HLA-DQB1 GENOTYPES AND ISLET-CELL ANTIBODIES IN THE IDENTIFICATION OFSIBLINGS AT RISK FOR INSULIN-DEPENDENT DIABETES (IDDM) IN FINLAND

The risk of progression to IDDM can be evaluated by diabetes-related a utoantibodies such as cytoplasmic islet cell antibodies (ICA) or genet ic determinants as markers. In this prospective study we wanted to est imate the predictive value of the combination of these markers in sibl ings of diabetic children. A sample of 770 siblings was observed from the time;of diagnosis in the index case for a median period of 5.8 yea rs (range 0.01-7.3 years) for development of ICA and insulin autoantib odies (IAA) and progression to clinical diabetes. The most important s usceptibility and protection associated DQB1 alleles were defined by f our sequence-specific oligonucleotide probes. DNA samples were availab le from 89 originally non-diabetic ICA positive siblings of whom 28 pr esented with IDDM during the study period, as well 100 randomly chosen ICA negative control siblings. More than half (11/28; 55%) of the sib lings who had the high risk DQB1 genotypes progressed to clinical IDDM compared to 6/37 (16%) of those who had protective/neutral genotypes (P=0.006). Of all genotyped secondary cases, 36% (n=33) had a genotype associated with the highest risk (DQB10302/0201), whereas 27% had ge notypes without any susceptibility alleles (P values <0.0001 and =0.00 02, respectively, compared with ICA negative siblings). The results de monstrate the feasibility of the combination of genetic and immunologi cal markers in the prediction of the risk for IDDM within families.