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Cytotoxic T Lymphocyte-Associated Molecule-4 Polymorphism and Relapse of Graves’ Hyperthyroidism after Antithyroid Withdrawal

Department of Internal Medicine (P.-W.W., R.-T.L., Y.-H.H., C.-J.H., M.-H.C., I.-Y.C., C.-L.W.), Chang Gung Memorial Hospital, Kaohsiung 83305, Taiwan; Columbia Genome Center and Department of Epidemiology (S.-H.H.J.), Columbia University, New York, NY 10032; and Department of Public Health (S.-T.W.), National Cheng Kung University Medical Center, Tainan 70101, Taiwan

Address all correspondence and requests for reprints to: Pei-Wen Wang, Department of Internal Medicine, Chang Gung Memorial Hospital, 123, Ta-Pei Road, Niao-Sung Hsiang, Kaohsiung Hsien 83305, Taiwan, Republic of China. E-mail: jhc1997{at}ms18.hinet.net.

We studied the A/G single nucleotide polymorphism (SNP) at position 49 in exon 1 of the cytotoxic T lymphocyte-associated molecule-4 gene in 148 Chinese Graves’ disease (GD) patients and 171 controls. Our primary aim was to test for the association of this SNP with the relapse of the hyperthyroidism after antithyroid withdrawal. Our secondary aim was to investigate the relationship between GD patients and controls according to the SNP genotypes. All GD patients were divided into the following three groups according to the time of relapse after drug discontinuation: group 1, early relapse within 9 months; group 2, relapse between 10 and 36 months; and group 3, relapse 3 or more years after discontinuation of treatment.

There was a significant difference of genotype frequencies (P < 0.001) and allele frequencies (P < 0.001) among the three groups of patients. The frequency of the G/G genotype decreased from 79% to 64% and 39% in groups 1, 2, and 3, respectively. Compared with controls, a strong association (P < 0.001) of G allele was found for group 1, and moderate significance (P = 0.04) was found for group 2, but no association (P = 0.33) was found for group 3. At the end of treatment, the percentage of patients with persistent TSH-receptor antibody was statistically different (A/A, 9.0%; A/G, 20.8%; G/G, 45.5%; P = 0.004). Using 3 yr as the cutoff point for multivariate logistic regression analysis, we found that the G/G genotype (adjusted odds ratio, 3.1 compared with A/G plus A/A; 95% confidence interval, 1.3–7.1), larger goiter size at the end of treatment, and positive TSH-receptor antibody at the end of treatment were independent risk factors of recurrence.

We conclude that the A/G polymorphism of the cytotoxic T lymphocyte-associated molecule-4 gene affects the progress of GD. The G/G genotype is associated with poor outcome.

Abbreviations: CI, Confidence interval; CTLA-4, cytotoxic T lymphocyte-associated molecule-4; GD, Graves’ disease; OR, odds ratio; SNP, single nucleotide polymorphism.

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