Linkage of HLA-DRβ specific restriction fragment length polymorphisms with Graves' disease

HLA-DR3 positive patients with Graves' disease (6 homozygotes, 7 heterozygotes, i.e. yielding 19 haplotypes) were studied by restriction fragment length polymorphism analysis using TaqI as restriction enzyme in order to look for polymorphisms in the HLA-DR3 allele of the human major histocompatibility complex. Polymorphic TaqI fragments of 11.6, 9.8 and 5.8 kb, each corresponding to HLA-DR beta sequences, were shown to differ in their prevalence in patients with Graves' disease and controls. The prevalence of DR3 polymorphisms in a total of 35 HLA-DR3-containing haplotypes was markedly different within patients with Graves' disease and Caucasian controls. Whereas a 11.6 kb fragment was rare in Graves' disease (2/19 haplotypes vs 8/16 in controls), the inverse ratio was found for a 9.8 kb fragment, with a prevalence of 17/19 and 8/16 haplotypes, respectively. A polymorphic fragment of 5.8 kb was exclusively seen in two DR3-containing haplotypes of patients with Graves' disease. Our data provide evidence that a DNA polymorphism of the HLA-DR beta genes, which is also reflected at the product level, is linked to Graves' disease.