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

Abstract

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 (Kg) (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 Kg 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 Kg (rs = −0.41; P < 0.001) and FPIR (rs = −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.