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The Journal of Clinical Endocrinology & Metabolism Vol. 88, No. 10 5039-5042
Copyright © 2003 by The Endocrine Society

Association of a Rare Thyroglobulin Gene Microsatellite Variant with Autoimmune Thyroid Disease

J. E. Collins, J. M. Heward, J. Carr-Smith, J. Daykin, J. A. Franklyn and S. C. L. Gough

Division of Medical Sciences, University of Birmingham, Queen Elizabeth Hospital (J.E.C., J.M.H., J.C.-S., J.D., J.A.F.); and Division of Medical Sciences, University of Birmingham, Heartlands Hospital (S.C.L.G.), Birmingham, United Kingdom B9 5SS

Address all correspondence and requests for reprints to: Dr. S. C. L. Gough, Department of Medicine, University of Birmingham, Birmingham Heartlands Hospital, Bordesley Green East, Birmingham, United Kingdom B9 5SS. E-mail: s.c.gough{at}bham.ac.uk.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Genetic and environmental factors contribute to the development of Graves’ disease and Hashimoto’s thyroiditis. These diseases, although clinically distinct, share many immunological and histological features. Susceptibility genes for autoimmune thyroid disease (AITD) have been investigated, although only the human leukocyte antigen and cytotoxic T lymphocyte-associated antigen-4 gene regions have been consistently associated with disease. Recent data, however, have shown linkage and association of chromosome 8q24 (containing the thyroglobulin gene) to AITD. Therefore, we performed a case-control association study on patients with AITD and controls using previously associated markers (D8S284 and Tgms2). No differences in allele frequencies were observed between AITD cases and controls for D8S284. Compared with the three common alleles (frequencies >10%), the rare alleles of Tgms2 were increased ({chi}2= 10.6; P = 0.001) at Tgms2. This group included the 336-bp allele (increased in cases vs. controls: {chi}2= 24.97; P < 0.001), which has previously been reported to be associated with AITD. The rarity of this allele in the United Kingdom, however, precluded analysis in our family dataset. Although these findings may represent a random chance event, in view of previous reports of linkage and association of this gene region to AITD, this may be an example of a rare causal variant of a complex disease.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
THE AUTOIMMUNE THYROID diseases (AITDs), including Graves’ disease (GD) and Hashimoto’s thyroiditis (HT), are common complex disorders affecting 2–5% of the western population. They result from a breakdown in the normal mechanisms that maintain tolerance to self-thyroid antigens. The reasons why patients with AITD develop a failure of immune tolerance whereby autoreactive lymphocytes and/or antibodies mount an inflammatory response against the thyroid remain unknown, although both genetic and environmental factors are important. Consistent associations between DNA variants of the human leukocyte antigen gene region on chromosome 6p21 (1, 2, 3, 4, 5) and the cytotoxic T lymphocyte-associated antigen-4 gene region on chromosome 2q33 (6, 7, 8, 9, 10) and AITD along with preliminary linkage data for a number of chromosomal regions support the genetic basis of this disease and explain in part both twin concordance and familial clustering data (11).

Genome-wide linkage analysis of Japanese sibling pairs recently demonstrated suggestive evidence for linkage between chromosome 8q23-q24 and HT (12). Linkage analysis of an additional dataset of families with AITD replicated this original finding, with evidence of allelic association between subjects with AITD and two chromosomal markers on chromosome 8q23-q24: namely, Tgms2, located within the thyroglobulin (Tg) gene, and D8S284, located in the Tg gene region (13). As human Tg is a major autoantigen for thyroid disease and is present in almost all patients with AITD (14, 15, 16), the Tg locus on chromosome 8q23–24 is a good candidate gene for AITD.

The aim of this study, therefore, was to test for evidence of allelic association between subjects with AITD in the United Kingdom and two microsatellite markers (D8S284 and Tgms2) on chromosome 8q23–24 previously reported to be linked and associated with AITD (13).


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

Caucasian patients of British origin with GD and HT were recruited from the thyroid clinics as described previously (1, 17). Briefly, patients with GD were defined by the presence of biochemical hyperthyroidism together with two of the following criteria: diffuse goiter; significant titer of thyroid peroxidase, Tg, or TSH receptor autoantibodies; or presence of dysthyroid eye disease (17A ). HT was defined by the presence of positive thyroid autoantibodies (thyroid peroxidase and/or Tg) and biochemical evidence of hypothyroidism. Microsomal and Tg antibodies were measured by gelatin particle agglutination (SERODIA-ATG, Fujirebio, Inc., Tokyo, Japan), and a titer of 1:100 was considered significant for both assays. TSH receptor antibody status was determined by a radioinhibition method (RSR Ltd., Cardiff, UK). Ethnically matched control subjects with no history of autoimmune disease were bled at various sites, including the Blood Transfusion Service, Birmingham Heartlands Hospital, and Queen Elizabeth Hospital (Birmingham, UK). For the purpose of replication and to exclude population stratification, 262 AITD families were also studied. These families comprised an index case with either GD or HT, both parents, and any unaffected siblings. Thyroid function and autoantibody status tests were performed in all unaffected siblings, and any with subclinical AITD were removed from the study before genotyping (1). The study was approved by the local ethics committees, and all subjects gave informed written consent.

