HLA-DQB1*0602 is associated with dominant protection from diabetes even among islet cell antibody-positive first-degree relatives of patients with IDDM.

HLA-DQB1 alleles confer susceptibility and resistance to insulin-dependent diabetes mellitus (IDDM). We investigated whether the susceptibility alleles DQB10302 and DQB10201 affect progression to diabetes among islet cell antibody-positive (ICA+) first-degree relatives of IDDM patients and whether the protective allele DQB10602 can be found and is still protective among such relatives. We human leukocyte antigen-typed and periodically tested beta-cell function (first-phase insulin release [FPIR] during the intravenous glucose tolerance test) in 72 ICA+ relatives, of whom 30 became diabetic on follow-up (longest follow-up 12 years); 54 (75%) relatives carried DQB10302 and/or DQB10201. The frequency of DQB10302 and DQB10201 and of the high-risk genotype DQB10302/DQB10201 did not differ significantly between diabetic relatives and those remaining nondiabetic. On follow-up, progression to IDDM was not statistically different for relatives with or without the DQB10302/DQB10201 genotype. However, those relatives with the DQB10302/DQB10201 genotype had a tendency to develop diabetes at an earlier age (log-rank P = 0.02). We found DQB10602 in 8 of 72 (11.1%) ICA+ relatives. Relatives with DQB10602 did not develop diabetes or show any decline of FPIR versus 28 of 64 DQB10602- relatives who developed IDDM (log-rank P = 0.006; Wilcoxon's P = 0.02). The protective allele DQB10602 is found in ICA+ relatives who have minimal risk of progression to IDDM. Therefore, DQB10602 is associated with protection from IDDM both in population studies and among relatives with evidence of autoimmunity who should not enter prevention trials.