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The Journal of Clinical Endocrinology & Metabolism Vol. 89, No. 1 169-173
Copyright © 2004 by The Endocrine Society

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

Pei-Wen Wang, Rue-Tsuan Liu, Suh-Hang Hank Juo, Shan-Tair Wang, Ya-Hui Hu, Ching-Jung Hsieh, Ming-Hong Chen, I-Ya Chen and Chia-Ling Wu

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.


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 References
 
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.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 References
 
AS KNOWLEDGE OF genome technologies and methodologies progresses, the application of pharmacogenetics will greatly influence the choice of treatment. For patients with Graves’ disease (GD), there are three choices of treatment, yet none of them is perfect. The primary goal of antithyroid drug therapy is to temporarily restore the patient to the euthyroid state. At the same time, we anticipate a remission of the disease and a reduction of the chance of iatrogenic hypothyroidism, which is often seen in subtotal thyroidectomy or I-131 radiation. Although certain pretreatment clinical features, such as a large goiter, more severe biochemical thyrotoxicosis, and high baseline serum TSH-receptor antibodies (1, 2, 3, 4, 5), have been reported to be associated with more frequent relapse, the ability to predict which patients are likely to have relapse/remission is limited. Genetic markers may provide additional information to predict the course of disease after withdrawing antithyroid drugs.

GD is an organ specific autoimmune disease with T lymphocyte abnormality (6, 7). The major histocompatibility complex gene has been the main focus of study because it harbors the genes for susceptibility for GD (8, 9, 10). However, the relationship between the candidate genes of major histocompatibility complex and GD is generally weak and varies considerably among different populations (11, 12, 13). In 1987, cytotoxic T lymphocyte-associated molecule-4 (CTLA-4) was discovered in a cDNA library of T cell-specific, activation-induced genes (14). There is increasing evidence that CTLA-4 is an extraordinarily important molecule to down-regulate T cell expansion and cytokine production (15, 16, 17). CTLA-4 expression on a T cell may well influence the course or presentation of an ongoing immune process (18, 19, 20). Therefore, it is a good candidate gene to test the hypothesis of relationship between the CTLA-4 genotypes and the duration of remission after a course of antithyroid drug treatment.

An A/G single nucleotide polymorphism (SNP) at position 49 (exon 1, codon 17) of the CTLA-4 gene leads to a Thr/Ala substitution and can be a functional related marker. It has been shown to be associated with GD in Caucasians (21, 22, 23, 24), Japanese (25, 26), Koreans (27), Tunisians (28), and Hong Kong Chinese children (29). However, to our knowledge, there is no report on the association between this SNP and the duration of remission after treatment. In this study, our primary aim was to test whether the G allele, which is associated with a higher risk of developing GD, is associated with early relapse of the disease after drug withdrawal in Chinese GD patients. Our secondary aim was to re-evaluate the association of this SNP with GD in Chinese because the previous studies on the Chinese population did not show consistent data; positive results were found in one study with children (29), but negative results were found in another study (73% with the G allele in 94 patients and 62% with the G allele in 77 controls) (30). Our study may shed light on using genetic markers to improve our clinical management of GD.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Discussion
 References
 
Patients and controls

We studied 148 Chinese patients with GD (122 females and 26 males; age, 38 ± 13 yr) from the Endocrine Clinic and 171 healthy controls (78 females and 93 males; age, 53 ± 11 yr) from the Health Screening Center of Chang Gung Memorial Hospital in Kaohsiung, Taiwan. The diagnosis criteria for GD were elevated serum T4 and/or T3 and suppressed TSH levels, diffusely increased thyroidal uptake of Technetium-99m or iodine-131, and the presence of TSH-receptor antibodies and/or antimicrosomal antibodies. Only patients who completed a treatment course of at least 1 yr and had adequate follow-up after drug withdrawal were included. Patients with a history of radioiodine therapy or previous thyroid surgery were excluded. The controls were healthy subjects without clinical evidence or family history of any autoimmune disease. They were in the euthyroid state according to the laboratory tests and had no obvious goiter as examined by one of the authors. The study plan was reviewed and approved by our institutional review committee, and informed consent was given by the patients and control subjects.

