EFFECT OF GENETIC RISK LOAD DEFINED BY HLA-DQB1 POLYMORPHISM ON CLINICAL CHARACTERISTICS OF IDDM IN CHILDREN

Clinical and autoimmune characteristics of 150 diabetic children of me an age 7.8 years (SD 4.1 years) were recorded at clinical manifestatio n and during the first 2 years of IDDM in order to investigate whether subjects with high risk HLA-DQB1 genotypes differ from those without these risk markers. When comparing subjects with the DQB10302/0201, D QB10302/x, DQB1*0201/x, or other DQB1 genotypes (x = no protective al lele), no differences were found in the age of the subjects at diagnos is, the duration of hyperglycaemic symptoms, or the length of clinical remission. The frequency of islet cell antibodies (ICA) and quantitat ive serum levels of these antibodies were of the same magnitude in all four groups. During the initial 2 years of IDDM serum C-peptide conce ntrations were observed to be inversely related to the degree of genet ic risk (P < 0.001 in two-way analysis of variance for repeated measur es), the lowest C-peptide levels being observed in the group of DQB10 302/0201 heterozygotes (P < 0.001 vs. DQB10201/x; P < 0.01 vs. DQB1*0 302/x; P = 0.05 vs. others). On the other hand, the subjects with the DQB10201 genotype had the highest serum C-peptide concentrations, the levels being even higher than those of the patients carrying neutral or protective DQB1 genotypes (P < 0.01). These subjects also had lower daily insulin doses and blood glycated haemoglobin A(1) (HbA(1)) leve ls over the initial 2 years of the disease when compared with the DQB1 0302/0201 heterozygotes (P < 0.05 and P < 0.01, respectively). We con clude that the DQB10302/0201 heterozygous individuals with the greate st genetic risk of IDDM lack the capacity for recovery of beta-cell fu nction commonly seen in other subjects after starting exogenous insuli n treatment. Our results also suggest that the DQB10201/x genotype is associated with a milder form of the disease, since these subjects we re characterized by a transient recovery of beta-cell function accompa nied by lower requirement of exogenous insulin and better metabolic co ntrol over the initial 2 years of IDDM.