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The Development of Graves’ Disease and the CTLA-4 Gene on Chromosome 2q33¹

Department of Medicine, University of Birmingham at Birmingham Heartlands (A.H.B., S.C.L.G., P.M.D.) and Queen Elizabeth Hospitals (J.M.H., A.A., J.C.-S., J.D., A.D., M.C.S., A.H.B., J.A.F., S.C.L.G.); the Department of Statistics, University of Birmingham (R.L.H.), Birmingham, United Kingdom B9 5SS; Royal Bournemouth Hospital (M.A.), Bournemouth, United Kingdom; and Royal Devon and Exeter Hospitals (A.H., K.M.), Exeter, United Kingdom

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

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Case-control studies suggest that the CTLA-4 gene may be a susceptibility locus for Graves’ disease. The previously reported A/G polymorphism at position 49 in exon 1 of the CTLA-4 gene was, therefore, investigated in a case-control (n = 743) and family-based (n = 179) dataset of white Caucasian subjects with Graves’ disease. The relationship between CTLA-4 genotype and severity of thyroid dysfunction at diagnosis was also investigated. An increase in frequency of the G (alanine) allele was seen in Graves’ patients compared with control subjects (42% vs. 31.5%, respectively; corrected P < 0.0002; odds ratio = 1.58), and a significant difference in the distribution of GG, GA, and AA genotypes was observed between the groups (² = 21.7; corrected P < 0.00003). Increased transmission of the G allele was seen from heterozygous parents to affected offspring compared to unaffected offspring (² = 5.7; P = 0.025). Circulating free T₄ concentrations at diagnosis were significantly associated with CTLA-4 genotype (F = 3.26; P = 0.04). These results support the hypothesis that CTLA-4 may play a role in regulating self-tolerance by the immune system and in the pathogenesis of autoimmune disorders such as Graves’ disease.

	Introduction

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INCREASING evidence supports the suggestion that Graves’ disease occurs in genetically susceptible individuals and that a number of genetic loci contribute to the development of disease. Genome screening has provided evidence for linkage of three human chromosomal regions, designated GD-1 (chromosome 14), GD-2 (chromosome 20), and GD-3 (X chromosome), for Graves’ disease (1, 2, 3). A more sensitive, but equally robust, approach employing allelic association and the transmission disequilibrium test (TDT) in families has confirmed the presence of linkage disequilibrium between Graves’ disease and the HLA haplotype DRB1_*0304-DQB1_*02-DQA1_*0501 (4). The cytotoxic T lymphocyte-associated 4 (CTLA-4) gene has also been shown in population-based case-control studies to be associated with Graves’ disease (5, 6, 7, 8). These results have not, however, been confirmed by classical linkage analysis (9). This suggests that the association reported in case-control studies is a false positive as a result of a random chance event or population stratification or that linkage analysis lacks the sensitivity to detect the contribution of the CTLA-4 gene region.

In the present study we have, therefore, used the two approaches of a large case-control study and the family-based TDT (10) in white UK Caucasian subjects with Graves’ disease to investigate the role of the A/G polymorphism at position 49 in exon 1 of the CTLA-4 gene, previously reported to be associated with disease (5, 6, 7, 8). We further examined the relationship between the CTLA-4 gene A/G polymorphism genotypes and the severity of hyperthyroidism at presentation of disease to determine whether there was a link between genotype and Graves’ disease phenotype.

	Materials and Methods

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Unrelated white Caucasian patients of UK origin with Graves’ disease were recruited from large thyroid clinics in Birmingham, Bournemouth, and Exeter, UK, as described previously (4). Patients were defined as having Graves’ disease by the presence of biochemical hyperthyroidism together with two of the following criteria: diffuse goiter; a significant titer of microsomal, thyroglobulin, or TSH receptor autoantibodies; and the presence of dysthyroid eye disease. Microsomal and thyroglobulin 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 autoantibody status was determined by a radioactive inhibition method (RSR Ltd., Cardiff, UK). Serum free T₄ concentrations were measured by Amerlex M RIA (Kodak Clinical Diagnostics, Bucks, UK; normal range, 9–24 pmol/L). Ethnically matched control subjects with no history of autoimmune disease were bled at several sites: the Blood Transfusion Service, Birmingham Heartlands Hospital, and the Queen Elizabeth Hospital (Birmingham, UK).

Families were also recruited, with blood samples obtained from the index case with Graves’ disease, both parents, and any unaffected siblings. All unaffected siblings had tests of thyroid function and autoantibody status, and any showing evidence of subclinical autoimmune thyroid disease were removed from the study before genotyping. In total, DNA was obtained from 379 index cases with Graves’ disease and 364 control subjects for the population case-control association study and from 179 families for TDT analysis.

