Linkage analysis and genetic models for IDDM.

The multiplex insulin-dependent diabetes mellitus (IDDM) families have been examined for linkage with the human leukocyte antigen (HLA), Gm, Km, and insulin loci. For the last three, no evidence of linkage (as measured by haplotype sharing in affected siblings) was found. For HLA, strong evidence of linkage was demonstrated, as expected from previous studies of both haplotype sharing and HLA association. The haplotype sharing in affected siblings from this and previous studies would explain a relative risk of about 3.7 in the sibling of an affected individual (95% confidence limits 2.8 to 5.4), considerably less than the values of 10-15 given by epidemiological studies. This discrepancy may be explained by other predisposing genes unlinked to HLA, or be due to common environmental factors. Analysis conditional on the affection status of all individuals, and on the parental HLA haplotypes clearly rejects both a dominant and recessive mode of inheritance in favor of a two-allele model with a reduced risk for heterozygotes, and provides some support for a three-allele model. Some evidence of age effects was found; in particular there was some suggestion of greater haplotype sharing in siblings both affected at a young age, and there was some suggestion that individuals with the predisposing HLA-DR3/DR4, DR3/DRx, and DR4/DRx genotypes were affected at a younger age. These results may be diagnostic artifacts, however, and need investigation in future studies.