HLA associations in insulin‐dependent diabetes: search for heterogeneity in different groups of patients from a homogeneous population

A total of 317 unrelated Danish patients with insulin‐dependent diabetes mellitus (IDDM) have been HLA‐DR typed and the antigen and phenotype frequencies compared with those in 1177 unrelated Danish controls. The strong positive associations with DR3 and 4 and the strong negative one with DR2 were confirmed, and the remaining antigens showed a hierarchy from weakly positive to strongly negative associations: DRw9, w8, 1, 5, w6, 7. The study population included various special groups of patients selected in order to study heterogeneity: very early (< 5 years) and very late (> 40 years) onset IDDM, pregnancy induced IDDM, IDDM nephropathy, and long‐term (> 40 years) survivors without complications. When comparing these groups, the following minor differences were seen: the DR3,4 phenotype is significantly (p = .02) more frequent in IDDM with onset before age 20 (35%) than in other cases (24%), and in familial IDDM (48%) than in other cases (28%); the frequency of the DR4 antigen was significantly (p = .008) more frequent in long‐term survivors (86%) than in other patients (69%), while it was significantly (p = .02) less frequent in IDDM nephropathy (63%) than in long‐term survivors. However, apart from the age‐at‐onset heterogeneity, which was suspected a priori, these differences may be due to chance, and the main conclusion of this study is that the HLA‐DR associations in IDDM are indeed extraordinarily homogeneous irrespective of the clinical characteristics at onset and course of the disease.