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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2007-0675
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The Journal of Clinical Endocrinology & Metabolism Vol. 92, No. 8 3197-3201
Copyright © 2007 by The Endocrine Society

Association between a C/T Polymorphism in Exon 33 of the Thyroglobulin Gene Is Associated with Relapse of Graves’ Hyperthyroidism after Antithyroid Withdrawal in Taiwanese

Jeng-Yueh Hsiao, Ming-Chia Hsieh, Kai-Jen Tien, Shih-Chie Hsu, Shyi-Jang Shin and Shiu-Ru Lin

Division of Endocrinology and Metabolism (J.-Y.H., M.-C.H., K.-J.T., S.-C.H., S.-J.S.), Department of Internal Medicine, Kaohsiung Medical University Chung-Ho Memorial Hospital, Kaohsiung 80761, Taiwan; and Graduate Institute of Medicine (J.-Y.H.) and Graduate Institute of Medical Genetics (M.-C.H., S.-J.S., S.-R.L.), Kaohsiung Medical University, Kaohsiung 80761, Taiwan

Address all correspondence and requests for reprints to: Shiu-Ru Lin, Ph.D., Department of Endocrinology and Metabolism, Kaohsiung Medical University Chung-Ho Memorial Hospital, 100 Shin-Chuan 1st Road, Kaohsiung 80761, Taiwan, Republic of China. E-mail: shruli{at}kmu.edu.tw.


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 References
 
Context: Graves’ disease (GD) is an autoimmune disorder with genetic predisposition. The thyroglobulin (Tg) is a major autoantigen for GD. The human Tg gene polymorphism has specific features that make it important in GD.

Objective: This study investigated whether Tg single nucleotide polymorphisms (SNPs) relate to GD development in a Taiwanese population.

Design and Setting: This was a case-control association study.

Patients and Main Outcome Measures: We enrolled 215 Taiwanese patients with GD and 141 controls from the Endocrine Clinic of Kaohsiung Medical University Chung-Ho Memorial Hospital. This study investigated the association between gene polymorphism and relapse of hyperthyroidism after medication was discontinued in three GD patient groups and a control group. We also compared clinical and laboratory data obtained from patients with the three different genotypes with the three different Tg SNPs (E10SNP158, E12SNP, and E33SNP).

Results: We found a significant increase in the T/T genotype of E33SNP compared with the control group (P < 0.001). We also found the E33SNP C/C genotype of the Tg gene was strongly associated with a subgroup of GD patients who were also characterized as having a higher relapse rate, significantly higher levels of persisting TSH-receptor antibody at the end of treatment, a higher frequency in smoking, and a higher incidence of ophthalmopathy (P < 0.05).

Conclusions: This study showed that Taiwanese patients with the C/C genotype of E33SNP, smoking, ophthalmopathy, and positive TSH-receptor antibodies at the end of the treatment were more likely to have a relapse of Graves’ hyperthyroidism after antithyroid medication is withdrawn.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 References
 
GRAVES’ DISEASE (GD) is an autoimmune thyroid disease (AITD), characterized by the production of TSH-receptor autoantibodies that cause hyperthyroidism by augmenting thyroid cell function (1, 2). Although autoimmune mechanisms are responsible for the syndrome of GD, management has been largely directed toward controlling the hyperthyroidism. It is not yet possible to treat the basic pathogenetic factors in GD. There are three therapies used to treat it: antithyroid drug therapy, surgery, and radioactive iodine therapy. Antithyroid drug therapy is only palliative, and there is a high relapse rate after withdrawal from antithyroid drugs.

As knowledge of genome technologies and methodologies progresses, pharmacogenetics will greatly influence the choice of treatment. The choice of therapy for GD is influenced by certain pretreatment clinical features, including large goiters, more severe thyrotoxicosis, and high-baseline serum TSH-receptor antibodies (3, 4, 5, 6), all of which have been associated with more frequent relapse. However, our ability to predict remission is limited. Because genetics may play important roles in GD, it might be helpful to identify the genes of GD that can be targeted when attempting to prevent the disease in a high-risk patient and when treating it.

GD most likely develops as a consequence of a complex interaction between genetic susceptibility and environmental effects. Although the exact pathogenic mechanisms involved in GD are not clear (7, 8, 9), human thyroglobulin (Tg) is one of the main autoantigens in AITD (7), and serological studies have shown that there are at least 40 antigenic epitopes in human Tg (10). Some studies (11, 12) demonstrated that anti-Tg antibodies in AITD are directed toward a restricted number of epitopes on Tg that are different than the epitopes recognized by anti-Tg antibodies found in healthy individuals. Therefore, the human Tg molecule has specific features that make it important in GD.

