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Codon 17 Polymorphism of the Cytotoxic T Lymphocyte Antigen 4 Gene in Hashimoto’s Thyroiditis and Addison’s Disease¹

Medical Clinic I, Center of Internal Medicine, Klinikum of the Johann Wolfgang Goethe-University (H.D., J.B., H.R., K.H.U., K.B.), and Institute for Transfusion Medicine and Immunohematology, Red Cross Blood Donor Service Hessen, (C.S.), 60590 Frankfurt/Main, Germany; Mount Sinai Hospital-Toronto and the Samuel Lunenfeld Research Institute of Mount Sinai Hospital, Division of Endocrinology and Metabolism, University of Toronto Medical School, Toronto M5G 1X5, Ontario, Canada (P.G.W.); and Medical Clinic, Endocrine Department, University Hospital Berlin Benjamin Franklin (R.F.); and IV. Medical Clinic, University Hospital Berlin-Charite (M.V.), 10117 Berlin, Germany

Address all correspondence and requests for reprints to: Dr. Badenhoop, Medizinische Klinik I, Klinikum der Johann Wolfgang Goethe-Universität, Theodor-Stern-Kai 7, 60590 Frankfurt/Main, Germany. E-mail: badenhoop{at}em.uni-frankfurt.de

Endocrine autoimmune disorders share susceptibility and resistance factors of the human leukocyte antigen system on the short arm of chromosome 6, but other gene loci also contribute to predisposition and protection. Because the cytotoxic T lymphocyte antigen 4 (CTLA4) alanine-17 encoded by the CTLA4 gene on chromosome 2q33 confers susceptibility to Graves’ disease, as well as to type 1 (insulin-dependent) diabetes mellitus , we investigated this dimorphism in the other endocrine autoimmune disorders: Hashimoto’s thyroiditis and Addison’s disease. We analyzed the CTLA4 exon 1 polymorphism (49 A/G) in 73 patients with Hashimoto’s thyroiditis, 76 with Addison’s disease, and 466 healthy controls. This dimorphism corresponds to an aminoacid exchange (Thr/Ala) in the leader peptide of the expressed protein. CTLA4 alleles were defined by PCR, single-strand conformational polymorphism analysis, and restriction fragment length polymorphism analysis using BbvI.

Patients with Hashimoto’s thyroiditis had significantly more Ala alleles than controls, both as homozygotes (22% vs. 15%) and heterozygotes (53% vs. 46%), and less Thr than controls as homozygotes (25% vs. 39%), P < 0.04. The phenotypic frequency for Ala was significantly higher in patients (75%), compared with controls (61%), P < 0.03. Patients with Addison’s disease did not differ significantly from controls, but those carrying the suceptibility marker, human leukocyte antigen DQA1*0501, were significantly more CTLA4 Ala¹⁷ positive than controls with the same DQA1 allele (P < 0.05). In conclusion, an alanine at codon 17 of CTLA4 confers genetic susceptibility to Hashimoto’s thyroiditis, whereas this applies only to the subgroup of DQA1*0501+ patients with Addison’s disease.

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