Treatment and follow-up

Antithyroid treatment was started with methimazole 30 mg or propylthiouracil 300 mg daily. The drug dosage was decreased to two thirds of the initial dose when normal levels of T4 and T3 were achieved, usually at 1–2 months after beginning treatment. The dose was then titrated gradually to reach a maintenance dose of methimazole 5–10 mg or propylthiouracil 50–100 mg daily by the third to fourth month of treatment. The duration of treatment extended from 1–3 yr. The mean times of antithyroid drug treatment were 23.5 ± 8.3, 19.2 ± 7.3, and 20.2 ± 7.9 months for groups 1, 2, and 3, respectively. After drug withdrawal, it was suggested to patients to follow-up every 3 months in the first year and then every 6 months thereafter. Relapse was confirmed by clinical presentation and the laboratory data. The common symptoms are palpitation, tremor, body weight loss, and menstruation irregularity. The laboratory data indicating recurrence is elevated serum T4 and/or T3 levels exceeding the upper limit of the normal range of our laboratory.

The 148 patients were divided into three groups according to the time of relapse. Group 1 patients (n = 47) had an early relapse within 9 months after drug withdrawal. Group 2 (n = 42) had a relapse between 10 and 36 months after stopping treatment. Group 3 (n = 59) had either remained in remission for more than 3 yr until the present time or relapsed after 3 yr of drug withdrawal. The rationale for selection of the cutoff point at 9 months instead of 1 yr for group 1 patients was to make the number of patients among the three groups evenly distributed. To be sure that the cutoff point of 9 months would not influence our results, we also analyzed the data using 1, 2, and 3 yr as the cutoff points and found the analytic results without difference.

Evaluation of patients

Clinical and laboratory evaluation included the CTLA-4 genotype; serum levels of T4, T3, and TSH; antithyroid treatment regimen (methimazole vs. propylthiouracil); and goiter size and TSH-receptor antibodies at the beginning and end of treatment. Goiter size was determined by palpation and classified as following: grade 1, a palpable goiter not reaching the medial edge of the sternocleidomastoid muscle; grade 2, a palpable goiter reaching the sternocleidomastoid muscle but not exceeding the lateral edge; and grade 3, a palpable goiter exceeding the lateral edge of the sternocleidomastoid muscle. Serum T4, T3, and TSH levels were determined by RIA. TSH levels were determined by a one-step sandwich assay with a normal range of 0.25–4.0 µU/ml (0.25–4.0 mU/liter; RIA-gnosthTSH; CIS Bio International, Gif-Sur-Yvette, Cedex, France) or a chemiluminescent assay with a normal range of 0.5–4.5 µU/ml (0.5–4.5 mU/liter; Nichols Institute Diagnostics, San Juan Capistrano, CA). TSH-receptor antibody was measured as TSH-binding inhibition immunoglobulin with a radioreceptor assay (TR-AB, CIS Bio International).

Genotype

DNA was extracted from peripheral blood leukocytes by a DNA extraction kit. The A/G SNP at position 49 of exon 1 at the CTLA-4 gene was genotyped by the PCR-restriction fragment length polymorphism method. The primers used were 5'-GGCTTGCCTTGGATTTCAACGGC-3' and 5'-GCTTCCAAAAGTCTCACTCACC-3'.

The amplified products were digested with the restriction enzyme, Ita1, and analyzed on the 3% agarose gel. The G allele corresponded to the presence of two 88-bp and 41-bp fragments generated by Ita1 digestion. The A allele corresponded to the 129-bp uncleaved fragment with no Ita1 site.

Statistics

Allele frequencies were estimated by direct gene counting. Observed numbers of each genotype were compared with those expected for Hardy-Weinberg equilibrium by using the {chi}2 test. Comparisons of individual clinical and laboratory variables between groups 1, 2, and 3 were assessed with one-way ANOVA for the continuous data, and the {chi}2 test or Fisher exact test for the categorical data. To assess the strength of association between the length of remission and the clinical and laboratory variables, multivariate logistic regression was performed. Odds ratio (OR) and its 95% confidence intervals (CI) were calculated by using SPSS 10.0, 1999, for Windows (SPSS Inc., Chicago, IL). A two-tailed P value < 0.05 was considered statistically significant.


