Linkage of HLA-DR beta specific restriction fragment length polymorphisms with Graves' disease
B O Boehm1, E Schifferdecker, P Kuehnl
1University Hospital of Frankfurt Medical School, Department of Endocrinology, FRG.
Insights
Graves' disease is linked to specific DNA variations in HLA-DR beta genes. These human leukocyte antigen (HLA) polymorphisms, detected via restriction fragment length polymorphism analysis, show different frequencies in patients versus controls.
Area of Science:
- Immunogenetics
- Human Molecular Genetics
- Endocrinology
Background:
- Graves' disease is an autoimmune disorder associated with the human leukocyte antigen (HLA) complex.
- The HLA-DR3 allele is a known susceptibility factor for Graves' disease.
- Understanding genetic polymorphisms within HLA alleles can elucidate disease associations.
Purpose of the Study:
- To investigate DNA polymorphisms within the HLA-DR3 allele in patients with Graves' disease.
- To determine if specific TaqI restriction fragment length polymorphisms (RFLPs) of HLA-DR beta genes are associated with Graves' disease.
- To compare the prevalence of these polymorphisms between Graves' disease patients and healthy controls.
Main Methods:
- Restriction fragment length polymorphism (RFLP) analysis was performed on HLA-DR3 positive individuals.
- TaqI restriction enzyme was used to identify polymorphic fragments corresponding to HLA-DR beta sequences.
- Prevalence of specific DNA fragments (11.6 kb, 9.8 kb, 5.8 kb) was compared between Graves' disease patients and Caucasian controls.
Main Results:
- Significant differences in the prevalence of HLA-DR beta TaqI RFLPs were observed between Graves' disease patients and controls.
- A 11.6 kb fragment was less common in Graves' disease patients (2/19 haplotypes) compared to controls (8/16 haplotypes).
- A 9.8 kb fragment was more prevalent in Graves' disease patients (17/19 haplotypes) than in controls (8/16 haplotypes).
- A 5.8 kb fragment was exclusively found in two Graves' disease patient haplotypes.
Conclusions:
- The study provides evidence for a DNA polymorphism in HLA-DR beta genes linked to Graves' disease.
- These genetic variations, detectable by RFLP analysis, are associated with the susceptibility to Graves' disease.
- The findings suggest that specific HLA-DR beta gene polymorphisms play a role in the pathogenesis of Graves' disease.
Abstract:
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.
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