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Journal of Clinical Endocrinology & Metabolism, doi:10.1210/jc.2004-0931
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The Journal of Clinical Endocrinology & Metabolism Vol. 90, No. 1 296-301
Copyright © 2005 by The Endocrine Society

Interleukin-13 Gene Polymorphisms Confer the Susceptibility of Japanese Populations to Graves’ Disease

Yuji Hiromatsu, Tomoka Fukutani, Michiko Ichimura, Tokunori Mukai, Hiroo Kaku, Hitomi Nakayama, Ikuyo Miyake, Shingo Shoji, Yoshiro Koda and Tomasz Bednarczuk

Department of Endocrinology and Metabolism (Y.H., T.F., M.I., T.M., H.K., H.N., I.M., S.S.) and Division of Human Genetics, Department of Forensic Medicine (Y.K.), Kurume University School of Medicine, Kurume, Fukuoka 830-0011, Japan; and Department of Endocrinology, Medical Research Center, Polish Academy of Science (T.B.), Warsaw, Poland 02-097

Address all correspondence and requests for reprints to: Dr. Yuji Hiromatsu, Department of Endocrinology and Metabolism, Kurume University School of Medicine, 67 Asahimatchi, Kurume, Fukuoka 830-0011, Japan. E-mail: yuji{at}med.kurume-u.ac.jp.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Graves’ disease (GD) is an autoimmune disorder with genetic predisposition. IL-13 is an important mediator of antiinflammatory immune responses and is expressed in the thyroid and orbit. The aim of the present study was to investigate whether IL-13 gene polymorphisms are associated with the development of GD. IL-13 gene polymorphisms were studied in Japanese GD patients (n = 310) and healthy control subjects without antithyroid autoantibodies or a family history of autoimmune disorders (n = 244). A C/T polymorphism at position –1112 of the promoter region was measured using the direct sequencing method, and an Arg130Gln (G2044A) polymorphism in exon 4 was examined using the PCR-restriction fragment length polymorphism method. There was a significant decrease in –1112T allele frequency in GD patients compared with controls (16% vs. 23%; P = 0.0019). The frequency of the 2044A allele on exon 4 also appeared lower in GD patients compared with controls. Haplotype analysis showed a significant decrease in the –1112T/2044A haplotype in GD patients. There was no association between IL-13 gene polymorphisms and ophthalmopathy, severity, or serum IgE levels. In conclusion, IL-13 gene polymorphisms are associated with GD susceptibility in Japan.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
GRAVES’ DISEASE (GD) is an autoimmune disorder frequently associated with varying degrees of hyperthyroidism and ophthalmopathy (1). Although the TSH receptor has been proposed as an autoantigen in GD patients, the nature of autoimmune reactions in the thyroid and orbit, and the mechanisms linking GD and Graves’ ophthalmopathy (GO) have not been fully elucidated (2, 3). Several lines of research support the involvement of environmental factors, such as smoking, and genetic factors in both GD and GO (4, 5, 6). The genetic susceptibility of these diseases is thought to be polygenic. It has been reported that major histocompatibility complex gene (7, 8), cytotoxic T lymphocyte antigen-4 gene (9, 10, 11), interferon-{gamma} gene (12, 13), and TNF-{alpha} gene (14) polymorphisms are associated with GD and GO; however, none of these associations has been fully confirmed.

There is now considerable evidence suggesting that IgE is associated with the severity of Graves’ hyperthyroidism (15, 16, 17) and GO (18, 19, 20). Recent studies of a Japanese population showed that serum IgE concentrations increased by 30–40% in GD patients, correlating with the recurrence of hyperthyroidism after antithyroid drug treatment. IgE deposits and mast cells have also been reported in the thyroid and eye muscle tissues of patients with GD and GO, suggesting that IgE might play a role in autoimmune inflammation (18, 21, 22).

IL-13 is an important immunoregulatory protein produced primarily by activated T helper 2 cells (23) and is involved in B cell maturation. It up-regulates CD23 and major histocompatibility complex class II expression (24) and promotes IgE isotype switching in human B cells (25). IL-13 also down-regulates macrophage activity, thereby inhibiting the production of proinflammatory cytokines and chemokines such as IL-1{alpha}, IL-1ß, IL-6, IL-8, and TNF-{alpha}. Numerous single nucleotide polymorphisms (SNP) have recently been identified in the IL-13 gene and have been found to be associated with IgE levels and/or allergic diseases (26). Thus, IL-13 might be a potential candidate gene contributing to the development of GD or influencing its clinical course. Currently two SNPs in the IL-13 locus have been identified as having a biological function. One is located in the 5'-flanking region at position –1112 (C to T change, termed C-1112T) and has been shown to regulate gene transcription (27, 28). The second is located in exon 4 at position 2044 (G to A change, termed as G2044A) and causes an amino acid exchange (arginine to glutamine at codon 130, termed Arg130Gln), which possibly affects ligand/receptor interactions (29, 30). The aim of the present study was to investigate whether IL-13 gene polymorphisms are associated with the development of GD and GO.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects

