A three-allele model for heterogeneity of juvenile onset insulin-dependent diabetes

A three-allele model is presented for the inheritance of 'juvenile' insulin-dependent diabetes mellitus (IDDM). The model postulates a susceptibility locus S tightly linked to the HLA complex. The model incorporates relative-risk and HLA-association data from the literature which suggest genetic heterogeneity within IDDM, together with population prevalence, twin and sib concordance rates, and distortions in HLA-haplotype concordance values for affected sib pairs. The model appears to provide a reasonable fit to existing data. It predicts low penetrances for some, but not all, genotypes and a strong association between HLA B8 and one of the S alleles. The model makes additional specific predictions about how different forms of IDDM are distributed in sporadic and familial cases. These predictions can be tested in future genetic-epidemiologic studies.