Microsatellite genotyping

DNA was extracted from the whole blood of subjects using the Nucleon Bacc II kit (Nucleon Biosciences, Manchester, UK), and target DNA was amplified by PCR using appropriate primers and optimal conditions, as stated below.

Tg: D8S284

From our clinical and DNA resource of 917 patients with AITD (Table 1Go), DNA from 855 AITD patients (711 with GD and 144 with HT) and 785 control subjects was successfully amplified using primers 5'-GGGCATGTTACTGCATGTC-3' and 5'-TTTGAACACAGGTCTGCCA-3' (18). PCR reactions were performed in a final volume of 25 µl, containing 100 ng genomic DNA, 5 pmol of each primer (one of which was fluorescent labeled), and PCR buffer containing 50 mmol/liter KCl; 10 mmol/liter Tris-HCl (pH 8.3); 2.0 mmol/liter MgCl2; 200 µmol/liter each of deoxy (d)-ATP, dGTP, dTTP, and dCTP; and 1 U AmpliTaq DNA polymerase (PerkinElmer, PE Applied Biosystems, Foster City, CA). Reaction mixtures were denatured at 94 C for 10 min and then cycled 30 times as follows: 30 sec at 94 C, 30 sec at 51 C, and 30 sec at 72 C. A final extension step at 72 C for 5 min was then performed.


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  		TABLE 1. Demographic and clinical data for patients with AITD

 
Tg: Tgms2

Eight hundred fourteen AITD patients (692 with GD and 122 with HT), 790 control subjects, and 262 AITD families were successfully genotyped using primers 5'-TTACGGCTCTTAGGAAGGGG-3' and 5'-ATGGACTTTGGGGACTTGGA-3' (13, 18). PCR conditions and cycling parameters were as described for D8S284, except 1.5 mmol/liter MgCl2 and an annealing step of 55 C were used.

PCR products were pooled and electrophoresed (19) using an ABI 377 DNA sequencer (PE Applied Biosystems) with 0.2 mM 4% polyacrylamide gels run for 2 h at 3000 V and a running temperature of 51 C. PCR products were accurately sized using GENESCAN 1.2 analysis software, by inclusion of a size standard (TAMRA-350, Genpak Ltd., New Milton, Hampshire, UK) in every lane of the gel. DNA fragment sizes were then categorized into allele names and manually checked using GENOTYPER 1.1.1 software (PE Applied Biosystems).

Statistical analysis

Comparison of allele frequencies between cases and control subjects for the two microsatellite markers was performed using the {chi}2 test, and any alleles with less than 10% frequency were grouped together for the analysis. The AITD family dataset was analyzed using the transmission disequilibrium test (TDT) (20). For both case-control and family-based analyses, P < 0.05 was considered significant.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Tg: D8S284

Sixteen individual alleles (size range, 244–276 bp) were observed in cases and control subjects for the marker D8S284. No differences in allele frequencies were observed between cases and control subjects for this locus (Table 2Go).


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  		TABLE 2. Allele frequencies for the marker D8S284 in AITD cases and control subjects

 
Tg: Tgms2

Similarly, for Tgms2, 19 alleles (size range, 326–364 bp) were observed. No differences in allele frequencies were observed between cases and control subjects for all alleles with a frequency of more than 10% (Table 3Go). Collectively, however, the rare alleles with a frequency of less than 10% were increased in subjects with AITD compared with the controls ({chi}2 = 10.6; P = 0.001). This group included the 336-bp allele previously associated by Tomer et al. (13), which in our dataset was present in 2.2% of cases and 0.25% of controls [{chi}2 = 24.97; P < 0.001, uncorrected; odds ratio (OR), 8.03; 95% confidence interval (CI), 2.83–22.62].


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  		TABLE 3. Allele frequencies for the marker Tgms2 in AITD cases and control subjects

 
Because of the association between the 336-bp allele and AITD in the case-control dataset, we tested the Tgms2 marker in our AITD family dataset. The rarity of the 336-bp allele precluded meaningful analysis with too few informative (heterozygote parents) families for TDT analysis (data not shown).


