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Remission of Graves’ Hyperthyroidism and A/G Polymorphism at Position 49 in Exon 1 of Cytotoxic T Lymphocyte-Associated Molecule-4 Gene

Second Department of Internal Medicine, University of the Ryukyus School of Medicine (Y.K., N.T., I.K., T.T., M.T., T.K., Y.S., K.Y.), Nishihara, Okinawa 902-0215, Japan; and Ito Hospital (H.Y.), Shibuya, Tokyo 150-8308, Japan

Address all correspondence and requests for reprints to: Yoshino Kinjo, M.D., Second Department of Internal Medicine, University of the Ryukyus School of Medicine, Uehara 207, Nishihara, Okinawa 902-0215, Japan. E-mail: . pm7500{at}dns.2naidomon.naha okinawa.jp

Abstract

We studied whether a patient with Graves’ disease will go into remission during antithyroid drug (ATD) treatment. Remission of Graves’ hyperthyroidism is predicted by a smooth decrease in TSH receptor antibody (TRAb) during ATD treatment. Cytotoxic T cell lymphocyte-associated molecule-4 (CTLA-4) may play an important role in the development of Graves’ hyperthyroidism and in its remission. We studied A/G polymorphism at position 49 in exon 1 of the CTLA-4 gene in 144 Japanese Graves’ patients. We intended to reveal the possible association of CTLA-4 gene polymorphism with the remission of Graves’ hyperthyroidism. All patients with Graves’ disease were treated with ATD. Thyroid-stimulating antibody and TSH binding inhibitory Ig were measured as TRAb. We analyzed CTLA-4 genotypes and alleles with PCR. We calculated the frequencies of CTLA-4 genotypes and alleles. A significant increase in the frequency of the G allele was seen in Graves’ patients compared with controls (P = 0.0095). Graves’ patients were divided into three groups (A, B, and C) according to time of TRAb disappearance after the start of ATD treatment. In group A patients TRAb had disappeared within 1 yr after the start of ATD treatment, in group B TRAb had disappeared between the beginning of the second year and the end of the fifth year of treatment, and in group C TRAb continued to be positive after 5 yr of ATD treatment. The frequencies of the GG genotype and the G allele were significantly higher in group C patients with persistently positive TRAb over 5 yr of ATD treatment than in the other groups (P < 0.0001). Group C patients did not have the AA genotype. The periods of time until remission were significantly shorter in the AA genotype. Graves’ patients with the G allele need to continue ATD treatment for longer periods.

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