Human Leukocyte Antigen Identity and DQ Risk Alleles in Autoantibody-Positive Siblings of Children With IDDM are Associated With Reduced Early Insulin Response

To investigate the relationship between human leukocyte antigen (HLA)-associated genetic factors and the development of β-cell dysfunction, we performed sequential intravenous glucose tolerance tests (IVGTTs) on 81 islet cell antibody (ICA)-positive and/or insulin autoantibody-positive healthy siblings of children with newly diagnosed insulin-dependent diabetes mellitus (IDDM). A lower glucose disappearance rate (K_g) (P < 0.5) and decreased first-phase insulin response (FPIR) (P < 0.05) were observed on multiple occasions in HLA-identical siblings compared with the haploidentical or nonidentical ones. Siblings carrying the DQB1*0302/0201, −0302/x, or −0201/x genotype also had lower FPIRs (P ≤ 0.05) at several time points than those with no DQB1 risk genotype. When all IVGTTs were taken into account, DQB1*0302/0201 heterozygous siblings had an abnormally low FPIR (< 45 mU/I; 3rd percentile) in at least one test more often than did siblings with no DQB1 risk genotype (50.0% vs. 6.1%; P = 0.001). Siblings carrying either the DQB1*0602 or the DQB1*0603 protective allele had lower serum peak ICA and glutamic acid decarboxylase (GAD)₆₅ antibody levels (P = 0.023 and 0.007, respectively) and higher FPIRs on several occasions (P < 0.05) than those with the DQB1 risk genotypes. Progression to IDDM was related to both HLA identity and the presence of the DQB1*0302/0201 genotype. Normal K_g and FPIR levels were observed in siblings who were positive for only insulin autoantibody, and none of them developed IDDM. Serum ICA concentrations were inversely correlated with K_g (r_s = −0.41; P < 0.001) and FPIR (r_s = −0.52; P < 0.001) in the first IVGTT, suggesting that high serum levels of ICA could to some extent be used as an indicator of impaired insulin-secretory capacity in the β-cells. We conclude that both HLA identity and the presence of DQB1 risk genotype were associated with a decreased early insulin response to intravenous glucose in ICA⁺ siblings of diabetic children. HLA identity was also associated with impaired glucose tolerance.