In total, 310 GD patients (71 males and 239 females; aged 11–83 yr; mean age, 42.4 ± 15.5 yr) being treated at Kurume University Hospital were enrolled in this study. GD diagnosis was determined by the presence of hyperthyroidism and serum anti-TSH receptor antibodies [TSH binding-inhibiting immunoglobulin (TRAb) and thyroid-stimulating antibody (TSAb)] and/or an increased 123I uptake ratio with diffuse uptake. Ophthalmopathy was classified according to the system recommended by the American Thyroid Association (ATA) committee (31). Ninety-eight of the GD patients (24 males and 74 females) showed ophthalmopathy defined as ATA class III or greater and were classified as GO. Two hundred and twelve patients showed no ophthalmopathy (ATA class 0), signs of ophthalmopathy without symptoms (ATA class I), or only soft tissue involvement (ATA class II). Two hundred and forty-four healthy unrelated Japanese medical students and staffs (97 males and 147 females; aged 18–79 yr; mean age, 30.7 ± 10.6 yr) with no family history of autoimmune diseases and no detectable antithyroid autoantibodies were enrolled as control subjects. The study plan was reviewed and approved by the institutional review committee, and informed consent was obtained from all patients and control subjects.

IL-13 gene polymorphism

Genomic DNA extracted from peripheral blood was subjected to PCR to amplify the polymorphic regions. The promoter region of the IL-13 gene (32) (GenBank accession no. U31120) was amplified by PCR using IL-13 primers originally reported by Laundy et al. (33). PCR was performed using 50 ng genomic DNA, 1.25 U Taq DNA polymerase (AmpliTaq, Applied Biosystems, Foster City, CA), 0.5 µM of each primer (forward, 5'-TCTGAGCGGGAATCCAGCAT-3'; reverse, 5'-AATGAGTGCTGTGGAG GGCG-3'), 1.5 mM MgCl2, and 200 µM of each deoxynucleotide triphosphate under the following conditions: 35 cycles of PCR consisting of 30 sec at 95 C, annealing for 30 sec at 60 C, extension for 1 min at 72 C, and a final extension for 5 min at 72 C in a thermocycler (PerkinElmer, Gene Amp PCR system 9600, Applied Biosystems). The PCR products were directly sequenced using an ABI sequencer (ABI PRISM 3100 Genetic Analyzer, PerkinElmer, Applied Biosystems) to determine the C/T polymorphism at position –1112 relative to the transcription start site (29).

A 236-bp PCR fragment including the Arg130Gln polymorphism was generated using the following primers: 5'-CTTCCGTGAGGACTGAATGAGACGGTC-3' and 5'-GCAAATAATGATGCTTTCGAAGTTTCAGTGGA-3', as previously reported (34). The underlined bases were modified to create NlaIV restriction sites. PCRs were carried out in a total volume of 50 µl containing approximately 50 ng genomic DNA, 10 mmol/liter Tris-hydrochloric acid (pH 8.3), 2.0 mM MgCl2, 200 µM of each deoxynucleotide triphosphate, 0.5 µM of each primer, and 1.25 U Taq DNA polymerase (Applied Biosystems). Samples were denatured at 95 C for 5 min, followed by 33 cycles of 95 C for 30 sec, 60 C for 30 sec, and 72 C for 1 min, and then a final extension for 10 min at 72 C. The PCR products were digested by the addition of 0.25 U NlaIV (New England Biolabs, Boston, MA) and incubation at 37 C for 8 h. NlaIV digests the PCR fragment 26 bp from the 5' end, which serves as a control for assessing whether digestion is complete. It also digests 32 bp from the 3' end of the fragment when the G nucleotide (Arg130) is present, producing a 178-bp fragment. The digested PCR products were electrophoresed on 3% agarose gels to separate the fragments.

Laboratory test

Serum concentrations of free T3, free T4, and TSH were determined by enzyme immunoassays. TRAb was measured by radioreceptor assay with a commercial kit (DiaSorin, Inc., Stillwater, MN), and antithyroglobulin and antithyroid peroxidase antibodies were measured by RIA using commercial kits (RSR Ltd., Cardiff, UK). The cut-off values for TRAb, antithyroglobulin antibodies, and antithyroid peroxidase antibodies were 10%, 0.3 kU/liter, and 0.3 kU/liter, respectively. Serum IgE was measured by nephelometric assay (Dade Bering Marburg GmbH, Marburg, Germany).