Patients attending the Queen Elizabeth Hospital thyroid clinic were subsequently analyzed for association between CTLA-4 genotype and severity of biochemical hyperthyroidism, determined by measurement of the serum concentration of free T₄ at diagnosis, before initiation of antithyroid therapy. Additional clinical information was obtained from the thyroid register (11), including gender, age at diagnosis, smoking history, and the presence and size of diffuse goiter.

The study was approved by local ethics committees, and all subjects gave informed, written consent.

Genotyping of datasets

DNA was prepared from 10 mL whole blood, using the Nucleon Bacc II kit (Nucleon Biosciences, UK). Amplification of target DNA in exon 1 of the CTLA-4 gene was carried out using the PCR with primers 5'-GTC AAG GGA CCA TTA GAA G-3' and 5'-CTT TGC AGA AGA CAG GGA TGA A-3'. The reaction was performed in a final volume of 25 µL containing 200 ng genomic DNA, 1 µmol/L of each primer, 0.4 U Taq polymerase with appropriate buffer, 2.5 mmol/L magnesium chloride, and 200 µmol/L/L deoxy-NTPs. Amplification was performed in a MJ Research, Inc. Tetrad thermal cycler and consisted of 25 cycles of 94 C for 30 s, 55 C for 30 s, and 72 C for 30 s. The amplicon was 685 bp in length and was visualized on a 2% agarose gel stained with ethidium bromide. The described polymorphism in exon 1 results in an A-G change, giving rise to a BbvI restriction site. Restriction fragment length polymorphism analysis was performed on 5 µL PCR product, digested in a final volume of 10 µL under appropriate buffer conditions with 1 U BbvI enzyme at 37 C over 2 h. The resulting digestion products were then visualized on a 4% Nusieve-agarose (3:1) gel stained with ethidium bromide.

Statistical analysis

Analysis of the case-control data was performed using the ² test with 95% confidence limits. Where appropriate, P values were corrected for the number of comparisons made, and P < 0.05 was considered significant. Odds ratios were calculated by the method of Woolf with Haldane’s modification for small numbers (12). The TDT (10) was used to test for linkage in the presence of linkage disequilibrium between the A/G polymorphism and disease in the family dataset. In this analysis a significant excess of transmission frequency of an allele from a heterozygous parent to an affected offspring compared to that to an unaffected offspring is evidence of linkage in the presence of linkage disequilibrium between the associated allele and disease. The CTLA-4 gene A/G polymorphism genotypes were also analyzed with respect to circulating free T₄ concentrations at diagnosis by ANOVA using the Minitab version 12 statistical package (Minitab, Inc., State College, PA). Log transformation of free T₄ concentrations resulted in a normal distribution of the residuals.

	Results

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Population-based case-control study

Three hundred and seventy-nine patients with Graves’ disease and 364 control subjects were genotyped for the A/G polymorphism in exon 1 of the CTLA-4 gene. All Graves’ patients and 363 of 364 control subjects were successfully genotyped at this locus. The distribution of the A and G alleles among Graves’ patients and control subjects is summarized in Table 1. A highly significant increase in the frequency of the G allele was seen in Graves’ patients compared with control subjects [42% vs. 31.5%, respectively; corrected P value (Pc) < 0.0002; odds ratio = 1.58]. The distribution of genotypes AA, AG, and GG among Graves’ patients and control subjects is summarized in Table 2. The distribution of the genotypes differed significantly between the two groups (² = 21.7; Pc < 0.00003). This difference reflected a significant decrease in the AA genotype in Graves’ patients compared with control subjects (32.1% vs. 45.1%, respectively; ² = 12.74; Pc < 0.001) and an increase in the GG genotype among Graves’ patients compared with control subjects (17.3% vs. 7.8%, respectively; ² = 6.64; Pc = 0.02).

Transmission of the G and A alleles from heterozygous parents to affected and unaffected offspring was analyzed using the standard TDT. Of the 179 families available for study, 96 were informative for transmission of these alleles. A 2 x 2 test of heterogeneity comparing transmission of the G and A alleles to affected and unaffected offspring (Table 3) confirmed that there was a significant difference in transmission frequencies to affected offspring compared with that to unaffected offspring (² = 5.7; P = 0.025).

Serum free T₄ concentrations at diagnosis were available for 247 patients with Graves’ disease. Serum free T₄ concentrations showed significant variation with goiter size (F = 18.18; P < 0.0005) and smoking status (F = 5.39; P = 0.021) and were, therefore, included as variables in the model. There was a significant association between the serum free T₄ concentration and the CTLA-4 genotype (F = 3.26; P = 0.04). Free T₄ concentrations were highest in patients with the GG genotype [estimated mean, 62.5 pmol/L; 95% confidence interval (CI), 53.9–72.4], lowest in patients with the AA genotype (mean, 50.9 pmol/L; 95% CI, 45.9–56.4), and intermediate in the AG heterozygote state (mean, 54.0 pmol/L; 95% CI, 49.7–58.6).

