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Annals of Clinical & Laboratory Science 35:259-264 (2005)
© 2005 Association of Clinical Scientists

CT60 Single Nucleotide Polymorphism of the CTLA-4 Gene Is Associated with Susceptibility to Graves’ Disease in the Taiwanese Population

Yu-Ching Weng1,2, Ming-Jiuan Wu2 and Wei-Sen Lin3
1 Clinical Laboratory, SinLau Christian Hospital; 2 Biotechnology and 3 Hospital Management Departments, Chia-Nan University of Pharmacy and Science, Tainan, Taiwan

Address correspondence to Dr. Ming-Jiuan Wu, Department of Biotechnology, Chia-Nan University of Pharmacy and Science, Tainan 717, Taiwan, ROC; tel 886 6 266 4911 ext 220; fax 886 6 266 6411; e-mail: imwu{at}mail.chna.edu.tw.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Graves’ disease (GD) is an autoimmune disease but the underlying etiology has not been completely elucidated. Genetic susceptibility has been believed to play a major role. Recent studies showed that the CT60 single nucleotide polymorphism (SNP), which is in the 3'-noncoding region of the CTLA-4 gene, is strongly associated with some immune-mediated diseases. The aim of this study was to test for association between GD susceptibility and polymorphisms of CTLA-4 (ie, the CT60 SNP and the exon 1 +49 SNP) in the Taiwanese population. Our results demonstrate significant differences in the frequencies of the genotypes and alleles between 107 GD patients and 101 control subjects in the CT60 and exon 1 +49 SNPs (p <0.05). Significant differences in phenotypes were only found for CT60 SNP (78.4% vs 67.8% between patients and controls; {chi}2 = 3.93, p = 0.047). Furthermore, we found that the G/G genotype of both CT60 and exon 1 +49 was associated with increased risk for GD (p = 0.022, OR = 1.97). Significant linkage disequilibrium was found between the CT60 SNP and the exon 1 +49 SNP in both GD patients and control subjects (D’ = 1.00). Because of tight linkage disequilibrium, a combination of these SNPs enhanced the role of the CTLA-4 gene in GD. The frequency of the disease-susceptible G allele of CT60 was comparable to that in Japanese and higher than in Caucasians. In conclusion, we provide evidence that CT60 SNP is associated with susceptibility to GD in the Taiwanese population.

(received 30 December 2004; accepted 11 March 2005)

Keywords: CT60 SNP, CTLA-4, exon 1 +49 SNP, Graves’ disease, single nucleotide polymorphism


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Graves’ disease (GD) is a common human autoimmune thyroid disease with population prevalence of 1 to 4 %. The disease has immunologic features, including high serum concentrations of antibodies against thyroglobulin, thyroid peroxidase, and thyrotropin receptor (TSHR), as well as lymphocyte infiltration of the thyroid gland. GD is organ-specific to the thyroid gland, and is characterized by hyperthyroidism [1–2]. Graves’ hyperthyroidism is clearly due to pathogenic immune mechanisms.

Although the basic etiology of GD has not been completely elucidated, several findings suggest that genetic, environmental, and endocrine factors are involved in its pathogenesis. Recently, whole genome linkage studies of GD patients have suggested that the cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) gene on human chromosome 2q33 is one of the candidate genetic markers [3–8]. The most remarkable function of the CTLA-4 gene is down-regulation of the humoral immune response.

Several polymorphic sites in the CTLA-4 gene (ie, A/G polymorphism in exon 1 +49 [9], C/T polymorphism in the promoter -318 [10], microsatellite (AT)n repeat in the 3'-untranslated region (UTR) of exon 4 [11], and 3 SNPs in the 6.1-kb 3' non-coding region, CT60, JO31, and JO30) have been reported to be associated with the organ-specific autoimmune disorders in several racial groups [12–19]. Among them, CT60 and exon 1+49 A/G SNPs were the markers most associated with autoimmune endocrinopathies [20]. Exon 1 +49 SNP is known to be associated with GD susceptibility and clinical outcome in the Taiwanese population [19]. However, there is no report about an association between the CT60 SNP and GD or linkage/combined effects of the CT60 SNP and other polymorphic sites of the CTLA-4 gene in the Taiwanese population.