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Discussion
 References
 
A/G polymorphism and relapse of GD

The 148 patients were divided into three groups according to their time of relapse after drug withdrawal. There was a significant difference of genotypic distribution (Fisher’s exact test, P = 0.0008) and allele frequencies ({chi}2 = 17.0, df = 2, P < 0.001) among the three groups (Table 1Go). Results according to the cutoff points of 1, 2, and 3 yr also showed a significant difference of genotype distribution (Fisher’s exact test, P = 0.0023) and allele frequencies ({chi}2 = 15.6, df = 2, P < 0.001) among the three groups. Therefore, we only presented the results of 9 months, 10–36 months, and more than 3 yr in the following analyses. Group 1, which had an early relapse within 9 months after drug withdrawal, had the highest proportion of the G/G genotype compared with groups 2 and 3. Group 2, which had a median period of remission, also had significant increase of the G/G genotype (decrease of A/G and A/A genotype) compared with group 3, which had a long remission period of at least 3 yr (P < 0.05). There was a trend of decreasing the G/G genotype from group 1 (79%) to group 2 (64%) to group 3 (39%). Similarly, there was a clear trend of decreasing frequency of the G allele and increasing frequency of the A allele from groups 1 to 3.


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  		TABLE 1. A/G polymorphism at the CTLA-4 gene and relapse of hyperthyroidism after discontinuation of medication in patients with GD

 
A/G polymorphism in the GD patients and controls

The genotype and allele frequency at position 49 in exon 1 of CTLA-4 gene in GD patients were compared with that of the controls. The distribution of the genotypes was compatible with that of Hardy-Weinberg equilibrium in both of the control and patient groups. Although there was no statistical significance between patients’ and controls’ genotypes (P = 0.12), there was a significant trend (P = 0.049) of increasing the GG genotype in the patient group. We also found a significant increase in the frequency of the G allele in the patient group, with a P value of 0.04 (Table 2Go). We further compared the patients in each group with the normal controls. Although there was no statistical significance (P = 0.33) of G allele frequency between the GD patients in group 3 and normal controls, we noticed moderate significance (P = 0.04) between group 2 and controls and striking significance (P < 0.001) between group 1 and controls. These findings are in concert with the previous association studies (21, 22, 23, 24, 25, 26, 27, 28, 29) in which the G allele was reported as a susceptibility allele for GD. Our findings also suggest genetic heterogeneity in GD because only a subset of GD is associated with the CTLA-4 gene.


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  		TABLE 2. Comparison of the frequencies of the genotypes and A/G alleles at the CTLA-4 gene between controls and the three groups of GD patients

 
Comparison of the clinical and laboratory variables among the patients with the three different genotypes (G/G, A/G, and A/A) is listed in Table 3Go. There was no statistical difference in age, sex, initial serum thyroid hormone levels, antithyroid treatment regimen, initial goiter size, initial TSH-receptor antibodies, and duration of treatment. The percentage of patients with persisting TSH-receptor antibody (i.e. TBII) at the end of treatment was statistically different (9, 20.8, and 45.5% in the A/A, A/G, and G/G genotypes, respectively; P = 0.004). As to the relapse rate between the A/G and A/A genotypes as shown in Tables 1Go and 3Go, the G allele appeared to behave as a recessive allele. Accordingly, the difference existed mainly between the A allele-containing genotypes (A/A or A/G) and the non-A allele-containing genotype (G/G).


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  		TABLE 3. Comparison of clinical variables among patients with different genotypes

 
Factors affecting outcome of antithyroid treatment

We further used 3 yr as the cutoff point for multivariate analysis (Table 4Go). The results showed that patients with the G/G genotype (adjusted OR, 3.1 compared with A/G plus A/A; 95% CI, 1.3–7.1), larger goiter sizes at the end of the treatment (grade 2 vs. grade 1: adjusted OR, 2.8; 95% CI, 1.0–7.6; grade 3 vs. grade 1: adjusted OR, 2.9; 95% CI, 0.9–9.6), and positive TBII at the end of the treatment (adjusted OR, 3.0; 95% CI, 1.2–7.9) were independent risk factors of the 3-yr recurrence. Among the three independent factors, only the genotypes can be assessed before the start of antithyroid drug treatment.