This study investigated the association between gene polymorphism and relapse of hyperthyroidism after medication was discontinued in three GD patient groups and a control group. We also compared clinical and laboratory data obtained from patients with the three different genotypes with the three different Tg single nucleotide polymorphisms (SNPs) (E10SNP158, E12SNP, and E33SNP). We also performed a case-control study of GD patients and control subjects to determine whether Tg SNPs relate to GD development in a Taiwanese population.


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

We enrolled 215 Chinese patients with GD (151 females and 64 males; age 40 ± 13 yr) from the Endocrine Clinic and 141 healthy controls (84 females and 57 males; age 41 ± 12 yr) from the health care center of Kaohsiung Medical University Chung-Ho Memorial Hospital. GD was diagnosed on the basis of clinical and laboratory evidence of hyperthyroidism and diffuse goiter, supported by the presence of TSH-receptor antibodies and/or antimicrosomal antibodies and/or anti-Tg antibodies, or exophthalmos. Only patients who completed a treatment course of at least 1 yr and had adequate follow-up after drug withdrawal were included. We excluded patients with a history of radioiodine therapy or previous thyroid surgery. 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 experienced research staff. The patients and control subjects were recruited after giving their fully informed consent.

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 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 lasted from 1–3 yr. The criteria for stopping antithyroid drug treatment were confirmed by the cessation of clinical hyperthyroidism symptoms and euthyroid thyroid function. The mean times of antithyroid drug treatment were 17.4 ± 7.3, 16.3 ± 6.3, and 12.8 ± 5.9 months for groups 1, 2, and 3, respectively. After drug withdrawal, patients were asked to come in for follow-ups 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 were palpitation, tremor, body weight loss, and menstrual irregularity. The laboratory data indicating recurrence were elevated serum T4 and/or T3 levels exceeding the upper limit of the normal range of our laboratory. The 215 patients were divided into three groups according to the time of relapse. Group 1 patients (n = 78) had an early relapse within 9 months after drug withdrawal. Group 2 (n = 71) had a relapse between 10 and 36 months after stopping treatment. Group 3 (n = 66) 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 ensure an even distribution of number of patients among the three groups. 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 results to be without difference.

Evaluation of patients

Clinical and laboratory evaluation included: the Tg SNPs (E10, E12, and E33) 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 into: 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. The severity of ophthalmopathy was assessed according to the NOSPECS classification (13). Patients with proptosis, extraocular-muscle dysfunction, exposure keratitis, and optic neuropathy (NOSPECS class III and higher) were considered to have clinical evidence. Serum T4, T3, and TSH levels were measured by RIA. TSH levels were measured using 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) 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 using a DNA extraction kit (GENETRA D50K; Radio Med, Tyngsboro, MA). The Tg SNPs (E10, E12, and E33) at the Tg gene were digested with the PCR-restriction fragment length polymorphism method; primers are listed in Table 1Go.


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  		TABLE 1. SNPs in the Tg gene

 
PCR was carried out in a 25-µl mixed solution, containing 0.2 mg genomic DNA (from blood leukocytes) 0.4 mmol/liter primers, 0.2 mmol/liter each of deoxy-ATP, -GTP, -CTP, -TTP, 2 mmol MgCL2, 0.5 U Taq DNA polymerase, 50 mmol/l KCl, 10 mmol/l Tris-HCl (pH 8.3). PCR involved initial denaturation step for 5 min at 95 C, 35 cycles of denaturation for 30 sec at 95 C, primer annealing for 30 sec at 58 C, and primer extension for 60 sec at 72 C, followed by a final extension step for 5 min at 72 C in a thermal-cycler (Gene Amp PCR System 9600; Perkin-Elmer, Foster City, CA). The amplified products were digested with the restriction enzyme, Bpu10I, BsaAI, and Hpy99I (New England BioLabs, Hitchin, UK; Table 1Go), and analyzed on 3% agarose gel.

Statistics

The laboratory data were express as the mean ± SD. Allele frequencies were estimated by direct gene counting. Observed numbers of each genotype were compared with those expected for Hardy-Weinberg equilibrium using the {chi}2 test. Comparisons of individual clinical and laboratory variables between groups 1, 2, and 3 were assessed using one-way ANOVA for the continuous data. The {chi}2 test or Fisher exact test was used for categorical data. In this study a two-tailed P value < 0.05 was considered significant.