Statistical analysis

The clinical data were expressed as the mean ± SD. Differences in clinical data between groups were evaluated using a t test or Welch’s t test. Haplotype frequencies were estimated by maximum likelihood using Arlequin software available from the ARLEQUIN website (http://lgb.unige.ch/arlequin/) (35). The statistical significance of any differences in frequency between each polymorphic allele and genotype of the patient and control groups was evaluated using the {chi}2 test or Fisher’s exact probability test. P values were corrected by multiplying by the number of different alleles or haplotypes tested. In this study a corrected P (Pc) < 0.05 was considered statistically significant.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Association between IL-13 gene polymorphisms and GD

The distributions of alleles and haplotypes for both groups (control and GD) are in good agreement with the Hardy-Weinberg equilibrium. We calculated pairwise linkage disequilibrium between the promoter and exon 4 variants. These two variants were in significant linkage disequilibrium (by Fisher’s exact test, P < 0.000001; D' = 0.803 in the control and 0.807 in the GD group).

The CC genotype frequencies at position –1112 in the promoter region of the IL-13 gene were significantly greater in GD patients compared with controls (71% vs. 59%, respectively; CC genotype vs. CT and TT genotypes, {chi}2 = 8.738, P = 0.0031, Pc=0.0186; Table 1Go). The C allele frequency at position –1112 in the promoter region of the IL-13 gene was significantly greater in GD patients compared with controls (84% vs. 77%; {chi}2 = 9.611; P = 0.0019; Pc = 0.0076; estimated power = 0.85; Table 1Go). The G allele frequency at position 2044 in exon 4 of the IL-13 gene appeared greater in GD patients than controls, but this difference was not statistically significant (73% vs. 67%; {chi}2 = 5.690; P = 0.0171; Pc = 0.0684).


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  		TABLE 1. IL-13 gene polymorphisms in patients with GD and healthy control subjects

 
The association of the C-1112T polymorphism of the IL-13 gene with GD was observed when the female GD patients (n = 239) and control subjects (n = 147) were analyzed (C allele frequency; 85% vs. 77%; {chi}2 = 6.512; P = 0.0107; Pc = 0.0428; data not shown).

The association was also observed when the nonsmoking GD patients (n = 191) and control subjects (n = 171) were analyzed (C allele frequency; 85% vs. 77%; {chi}2 =11.845; P = 0.0027; Pc = 0.0108; data not shown).

Although the distribution of haplotype combinations did not differ between the GD patients and healthy controls ({chi}2 = 14.887; P = 0.0614), the –1112C/2044G haplotype frequency was greater in GD patients than in healthy controls ({chi}2 = 6.856; P = 0.0088; Pc = 0.0352; Table 2Go), and the –1112T/2,044A haplotype frequency was significantly less in GD patients than in controls ({chi}2 = 8.530; P = 0.0035; Pc = 0.0140; Table 2Go).


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  		TABLE 2. Haplotype frequency of IL-13 gene polymorphisms in patients with GD and healthy control subjects

 
Association between IL-13 gene polymorphisms and ophthalmopathy

There was no significant difference in genotype or allele frequencies of IL-13 gene polymorphisms between the patients with evident ophthalmopathy (ATA class III or more; GO) and those without or with mild ophthalmopathy (ATA class 0–II; Table 3Go). However, the C allele frequency at position –1112 in the promoter region of the IL-13 gene in GO patients was significantly greater than that in controls (87% vs. 77%; {chi}2 = 8.755; P = 0.0031; Pc = 0.0124; Tables 1Go and 3Go). The G allele frequency at position 2044 in exon 4 of the IL-13 gene was greater in GO patients than in controls (76% vs. 67%; {chi}2 = 4.983; P = 0.0256; Pc = 0.1024; Tables 1Go and 3Go).


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  		TABLE 3. IL-13 gene polymorphisms in patients with GO and in patients with Graves’ hyperthyroidism without clinically evident ophthalmopathy

 
Association between IL-13 gene polymorphisms and severity of Graves’ hyperthyroidism

There were no significant differences in the levels of serum free T4, free T3, and TSH receptor antibodies among the genotypes of the C-1112T polymorphism or the G2044A polymorphism. However, differences in TRAb levels were observed at the time of diagnosis (Table 4Go). TRAb titers tended to be low in patients with the TT genotype.


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  		TABLE 4. Association of IL-13 gene polymorphisms with laboratory features of patients with GD

 
Association between IL-13 gene polymorphisms and serum IgE levels in GD patients and normal controls

Serum IgE levels were elevated in 34% of the GD patients at the time of diagnosis or during treatment with antithyroid drugs and in 28% of the control subjects (Table 5Go). Mean serum IgE levels tended to be greater in the CC and CT genotypes than in the TT genotype at position –1112 of the IL-13 promoter region in GD patients (Table 5Go). However, this difference was not significant. There was no significant association between the G2044A polymorphisms and serum IgE levels in either GD or control subjects.


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  		TABLE 5. Association of IL-13 gene polymorphisms with serum total IgE in patients with GD and control subjects

 
When GD patients and control subjects, whose serum IgE levels were less than 170 kIU/liter, were analyzed, the CC genotype and the C allele frequencies at position –1112 of the promoter region of the IL-13 gene were significantly greater in GD patients compared with controls (CC genotype vs. CT and TT genotypes: {chi}2 = 9.405; P = 0.0022; Pc = 0.0132; C allele vs. T allele frequencies: {chi}2 = 8.392; P = 0.0038; Pc = 0.0152; Table 6Go).


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  		TABLE 6. IL-13 gene polymorphisms in patients with GD and healthy control subjects whose serum IgE levels were less than 170 kIU/liter

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
GD is an organ-specific autoimmune disorder characterized by diffuse goiter and thyroid hormone oversecretion as a result of TSH receptor antibody stimulation. Although the etiology of GD remains unclear, it is believed to be caused by a complex interaction between genetic and environmental factors. Recent genome-wide research has provided evidence for the linkage of GD to loci on multiple chromosomes, including loci on chromosomes 5 in regions 5q31-q33 (36, 37, 38), which have been linked to autoimmune thyroid disorders, including GD in Japanese and Chinese populations, but not in Caucasian populations. This might suggest that these loci are specific to eastern Asian populations. The loci in regions 5q31-q33 have also been identified as being susceptible to IgE synthesis (39, 40, 41, 42). This region encodes a cluster of cytokine genes, including IL-3, IL-4, IL-5, IL-9, and IL-13, that are involved in inflammation and IgE synthesis (43). Furthermore, IL-13 mRNA expression has been demonstrated in thyroid and orbital tissues from GD patients (44, 45), suggesting that IL-13 might be a potential candidate gene contributing to the development of GD or influencing its clinical severity and course.

Our previous study with a power of 60–85% suggested that in the Polish-Caucasian population studied, IL-13 gene SNPs at positions –1112 (C->T) and 2044 (G->A), 1) do not confer genetic susceptibility to GD, 2) do not contribute to the development of clinically evident GO, and 3) are not associated with the severity of Graves’ hyperthyroidism (34). In the present study a positive association between IL-13 gene polymorphisms and GD was demonstrated for the first time. In this study the C allele frequency in GD patients was significantly greater than that in control subjects. This contradictory result might reflect the insufficient power of the studies or the different genetic susceptibilities of different ethic groups to GD, supporting the idea that the 5q31 locus is specific to eastern Asian populations. Additional large-scale studies are needed to make a definitive conclusion.

IL-13 is an important immunoregulatory protein that plays a role in the regulation of IgE synthesis (43). An IL-13 promoter C to T polymorphism alters the regulation of IL-13 production (27) and possibly contributes to asthma (27, 28). Another polymorphism, the Gln form of Arg130Gln, was shown to be associated with increased serum IgE levels in three Caucasian populations (29). In the present study, however, an association between C-1112T or Arg130Gln polymorphisms and serum IgE levels could not be found in either GD patients or control subjects. This discrepancy between studies of Caucasian and Japanese populations with regard to IgE synthesis suggests that different genetic factors influence IgE synthesis in different ethnic groups. The present study also showed that the C allele frequency was significantly greater in GD patients than control subjects even when those with high titers of IgE were excluded from the study. The results, therefore, suggest that IL-13 polymorphisms independently confer susceptibility to GD.

The relationships between IL-13 polymorphisms and the severity of hyperthyroidism and ophthalmopathy were also investigated. There were no differences in IL-13 polymorphism allele frequency between patients with clinically evident ophthalmopathy and patients without ophthalmopathy or those with mild ophthalmopathy. IL-13 gene polymorphisms were likely to be associated with serum levels of TRAb. However, there were no differences in the other clinical markers investigated, namely, free T4, free T3, or TSH receptor antibodies. Additional studies are necessary to determine whether IL-13 polymorphisms are associated with the outcome of antithyroid drug treatments. In conclusion, this study has shown for the first time that IL-13 gene polymorphisms are associated with the development of GD, but not with ophthalmopathy, in Japanese populations.


   Footnotes
 
This work was supported in part by a grant-in-aid for scientific research from the Ministry of Education, Science, Sports, and Culture, Japan.

First Published Online October 13, 2004

Abbreviations: GD, Graves’ disease; GO, Graves’ ophthalmopathy; Pc, corrected P; SNP, single nucleotide polymorphism; TRAb, TSH binding-inhibiting Ig; TSAb, thyroid-stimulating antibody.

Received May 17, 2004.

Accepted October 1, 2004.


   References
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 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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