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  		TABLE 4. Multiple logistic regression analysis for determinants of treatment outcome

 

   Discussion
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
References
 
Our study demonstrated two major points. First, the A/G SNP at position 49 in exon 1 of the CTLA-4 gene may influence the duration of remission of hyperthyroidism after antithyroid drug withdrawal in Chinese patients with GD. Second, the A/G SNP is strongly associated with a subgroup of GD patients who were likely to have an early relapse. The 3-yr relapse rate was 74, 42, and 36% in patients with G/G, A/G, and A/A, respectively. This study provides evidence that the A/G SNP in exon 1 can be a useful marker to predict drug therapy.

Our results enforce the observation of Kinjo et al. (31) who showed the association of this SNP with the change of TSH-receptor antibody during antithyroid treatment in Japanese patients. Because remission of GD can be predicted by a smooth decrease in the autoantibody after treatment (32), their results suggested that this SNP may affect the remission of Graves’ hyperthyroidism. Our data provided direct support to their hypothesis with an OR of 3.1 for patients with the G/G genotype compared with patients with the A/G or A/A genotypes.

Before Kinjo’s report, the CTLA-4 gene has been focused only on the susceptibility of GD (21, 22, 23, 24, 25, 26, 27, 28, 29). Our data not only indicated that a subgroup of GD patients were strongly associated with the A/G SNP but also suggested that, among GD patients, a patient with the G/G genotype may have a higher relapse rate.

Although we did not measured thyroid antibody in controls, we believe that the strong statistical evidence (P < 0.001) between group 1 patients and controls cannot be explained by the minor chance of misclassifying some controls. Our findings are consistent with the major role of CTLA-4 gene. This gene is more likely to modulate the progress of an autoimmune disorder without disease specificity. Tomer et al. (33) has pointed out that the CTLA-4 gene contributed to the genetic susceptibility to thyroid autoantibody production but not specifically to GD or Hashimoto’s thyroiditis. In a functional study, Kouki et al. (34) reported that lymphocytes of GD patients with the G/G genotype had greater proliferation than those with A/A. When using antihuman CTLA-4 antibody to unmask its negative regulatory action, T cell proliferation was found to be related to the G/G genotype in individuals with GD and Hashimoto’s thyroiditis and in normal controls. Their results were supported by Mäurer et al. (18) who compared the T cell response between A/A and G/G homozygous healthy donors. Under suboptimal stimulation, a greater proliferation response of T cells was found in the G/G donors. All the above information indicates that the CTLA-4 gene is more involved in disease progression rather than disease specificity, and the A/G SNP is a functional related locus. In our results, maybe the impairment of the G allele in breaking the T cell proliferation leads to an early relapse of hyperthyroidism after stopping medication. Besides GD, this SNP has been mentioned to influence the disease presentation in patients with early rheumatoid arthritis (35) and mode of onset in patients with diabetes mellitus (36). In clinical practice, manipulation of the B7-CD28/CTLA-4 costimulatory pathway has enabled a distinctive immunomodulatory strategy to treat patients with autoimmune disorders (37, 38). The pioneering work was using CTLA-4Ig (the extracellular domain of the CTLA-4 receptor fused to the heavy chain of human IgG1) in treating patients with psoriasis vulgaris (38, 39) This therapy affects only those antigen-specific T cells undergoing activation and dose not require identification of the antigen itself.

In this study, besides the A/G SNP genotypes at the CTLA-4 gene, the persistence of TSH-receptor antibody and a large goiter were also independent determinants of treatment outcome. Our data on the TSH-receptor antibody was quite consistent with that of Kinjo et al. (31), in which they pointed that the G/G genotype and G allele were significantly higher in patients with persistently positive TSH-receptor antibody. Unfortunately, the changes of TSH-receptor antibody only can be evaluated at the end of the time-consuming therapy. Therefore, the CTLA-4 genotypes provide a more valuable parameter to assess and decide clinical management before the treatment starts.

In conclusion, our study offered direct evidence that the A/G SNP in exon 1 of the CTLA-4 gene may influence the progress and the outcome of the treatment of an autoimmune disease. The G allele is associated with a subset of GD patients who have a higher relapse rate. The GD patients with the G/G genotype may not be the candidates for antithyroid drugs.


   Acknowledgments
 
We thank Mr. Patrick Chan for the preparation of this manuscript.


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

Received May 16, 2003.

Accepted October 1, 2003.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 

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