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Discussion
 References
 
Gene polymorphism and relapse of hyperthyroidism after discontinuation of medication among controls and the three groups of GD patients

The 215 patients were divided into three groups based on time to relapse after drug withdrawal, cutoff points being 9 months, 9 months to 3 yr, and more than 3 yr. We then measured the difference of genotypic distribution and allele frequencies among controls and the three groups of GD patients. The genotype and allele frequency at E10SNP158, E12SNP, and E33SNP in GD patients were compared with those of the controls. The three patient groups and controls had similar genotype distributions; this site as estimated by Hardy-Weinberg equilibrium. Both GD patients and controls had similar allele frequencies and genotype distributions for the two Tg SNPs (E10SNP158, E12SNP). The GD patients were found to have significantly higher frequencies T/T genotype of E33SNP than the controls (P < 0.001) (Table 2Go).


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  		TABLE 2. Comparison of the frequencies of the genotypes and C/T alleles at the E33SNP between controls and the three groups of GD patients

 
Comparison of the clinical and laboratory variables among patients with the three different genotypes in three different Tg SNPs (E10SNP158, E12SNP, and E33SNP)

The 215 patients were divided into three groups based on time to relapse after drug withdrawal, cutoff points being 9 months, 9 months to 3 yr, and more than 3 yr. We calculated the differences in clinical and laboratory data among the GD patients with the three genotypic distribution. We analyzed differences in age, gender, smoking, ophthalmopathy, initial serum thyroid hormone levels, antithyroid treatment regimen, initial goiter size, goiter after treatment, initial TSH-receptor antibodies, and TSH-receptor antibodies during and after treatment of patients with the three different genotypes in three different Tg SNPs (E10SNP158, E12SNP, and E33SNP). We compared the clinical and laboratory data of patients belonging to the three different genotypes (C/C, C/T, and T/T) of E33SNP (Table 3Go). We found no significant difference with regard to age, sex, initial serum thyroid hormone levels, antithyroid treatment regimen, initial goiter size, initial TSH-receptor antibodies, and duration of treatment. There was a significant difference in percentage of patients with persistent expression of TSH-receptor antibody (i.e. TBII) at the end of treatment (C/C 89%, C/T 30%, and T/T 37%; P = 0.001) and a significant difference in percentage of smoking (C/C 89%, C/T 21%, and T/T 14%; P = 0.001). Comparing the C/T and T/T genotypes relapse rates (Table 3Go), we found that the C allele seemed to behave as a recessive allele because of the low frequency of the allele; the greatest difference was found between the genotypes containing the T allele (C/T or T/T) and those not containing the T allele (C/C).


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  		TABLE 3. Comparison of the clinical and laboratory variables among patients with the three different genotypes in E33SNP

 

   Discussion
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
References
 
This study had three major findings. First, Taiwanese patients with GD had a significantly increased frequency of T/T genotype of E33SNP in exon 33 of the Tg gene than the normal controls. Second, in that group of patients, the E33SNP C/C genotype of the Tg gene may influence the duration of remission of hyperthyroidism after antithyroid drug withdrawal. Third, the E33SNP C/C genotypes of the Tg gene were strongly associated with a subgroup of GD patients who were likely to have a higher relapse rate, persistent positive TSH-receptor antibodies at the end of treatment, and higher frequency of smoking and ophthalmopathy. This study provides the following evidence. First, the E33SNP T/T genotype of the Tg gene can be a useful marker to predict drug therapy. Second, the results showed that Taiwanese patients with the C/C genotype of E33SNP, smoking, ophthalmopathy, and positive TSHreceptor antibodies at the end of the treatment were more likely to have a relapse of Graves’ hyperthyroidism after antithyroid medication is withdrawn.

GD develops as a result of a complex interaction between predisposing genes and nongenetic factors. Our result confirms the observation of Tomer and Greenberg (14), who showed that the Tg gene was a strong candidate gene for GD. Our study has sufficient power to exclude association with the size of effect seen in the study by Tomer and Greenberg (14). In our study, a sample size of 356, which includes 215 GD patients and 141 controls, will have greater than 80% power to detect a difference in means of 1.000 assuming that the common SD is 2.000 using a two group t test with a 0.050 two-sided significance level. However, there have been no reports regarding the possible association between Tg sequence changes and GD. One study by Sakai et al. (15) of Japanese sib-pairs identified a major AITD locus on chromosome 8q24 very close to the locus, which has been identified. Although their study did not test the Tg gene directly, they suggested that the Tg gene may predispose to AITD across populations of different ethnic backgrounds. In this study we found strong evidence of a susceptibility gene for AITD on 8q24. This locus contained the Tg gene, which has to be associated with AITD. Therefore, polymorphisms in the Tg gene may be involved in the etiology of AITD (16). Unlike the other putative AITD susceptibility genes [e.g. cytotoxic T lymphocyte antigen 4 (CTLA-4)], which are immune regulators, Tg is a thyroid-specific gene, which may explain the targeting of the autoimmune response to the thyroid gland and may make it an excellent candidate for GD.