The aim of our research was to use the case-control approach to establish a database of CTLA-4 polymorphisms in the Taiwanese population in order to compare Western and Taiwanese distributions and to evaluate CTLA-4 polymorphisms as an indicator of GD susceptibility. Our results demonstrate that the CT60 SNP of the CTLA-4 gene is associated with susceptibility to GD in the Taiwanese population. In addition, both the G alleles of the CT60 SNP and the exon 1+49 SNP of the CTLA-4 gene are strongly associated with GD patients.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Experimental Subjects.  One hundred and seven unrelated Taiwanese patients with GD (94 females, 13 males) were randomly selected from a series of 650 patients. The age (mean ± SD) of the GD patients was 34.0 ± 11.8 yr (range 8 to 65 yr). The ratio of female to male was 7.23:1. The diagnosis of GD was based on clinical features and laboratory results including (a) diffuse enlargement of thyroid gland, (b) raised serum thyroxine (T4) or 3,5,3'-triiodothyronine (T3) levels, suppressed serum thyrotropin (TSH) levels, (c) ophthalmopathy and (d) the presence of antimicrosomal and/or antithyroglobulin antibodies. Data from the patients were compared with those obtained from 101 healthy control subjects from the same geographic area and with similar ethnic background. All of the control subjects gave a negative family history of type 1 diabetes, autoimmune thyroid disease, or other autoimmune disorders.

Analysis of the CT60 SNP.  Whole blood was collected in tubes containing EDTA. Genomic DNA was isolated from whole blood with Chemagic DNA Blood kit (Biopolymer-Technologie, Akt, Germany). The CT60 SNP was determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). In the CT60 SNP, PCR was performed with oligonucleotide primers (forward, 5'-CTTCATGAGTCAGCTTTGCACCAGC-3'; reverse, 5'-AGCTGAGAAAGCAGGCGGTAAGAAA-3'). The reaction was carried out with 0.2 µg of genomic DNA, 1 U of Taq polymerase, 10 pmol of each primer, and 200 µmol/L of each dNTP under the following conditions: initial denaturation for 4 min at 94°C; 35 cycles of denaturation for 45 sec at 94°C; annealing for 45 sec at 58 °C; and extension for 45 sec at 72°C; followed by a final extension for 4 min at 72°C.

The 200-bp PCR products were incubated for 4 hr at 37°C with a restriction enzyme HpyCH4 IV (New England BioLabs, Beverly, MA, USA), which cuts the sequence if a G allele is present at the CT60 SNP and resultes in 100-bp fragments. If an A allele is present in the CT60 SNP, no digestion of the 200-bp PCR fragment occurs. DNA fragments are resolved in 2.5% agarose gels, and representative patterns are shown in Fig. 1Go.



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  		Fig. 1. Agarose gel electrophoresis of PCR-RFLP products of CT60 SNP. Lane 1: genotype of A/A.; arrow shows the size of the fragment (size: 200-bp). Lane 2: genotype of G/G; arrow shows the size of the fragment (size: 100-bp). Lane 3: genotype of A/G; arrows show the size of the fragments (size: 200-bp and 100-bp).

 
Analysis of the exon 1 +49 SNP.  The exon 1 +49 SNP was also determined by PCR-RFLP. Amplification of target DNA in exon 1 +49 SNP was performed with oligonucleotide primers (forward 5'-TTGCTCTACTTCCTGAAGACCTGAA-3' and reverse 5'-AAAGTCTCACTCACCTTTGCAGAAG-3'), according to the published human CTLA-4 complementary DNA sequence [21]. The reaction was carried out with 0.2 µg of genomic DNA, 1 U of Taq polymerase, 10 pmol of each primer, and 200 µmol/L of each dNTP under the following conditions: initial denaturation for 4 min at 94°C; 35 cycles of denaturation for 45 sec at 94°C; annealing for 45 sec at 55°C; extension for 45 sec at 72°C; followed by a final extension for 4 min at 72°C.

The 166-bp PCR products were digested with a restriction enzyme, BbvI (New England BioLabs). The digested PCR products were separated on 2.5% agarose gel in 0.5X TBE buffer. The two alleles were easily separated using this method; the genotype A/A resulted in undigested PCR product of 166-bp, whereas the genotype G/G resulted in digested PCR product with two fragments of 90/76-bp, and the genotype A/G generated 166-bp and 90/76-bp bands. Representative patterns are illustrated in Fig. 2Go.



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  		Fig. 2. Agarose gel electrophoresis of PCR-RFLP products of exon 1 +49 SNP. Lane 1: genotype of A/G.; arrows show the size of the fragments (size: 166-bp and 90/76-bp). Lane 2: genotype of A/A; arrow shows the size of the fragment (size: 166-bp). Lane 3: genotype of G/G; arrow shows the size of the fragment (size: 90/76-bp).

 
Thyroid function tests.  Serum T3, T4, and TSH concentrations were measured using chemiluminescenent immunoassays by IMMULITE 2000 kits (Diagnositic Products Co, Los Angeles, CA, USA); the normal ranges were 0.82–1.79 ng/ml, 4.5–12.5 µg/dl, and 0.40–4.00 µIU/ml, respectively.

Statistical analyses.  Data were analyzed using SPSS 10.0 computer software. Significant differences between patients and test or the Fisher exact controls were examined by using the {chi}2 test. Tests for Hardy-Weinberg equilibrium were carried out by the {chi}2 test. The standardized disequilibrium coefficient value (D’) was evaluated by the software package, SNPAlyze (Dynacom Co., Kanagawa, Japan). Serum T3, T4, and TSH concentrations in all groups of patients were assessed by ANOVA. A p value <0.05 was regarded as significant.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
We performed a population-based case-control study to investigate the association of the polymorphisms of the CTLA-4 gene with GD by comparing the frequency of the alleles in GD patients and normal controls. DNAs from 107 patients with GD and 101 control subjects were genotyped for A/G polymorphisms in the CT60 and the exon 1+49 SNPs. The observed numbers of individuals with genotypes of the CT60 SNP and the exon 1 +49 SNP showed that all alleles fit the Hardy-Weinberg equilibrium in control and patient groups (p > 0.05).

Table 1Go shows the population frequencies of the 3 genotypes for alleles and phenotypes of CT60 SNP in GD patients and control subjects. Compared to the control subjects, there was significantly higher frequency of the G/G genotype in GD patients (72.9% vs. 53.4%; {chi}2 = 8.46, p = 0.004), and significantly lower frequency of the A/G genotype. The frequency of the G allele was also significantly higher in GD patients than in control subjects (85.6 % vs 75.7 %; {chi}2 = 6.39, p = 0.011). Analysis of frequency distributions of phenotypes in patients showed significant differences from control data in CT60 SNP (78.4% vs 67.8%; {chi}2 = 3.93, p = 0.047).


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  		Table 1. Population frequencies of genotypes for alleles and phenotypes at the CT60 SNP in GD patients and control subjects.
 
Table 2Go shows the population frequencies of the 3 genotypes for alleles and phenotypes of exon 1 +49 SNP in GD patients and control subjects. The frequency of G/G genotype was significantly higher in GD patients than in control subjects (43.0% vs 27.7%; {chi}2 = 5.28, p = 0.021). The frequency of the G allele was also significantly higher in GD patients than in control subjects (67.9% vs 56.5%; {chi}2 = 5.66, p = 0.017). Analysis of frequency distribution of phenotypes in patients revealed no significant difference vs controls (61.9% vs 54.0%; {chi}2 = 1.98, p = 0.159).


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  		Table 2. Population frequencies of genotypes for alleles and phenotypes at the exon 1 +49 SNP in GD patients and controls.
 
We analyzed the subgroups for co-occurrence of the 3 polymorphisms (Table 3Go). We found the frequency for homozygous G genotype (GG/GG) at the CT60 SNP and the exon 1 +49 SNP was significantly higher in GD patients than in control subjects (42.9% vs 27.7%; {chi}2 = 5.28, p = 0.022). Using SNPAlyze software, we found that the CT60 SNP showed strong linkage disequilibrium with the exon 1 +49 SNP (D’ = 1.00 for GD patients, and D’ = 1.00 for control subjects).


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  		Table 3. Distribution of the joint effects of the CT60 SNP and the exon 1 +49 SNP in GD patients and controls.
 