   Discussion
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 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
The search for novel susceptibility loci for the common diseases has proved problematic, with the identification of very few functional DNA variants. Case-control and family-based candidate gene association studies have identified both the human leukocyte antigen (1, 2, 3, 4, 5 ; reviewed in Refs. 21 and 22) and cytotoxic T lymphocyte-associated antigen-4 gene regions (6, 7, 8, 9, 10 ; reviewed in Refs. 21 and 22) as susceptibility loci for AITD. Although linkage analysis in families has to some extent confirmed these findings (9, 23), and linked chromosomal regions have been reported (9, 18, 24, 25, 26, 27), no novel loci have yet been identified. It is becoming increasingly evident that the reason for this is that susceptibility loci in complex diseases are individually probably contributing to less than 5% of familial clustering. There is currently much debate over whether the genetic basis to complex diseases will be explained by either the common disease-common variant hypothesis (28, 29, 30, 31, 32), the multiple rare variant hypothesis (30, 31, 32, 33), or, as seems likely, a mixture of both. Nonetheless, as linkage studies are failing to deliver in complex disease, larger datasets, even for association studies, are required to detect such effects, including those contributing to the common disease-common variant hypothesis. Recent studies focusing on chromosome 8q23–24 in AITD (12, 13) are a good example of some of the difficulties being encountered.

Evidence suggestive of linkage between HT and chromosome 8q23-q24 was first reported in a Japanese dataset of 123 sibling pairs and was maximal at the microsatellite marker D8S272 (12). In an extended dataset of 102 mixed American, Middle Eastern, and European multiplex AITD families, linkage was also reported to chromosome 8q24 and was maximal at marker D8S284 (13). In a case-control dataset, which included probands from the same family dataset, association was also reported between the 336-bp allele of a novel CA repeat marker, Tgms2 in intron 27 of the Tg gene located on chromosome 8q24 (13). Using the TDT analysis in the AITD families, the same researchers reported an association between AITD and 2 alleles of D8S284 and 2 further alleles (not the 336-bp allele) of Tgms2 (13). In the present study, which has sufficient power to exclude association with the size of effect seen in the study by Tomer et al. (13) (where allele frequency was 10%; OR, 2.3; P = 1 x 10-8; power, 99.5%), we were unable to detect association between the common alleles of either D8S284 or Tgms2 and AITD in the United Kingdom. We did, however, observe a difference in allele frequencies for Tgms2 for all alleles, with a combined frequency of less than 10%. This included the 336-bp allele (which in the United Kingdom is a rare allele) that was present in 2.2% of subjects with AITD and 0.25% of control subjects. Because of the low frequency of this allele, we were unable to perform meaningful replication analysis in our family dataset and exclude population stratification.

So what conclusion can be drawn from our data? Either this positive result is due to a random chance event, or it may represent an example of a marker being in linkage disequilibrium with a rare causal variant. As evidence suggestive of linkage and possibly association has previously been reported in this region (12, 13, 18), we cannot exclude the rare causal variant hypothesis. Further large association studies will be required to help resolve this question. However, in the present study the 336-bp allele conferred an OR of 8.03 (95% CI, 2.83–22.62). Power estimates would suggest that to achieve 90% power to exclude this effect, 600 cases and 600 control subjects would be required. If we have overestimated the size of the effect, and the lower 95% CI limit is taken, 4000 cases and 4000 control subjects would be required (86% power) to confidently exclude a rare allele effect at Tgms2.

Although caution needs to be applied to overinterpretation of the "positive" data, the Tg gene is an attractive candidate gene for AITD. Restricted epitope Tg autoantibodies are present in most subjects with AITD (14, 34), and Tg immunization has been shown to induce autoimmune thyroiditis in mice (35) in a major histocompatibility complex-dependent manner (36). In the present study TgAb was only measured in 376 patients with AITD. Of these, 138 (36.7%) were found to have positive titers. The allele frequencies in this subgroup of patients were no different from those in the complete dataset (data not shown). Furthermore, subgroup analysis of patients with GD and HT separately revealed no differences between the groups (data not shown), although a difference cannot be completely excluded because of the rarity of the associated allele. At the present time, therefore, it is only possible to speculate on the mechanism by which Tg and/or the Tg gene may predispose to AITD. Clearly, there are a number of potential ways in which Tg could lead to a loss of immune tolerance either peripherally or centrally, including effects mediated by the recently discovered role of the transcription factor autoimmune regulator in the thymus (37).

Despite the attractiveness of the Tg gene as a susceptibility locus for AITD, further studies using large datasets are needed to determine whether it truly is involved in the disease process. It is also just as likely that positive linkage and association at chromosome 8q23–24 could reflect another susceptibility locus, and that the reported association is merely in linkage disequilibrium with a functional variant in a neighboring gene.


   Acknowledgments
 
We acknowledge physicians in Birmingham (P. Dodson), Exeter (A. Hattersley and K. Macleod), Bournemouth (M. Armitage), and Walsall (T. Harvey) and research nurses (including A. Daly) for help in recruiting patients.


   Footnotes
 
This work was supported by a grant from the Wellcome Trust and a Diabetes Research and Wellness Foundation Ph.D. studentship (to J.E.C.).

Abbreviations: AITD, Autoimmune thyroid disease; CI, confidence interval; d, deoxy; GD, Graves’ disease; HT, Hashimoto’s thyroiditis; OR, odds ratio; TDT, transmission disequilibrium test; Tg, thyroglobulin.

Received January 22, 2003.

Accepted May 18, 2003.


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