In this study we have shown strong evidence that an exon 33 SNP in Tg is significantly associated with GD, a finding similar to that of Ban et al. (17), who showed a strong association between the exon 33 SNP and GD. To date, three immunomodulatory genes have conferred susceptibility to AITD: the human leukocyte antigen (HLA) genes (18), the CTLA-4 gene (19, 20, 21), and the CD40 gene (22, 23). Thus, it is likely that susceptibility to AITD involves an interaction between immunoregulatory genes and at least one thyroid autoantigen-specific gene, namely Tg, as well as environmental factors. Because CTLA-4 is a nonspecific costimulatory molecule, it is expected to confer susceptibility to AITD and autoimmunity in general, but not specifically to GD. The interaction of immunoregulatory genes and an autoantigen-specific gene may be a general mechanism related to the development of organ-specific autoimmune diseases. In fact, no single gene is known to cause GD or be necessary for its development. There is a well-established association with certain HLA alleles that varies among racial groups. In whites, HLA-DR3 and HLA-DQA1*0501 are positively associated with the development of GD, whereas HLA-DRB1*0701 protects against it (24, 25). GD is also associated with polymorphisms of the CTLA-4 gene in several racial groups (26, 27). The affect of PD-L1 on the function of T cells through linkage analysis and similar responses have identified loci on chromosomes 14q31, 20q11.2, and Xq21, and associated them with susceptibility to GD (28, 29, 30), but confirmation of the importance of these loci as homologs will require screening large numbers of families with multiple affected members. Our data not only found a strong association between E33 C/T SNP of the Tg gene in one subgroup of GD patients but also that GD patients with the E33 C/C SNP genotype of the Tg gene, either by itself or by linkage disequilibrium with a functional SNP, might have a higher relapse rate.

GD is characterized by remissions and relapses. Many factors affect the duration of remission once antithyroid therapy is stopped (31). Various environmental and genetic factors play a part in the pathogenesis of GD (32). For example, smoking can be an environmental promoter for GD in patients who are genetically predisposed to the disease (33, 34), and it is one of the most evident environmental risk factors for thyroid associated ophthalmopathy. Smoking is thought to directly affect ophthalmopathy through irritation or modulating the immune reactions that occur in GD (35). Our results, too, found that cigarette smoking adversely affected Graves’ ophthalmopathy. We wondered how smoking would affect the relapse of Graves’ hyperthyroidism. To find out, we studied three factors in our patients: 1) the period from initiation of therapy until first remission, as indicated by normal TSH, T3, and T4 during treatment (initiation of remission); 2) the duration of remission after cessation of antithyroid therapy (duration of remission); and 3) the number of relapses that occurred during the 3-yr period. Like the observation made by Glinoer and Bex (36), we found an independent association between smoking and the presence or absence of TSH-receptor antibodies at the end of antithyroid drug treatment, and an increased recurrence rate among smokers. We concluded that cigarette smoking and Graves’ ophthalmopathy may increases the likelihood that GD recurs. Alterations in Tg might also explain the interactions between genetic and environmental factors in the etiology of GD. Tg is iodinated to form thyroid hormones, and dietary iodine may influence the development of GD (37, 38).

In conclusion, GD is an autoimmune disease and is thought to be caused by several genetic factors, one being the Tg gene polymorphism. Our study offers direct evidence that the E33SNP C/C genotype of the Tg gene is strongly associated with a subgroup of GD patients, also characterized by having a higher relapse rate, higher frequency of smoking, and being prone to having ophthalmopathy. Consequently, the E33SNP C/C genotype of the Tg gene may influence the progress and outcome of the treatment of GD. The GD patients with E33SNP C/C genotype of the Tg gene may not be good candidates for antithyroid drugs.


   Acknowledgments
 
We thank all of the Graves’ disease and control patients who graciously agreed to participate in the study.


   Footnotes
 
The clinical trial has been registered at Institutional Review Board, Kaohsiung Medical University Chung-Ho Memorial Hospital (KMUH-IRB-960130).

Disclosure Statement: The authors have nothing to disclose.

First Published Online June 5, 2007

Abbreviations: AITD, Autoimmune thyroid disease; CTLA-4, cytotoxic T lymphocyte antigen 4; GD, Graves’ disease; HLA, human leukocyte antigen; SNP, single nucleotide polymorphism; Tg, thyroglobulin.

Received March 30, 2007.

Accepted May 29, 2007.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 

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Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals