THE MODES OF INHERITANCE OF INSULIN-DEPENDENT DIABETES-MELLITUS OR THE GENETICS OF IDDM, NO LONGER A NIGHTMARE BUT STILL A HEADACHE

Abstract

The discovery of HLA antigen associations with juvenile-type insulin-dependent diabetes mellitus (IDDM) provided strong evidence separating this disorder, or group of disorders, from maturity-type noninsulin-dependent diabetes, as well as adding to the evidence for an immunologic pathogenesis. The use of these diseasemarker associations in appropriate studies might clarify the genetics of IDDM. While these associations have provided a useful tool to further investigate the genetics and pathogenesis of IDDM, the mode or modes of inheritance of this group of disorders remain an area of great controversy. Susceptibility to IDDM is currently being proposed as being inherited as a single autosomal dominant, as a single autosomal recessive, as recessive and some dominant forms, in an intermediate gene dosage model, in a heterogeneous 3-allele or 2 HLA loci model and as a 2-locus disorder. The arguments for each of these proposals is presented, as well as the problems of each. The weight of evidence seems to support the heterogeneity hypothesis, but the modes of inheritance of IDDM will be fully resolved only when the diabetogenic genotype can be reliably identified, rather than being limited to the study of only full-blown clinical disease.