Islet cell antibodies (ICAs) were determined in a large cohort of white nondiabetic schoolchildren (n = 4287) from a homogenous population in southern Germany. The prevalence of ICA levels ≥5 Juvenile Diabetes Foundation (JDF) U was 1.05% (95% confidence interval 0.8–1.4%). Analysis of HLA-DRβ and -DQβ alleles revealed that the specificities found to be increased in insulin-dependent (type I) diabetic subjects with the same ethnic background were also associated with ICA positivity in the nondiabetic schoolchildren. HLA-DR3 (P < 0.01) and -DR4 (P < 0.01) phenotypes and absence of Asp residue (P < 0.01) at codon 57 of the HLA-DQ β-chain were significantly increased in ICA+ compared with control subjects. High levels of ICAs, which were categorized as either ≥17 or ≥30 JDF U, were found to be associated with amino acids other than Asp at position 57 of the HLA-DQ β-chain. No association of ICA level was found for HLA-DR phenotypes.
Graves' disease (GD) is a human leukocyte antigen (HLA) linked organ-specific autoimmune disease. In German GD patients the disease is associated with HLA specificities of the HLA-DRw52 family (HLA-DR3, -DR5, and DR6; HLA-DRB3 positive HLA haplotypes). Recently, a strong association with a HLA-DRB3 restriction fragment length polymorphism gene has been described. To study HLA-DRB3 alleles and their association with the disease, a large cohort of controls (n = 3724) and GD patients (n = 304) was analyzed. HLA-DR allelic combinations revealed an increase in HLA-DR3/DR5 heterozygous patients (relative risk 2.9; P < 0.001). HLA-DRB3 alleles, as defined by DNA typing in HLA-DR matched groups revealed a significant increase in DRB3*0101 homozygosity (relative risk 17.5; P < 0.001) in HLA-DR3 homozygous patients. In GD patients with ophthalmopathy (grade II or higher, according to Werner) DRB3*0101/*0202 heterozygosity revealed an increased relative risk of 5.5 (P < 0.001). Non-HLA-DR3 homozygous, DRB3*0101/*0202 heterozygous patients were at the highest risk for endocrine ophthalmopathy (relative risk 10; P < 0.001). Our data, based on DNA typing methods of HLA-D genes, provide evidence that the susceptibility is strongly associated with HLA-DRB3 genes.
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