are 26 times more likely to develop type I diabetes than other children. There is a highly significant disturbance in the zygotic assortment of HLA haplotypes in these sib pairs, providing conclusive evidence for the existence of major susceptibility genes in the HLA complex. The present data exclude a simple dominant or recessive model of inheritance. It is likely that both parents contribute to the susceptibility, indicating the presence of two HLA-linked genes (or clusters of genes in linkage disequilibrium) that influence the predisposition to the disease. There is no evidence that type I diabetic multiplex families have an increased HLA risk or increased predisposition to autoimmunity compared with families with one affected child.