CODON-17 POLYMORPHISM OF THE CYTOTOXIC T-LYMPHOCYTE ANTIGEN-4 GENE INHASHIMOTOS-THYROIDITIS AND ADDISONS-DISEASE

Endocrine autoimmune disorders share susceptibility and resistance fac tors of the human leukocyte antigen system on the short arm of chromos ome 6, but other gene loci also contribute to predisposition and prote ction. Because the cytotoxic T lymphocyte antigen 4 (CTLA4) alanine-17 encoded by the CTLA4 gene on chromosome 2q33 confers susceptibility t o Graves' disease, as well as to type 1 (insulin-dependent) diabetes m ellitus, we investigated this dimorphism in the other endocrine autoim mune disorders: Hashimoto's thyroiditis and Addison's disease. We anal yzed the CTLA4 exon 1 polymorphism (49 A/G) in 73 patients with Hashim oto's thyroiditis, 76 with Addison's disease, and 466 healthy controls . This dimorphism corresponds to an aminoacid exchange (Thr/Ala) in th e leader peptide of the expressed protein. CTLA4 alleles were defined by PCR, single-strand conformational polymorphism analysis, and restri ction fragment length polymorphism analysis using BbvI. Patients with Hashimoto's thyroiditis had significantly more Ala alleles than contro ls, both as homozygotes (22% vs. 15%) and heterozygotes (53% vs. 46%), and less Thr than controls as homozygotes (25% vs. 39%), P < 0.04. Th e phenotypic frequency for Ala was significantly higher in patients (7 5%), compared with controls (61%), P < 0.03. Patients with Addison's d isease did not differ significantly from controls, but those carrying the suceptibility marker, human leukocyte antigen DQA10501, were sign ificantly more CTLA4 Ala(17) positive than controls with the same DQA1 allele (P < 0.05). In conclusion, an alanine at codon 17 of CTLA4 con fers genetic susceptibility to Hashimoto's thyroiditis, whereas this a pplies only to the subgroup of DQA10501+ patients with Addison's dise ase.