	Discussion

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Although autoimmune disorders, including Graves’ disease, have a genetic basis, disease presentation is likely to be the result of a complex interaction of genetic and environmental factors. Evidence from type 1 diabetes suggests that a number of susceptibility genes contribute to the development of autoimmune disease, most with a relatively modest effect (13). Genetic linkage studies that look for cosegregation of disease and genetic loci in families are unable to detect many loci with modest effects (9, 14, 15, 16). Robust, alternative approaches are, therefore, necessary if autoimmune susceptibility loci are to be found (17). The present study has used two complementary genetic approaches to explore the hypothesis that the CTLA-4 gene plays a role in the etiology of Graves’ disease.

In our first dataset, analysis of findings from a large population-based case-control study supports the previously reported allelic association between the G allele of the CTLA-4 gene and Graves’ disease (5, 6, 7, 8). The large numbers used in the present study make the possibility of a false positive result due to a random event highly unlikely (² = 16.6; Pc = 0.0002). Although this method has the ability to detect allelic association with a high degree of specificity, it lacks the sensitivity to determine whether the differences observed between diseased and control populations are due to allelic association between the marker allele and the disease. It is not possible, for example, to exclude population stratification as an alternative explanation of the results (18). We, therefore, used the TDT in a second family-based dataset to confirm that our findings were the result of linkage disequilibrium. The TDT examined the frequency with which the G allele in exon 1 of the CTLA-4 gene was transmitted from parents heterozygous for this allele to offspring affected and unaffected by Graves’ disease. We found a significant preferential transmission of the G allele to affected offspring (57.9%) compared with that to unaffected offspring (43.8%). This confirms allelic association of the G allele with Graves’ disease found in the case-control study. The TDT analysis has, therefore, allowed detection of the CTLA-4 gene as a susceptibility locus in Graves’ disease families, which has previously been undetected by classical linkage analysis (9). This form of analysis is more powerful because the selection of informative heterozygous parents overcomes the problem of high population frequencies of disease alleles encountered in linkage studies. Although linkage and linkage disequilibrium have been demonstrated between these polymorphisms and type 1 diabetes in family-based studies (6, 19), this is the first report in Graves’ disease.

The CTLA-4 molecule is a member of the same family of cell surface molecules as CD28 and, along with CD28, can bind to B7. The CTLA-4/B7 complex competes with the CD28/B7 complex and delivers negative signals to the T cell, thereby affecting T cell expansion, cytokine production, and immune responses (20). Although the CTLA-4 molecule may control peripheral T cell tolerance during the course of an immune response, it remains unknown how it may be contributing to the development of Graves’ disease. Antibody formation in Graves’ disease appears to be the result of T helper 2 cell action (21), with increases in interleukin-4 and interleukin-10 levels in patients with disease (22). A functional mutation of the CTLA-4 gene could, therefore, have a negative affect on the down-regulation of T cell function, with subsequent increases in autoantibody formation and the development of disease. We have presented evidence for a relationship between allelic variation of the CTLA-4 gene and circulating free T₄ concentrations at the time of diagnosis of disease, which serves as a marker of the severity of disease. The greatest degree of biochemical dysfunction was seen in those subjects homozygous for the G allele. Although the G (alanine) polymorphism in exon 1 of the CTLA-4 gene has no known functional role, it is in linkage disequilibrium with the (AT)_n microsatellite in the 3'-untranslated region and could, therefore, affect ribonucleic acid stability, down-regulation of T cell function, and subsequent development of disease. Equally, it may be in linkage disequilibrium with another, as yet unknown, disease-causing mutation.

Taken together, therefore, our findings not only show that the G allele of the A/G polymorphism is linked to Graves’ disease, but that the GG genotype is associated with more severe biochemical disease at presentation. These results support the hypothesis that CTLA-4 may play an important role in regulating self-tolerance by the immune system and hence in the pathogenesis of autoimmune disorders such as Graves’ disease. However, further genetic and functional immunological studies are needed to discover the true identity and mechanism of action of the etiological mutation at this locus.

View larger version (18K): [in this window] [in a new window]   Figure 1. Relationship between CTLA-4 genotype and mean free circulating free T4 concentrations at diagnosis. Data presented as estimated means and 95% confidence interval of the mean. Association between free T4 concentrations and CTLA-4 genotype, F = 3.26, P = 0.04.

	Acknowledgments

	Footnotes

 
¹ This work was supported by an award of a project grant from the Wellcome Trust (Grant M/95/3717), Eli Lilly & Co. UK, and the trustees of the former United Birmingham Hospitals.

² Smith and Nephew Medical Research Fellow.

Received February 1, 1999.

Accepted March 17, 1999.

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