Effects of HLA genotype, age and birth order on empirical risk estimates for insulin-dependent diabetes in siblings of diabetic children. An actuarial evaluation.

The incidence of insulin-dependent diabetes (IDDM) was evaluated as a function of time of follow-up among the 371 siblings of 193 diabetic children using actuarial methods and comparisons were carried out according to HLA genotype, sex, age and birth order. The following parameters appeared to be relevant for empirical discrimination in terms of the risk of recurrence of the disease among siblings: The number of HLA-haplotypes shared with the first affected sibling considered as the proband. Cumulative proportions 15 yr after onset of IDD in the proband were 35%, 20% and 3% in the case of 2, 1 and 0 haplotypes in common, respectively (p less than 0.02). The birth order. Cumulative risk estimates were 26% for sibs born after the proband and 11% for sibs born before the proband (p less than 0.001). The age. Risk estimates were 24% for sibs who were aged less than 10 yr at the time of the proband's onset and 5% in sibs aged greater than 10 yr (p less than 0.001). The joint analysis of birth order or age with HLA genotypes showed significantly higher risks for both identical and haplo-identical sibs with later birth order and/or younger age. Even though these results do not reflect true incidence rates because of retrospective recruitment of part of the material, the comparison of the risk figures points out the important role of some age-related effect, probably environmental, in addition to the genetic susceptibility borne by MHC genes.