Table 4Go shows clinical test results and age distributions for 107 patients with genotype A/A, A/G, and G/G of the CT60 SNP and the exon 1 +49 SNP. There were no significant differences in serum T3, T4, or TSH levels among the CTLA-4 polymorphism groups in the Taiwanese population.


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  		Table 4. The clinical characteristics of the GD patients in relation to CTLA-4 SNPs (data are means ± SD).
 

   Discussion
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
CTLA-4 plays an important role in maintaining tolerance to self-antigens. In addition to TCR-mediated Ag recognition, binding of B7 on stimulator cells to CD28 provides a second signal to the T cells, leading to their activation. CTLA-4 also binds to B7, but antagonizes the activating signals, thus attenuating T lymphocyte proliferation and antigen-specific apoptosis of T cells [22].

Although there have been reports of association between the CTLA-4 gene polymorphisms and autoimmune thyroid disorders, the primary risk marker for the diseases is unknown. It has been postulated that the polymorphisms of the CTLA-4 gene linked to GD might correspond with lessened inhibitory effectiveness of CTLA-4 protein [9]. In this study, we demonstrated that the G/G genotype of the CT60 SNP is most prevalent in the Taiwanese population and there are more GD patients having G allele (G/G genotype) and fewer patients having A allele (A/A or A/G genotype), compared to the control subjects. The CT60 SNP is potentially important because it may be associated with an alteration in the ratio of splice forms of the CTLA4 gene and this ratio may affect disease susceptibility, as reported by Ueda et al [12]. Furthermore, our study indicates that the G/G genotype in the exon 1 +49 SNP is predominant in the Taiwanese population and the frequency of G allele is also higher in GD patients, compared to control subjects (p = 0.017). Compared to studies of other racial groups, our results are similar. A number of findings, including our study of association between exon 1 +49 SNP and GD, supported the theory that the exon 1 +49 SNP of CTLA-4 gene leads to genetic susceptibility to GD as a general rule [11,13,19,23]. Although the function of CTLA-4 protein is probably unaffected by the exon 1 +49 SNP, it may influence the level or pattern of protein expression. The G allele is associated with reduced control of T cell proliferation and thus contributes to the pathogenesis of GD and presumably of other autoimmune diseases [9]. We did not find strong linkage between the two SNPs and serum T3, T4, and TSH levels in the Taiwanese GD population. However, recent reports indicate that A/A SNP in the exon 1 +49 SNP is associated with the remission of Graves’ hyperthyroidism in antithyroid drug (ATD)-treated Japanese and Taiwanese patients [9,19]. The effect of CT60 SNP on the remission of Graves’ hyperthyroidism remains unknown.

In the co-occurrence of the 2 polymorphisms, there are significantly more GD patients that carry G alleles in the CT60 SNP and exon 1 +49 SNP, compared to control subjects. When the CT60 SNP genotype is G/G, the frequency of G/G genotype in the exon 1 +49 SNP is higher. Our results also show that the frequency of genotype of A/A in CT60 SNP or exon 1 +49 SNP is lower in the Taiwanese population than in most other populations [11–13,18,23].

Although the size of our samples (patients and healthy controls) was not very large, the difference in CTLA-4 composition between control subjects and patients was significant and the frequencies of both alleles were in Hardy-Weinberg equilibrium. The CT60 SNP and exon 1 +49 SNP were in tight linkage disequilibrium with each other using SNPAlyse (D’=1.00). Because of the tight linkage disequilibrium, contribution to GD susceptibility cannot be genetically dissected. Probably incorporation of both SNP markers further increases predictive accuracy and enhances the position of the CTLA-4 in GD. The fact that some controls bearing G/G genotype with the CT60 SNP and the exon 1 +49 SNP did not develop Graves’ disease, whereas some patients with A/A genotype developed auto-immunity, underlines the multiple mechanisms of autoimmune diseases. Indeed, GD susceptibility is also linked closely with other polymorphisms such as HLA and THSR [3,6] and depends on multiple genetic predisposition factors.

In conclusion, our findings are consistent with the proposition that the G allele of CT60 SNP and exon 1 +49 SNP of the CTLA-4 gene is associated with susceptibility to Graves’ disease in the Taiwanese population.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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