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Genetic Factors in Autoimmune Thyroid Disease Analyzed by Restriction Fragment Length Polymorphisms of Candidate Genes^*

Thyroid Study Unit, Department of Medicine, and the Howard Hughes Medical Research Institute, University of Chicago Chicago, Illinois 60637

Address all correspondence and requests for reprints to: Leslie J. DeGroot, M.D., Thyroid Study Unit, Box 138, University of Chicago, 5841 South Maryland Avenue, Chicago, Illinois 60637.

Possible genetic effects on the development of autoimmune thyroid disease were studied by analysis of restriction fragment length polymorphisms (RFLPs) of candidate genes. Peripheral blood leukocyte DNA was obtained from 65 Caucasian patients with Graves’ disease, 63 Caucasian patients with Hashimoto’s thyroiditis, and 65 Caucasian controls. RFLP analysis was carried out on genomic DNA, using probes for DRβ, DQ, DQβ, DP, DPβ, T-cell receptor TCR, and thyroid peroxidase. The methodology allowed HLA-DR and DQ typing and provided information on specific RFLP patterns related to T cell receptor (TCR), DP and -β, and -β, and thyroid peroxidase. HLA-DR3 frequency was significantly increased in patients with Graves’ disease, as reported previously by others, but neither DNA-derived subtype of DR3 was differentially increased. HLA-DQw2 was also present in increased frequency because of its linkage disequilibrium with HLA-DR3. It is uncertain whether the primary susceptibility is with DQ, DR, or another nearby locus. Susceptibility was not related in these studies to genetic loci recognized in these studies involving DQ, DP, TCR, or thyroid peroxidase. A significant linkage disequilibrium between DR3 and a specific DX RFLP was observed in Graves’ disease, but is believed to be representative of a generalized linkage disequilibrium between DR3 and DX, rather than a specific abnormality in Graves’ disease. Previous studies indicating association with specific TCR RFLPs could not be reproduced. The relative risk for carriers of HLA-DR3 subtype A in this study was 7.37-fold. RFLP analysis offers the possibility of investigating linkage in a variety of candidate genes as well as established genetic relationships for potentially important subtypes. While the significant relationship with HLA-DR3/DQw2 was reconfirmed, the involvement of other genes or haplotypes could not be established.

^* This work was supported by grants from the Boots Pharmaceutical Co., the March of Dimes Birth Defects Foundation (1–1166), USPHS (DK-27384), and the David Wiener Research Fund.

Received December 17, 1990.

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