HLA-DQB1-DEFINED GENETIC SUSCEPTIBILITY, BETA-CELL AUTOIMMUNITY, AND METABOLIC CHARACTERISTICS IN FAMILIAL AND NONFAMILIAL INSULIN-DEPENDENT DIABETES-MELLITUS

Familial aggregation of insulin-dependent diabetes mellitus (IDDM) is a common phenomenon, but the reasons behind it are poorly understood. To investigate whether there is heterogeneity between familial and non familial forms of IDDM we compared genetic, immunological, and clinica l characteristics of diabetic children with and without an affected fi rst-degree relative in a population-based series of Finnish children w ith IDDM. The frequencies of HLA-DQB1 genotypes known to be associated with high (DQB10302/0201) or moderate (*0302/x) IDDM risk in the Fin nish population were increased, while the proportions of DQB1 genotype s associated with low or decreased risk for IDDM were reduced in the 1 21 familial cases as compared with the 574 nonfamilial cases (32.7 vs. 21.3%, 41.3 vs. 35.9%, 18.3 vs. 31.4%, and 7.7 vs. 11.4%, respectivel y; P = 0.002). The frequencies and serum concentrations of islet cell antibodies, insulin autoantibodies, and antibodies to the 65-kD isofor m of glutamic acid decarboxylase were similar at diagnosis in the fami lial and nonfamilial cases. The 31 first-affected cases in the multipl e case families were younger at diagnosis than the nonfamilial cases ( 6.9 vs. 8.5 yr; P < 0.05). The 90 second-affected familial cases had l ess severe metabolic decompensation at diagnosis than either the first -affected familial or nonfamilial cases. In conclusion, familial aggre gation of IDDM in Finland is at least partly explained by a higher fre quency of IDDM susceptibility genes in families with multiple affected individuals. The lack of differences in autoantibody levels between t he familial and nonfamilial cases indicates homogeneity rather than he terogeneity in the pathogenetic process of beta cell destruction.