The genetics of Type 1 (insulin-dependent) diabetes.

Abstract

The major genetic susceptibility to Type 1 (insulin-dependent) diabetes is determined by genes within the HLA region located on the short arm of chromosome 6. Ninety-seven percent of Type 1 diabetic patients belonging to the Barts-Windsor family study possess either DR3 or DR4 and about 50% possess both these antigens. This excess of DR3, DR4 heterozygosity can be best explained by postulating two different susceptibility genes which react in an interactive way. No increase in DR3 or DR4 homozygosity is found, nor is there an increase in recombination frequency in these families. Linkage disequilibrium between certain B and DR antigens differs in "diabetic" compared to "non-diabetic" haplotypes. In families with two or more Type 1 diabetic children, the affected siblings are with rare exception either HLA identical or haplo-identical. The results from the prospective Barts-Windsor family study indicate that complement fixing islet cell antibodies are a good marker of on-going immune destruction in the pancreatic islets. There is also a high prevalence of antibodies reacting with certain cells in the pituitary gland in newly diagnosed cases and their unaffected first degree relatives. A possible explanation is that a common virus may be acting to produce damage in several endocrine tissues. The Barts-Windsor family study was initiated in 1978 by the late Andrew Cudworth as a prospective family study to investigate the genetic, immunological and environmental factors involved in Type 1 (insulin-dependent) diabetes. About 200 families with a Type 1 diabetic child and at least one other unaffected sibling under the age of 20 years were ascertained from a defined geographical area of approximately 1500 square km, centered around Windsor, East Berkshire, UK. These families are visited every 3 to 4 months and are regularly screened for autoantibodies, in particular islet cell antibodies, and for viral antibodies and they have all been HLA-A, B, C genotyped. A large proportion have also been genotyped for HLA-DR and for the complement factors Bf, C2 and C4, which are coded by genes within the HLA-region.