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Codon 17 Polymorphism of the Cytotoxic T Lymphocyte Antigen 4 Gene in Hashimoto’s Thyroiditis and Addison’s Disease¹

Medical Clinic I, Center of Internal Medicine, Klinikum of the Johann Wolfgang Goethe-University (H.D., J.B., H.R., K.H.U., K.B.), and Institute for Transfusion Medicine and Immunohematology, Red Cross Blood Donor Service Hessen, (C.S.), 60590 Frankfurt/Main, Germany; Mount Sinai Hospital-Toronto and the Samuel Lunenfeld Research Institute of Mount Sinai Hospital, Division of Endocrinology and Metabolism, University of Toronto Medical School, Toronto M5G 1X5, Ontario, Canada (P.G.W.); and Medical Clinic, Endocrine Department, University Hospital Berlin Benjamin Franklin (R.F.); and IV. Medical Clinic, University Hospital Berlin-Charite (M.V.), 10117 Berlin, Germany

Address all correspondence and requests for reprints to: Dr. Badenhoop, Medizinische Klinik I, Klinikum der Johann Wolfgang Goethe-Universität, Theodor-Stern-Kai 7, 60590 Frankfurt/Main, Germany. E-mail: badenhoop{at}em.uni-frankfurt.de

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Endocrine autoimmune disorders share susceptibility and resistance factors of the human leukocyte antigen system on the short arm of chromosome 6, but other gene loci also contribute to predisposition and protection. Because the cytotoxic T lymphocyte antigen 4 (CTLA4) alanine-17 encoded by the CTLA4 gene on chromosome 2q33 confers susceptibility to Graves’ disease, as well as to type 1 (insulin-dependent) diabetes mellitus , we investigated this dimorphism in the other endocrine autoimmune disorders: Hashimoto’s thyroiditis and Addison’s disease. We analyzed the CTLA4 exon 1 polymorphism (49 A/G) in 73 patients with Hashimoto’s thyroiditis, 76 with Addison’s disease, and 466 healthy controls. This dimorphism corresponds to an aminoacid exchange (Thr/Ala) in the leader peptide of the expressed protein. CTLA4 alleles were defined by PCR, single-strand conformational polymorphism analysis, and restriction fragment length polymorphism analysis using BbvI.

Patients with Hashimoto’s thyroiditis had significantly more Ala alleles than controls, both as homozygotes (22% vs. 15%) and heterozygotes (53% vs. 46%), and less Thr than controls as homozygotes (25% vs. 39%), P < 0.04. The phenotypic frequency for Ala was significantly higher in patients (75%), compared with controls (61%), P < 0.03. Patients with Addison’s disease did not differ significantly from controls, but those carrying the suceptibility marker, human leukocyte antigen DQA1*0501, were significantly more CTLA4 Ala¹⁷ positive than controls with the same DQA1 allele (P < 0.05). In conclusion, an alanine at codon 17 of CTLA4 confers genetic susceptibility to Hashimoto’s thyroiditis, whereas this applies only to the subgroup of DQA1*0501+ patients with Addison’s disease.

	Introduction

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GENETIC susceptibility to thyroid and adrenal autoimmune disease is conferred by genes in the human leukocyte antigen (HLA) region on the short arm of chromosome 6, but the associations are not as strong as observed for type 1 (insulin-dependent) diabetes mellitus (IDDM). Other gene regions also predispose to Hashimoto’s thyroiditis and Addison’s disease. One candidate region is located on chromosome 2q33 in man, where a susceptibility gene has been mapped for IDDM and named IDDM12 (1). This region contains the CTLA4 (cytotoxic T lymphocyte antigen 4) gene that encodes a receptor on T cells interacting with the B7 accessory molecules. The B7:CD28/CTLA4 costimulatory pathway consists of two costimulatory ligands on antigen-presenting cells. CTLA4 is only expressed on activated T cells. B7–1 and B7–2 have a higher affinity to CTLA4 than to CD28, which is also expressed by resting T cells. CTLA4 may thus be regarded as the predominant B7 receptor on activated T cells and a key regulatory element in the interaction with antigen-presenting cells (reviewed in Ref.2). Because CTLA4 has been shown to mediate antigen-specific apoptosis, it represents a negative regulator for T cell function (3). In a murine model of autoimmune encephalomyelitis, CTLA4 mediates the down-regulation of the immune response (4). Because it is generally believed that T cells are the effector cells in endocrine autoimmune disease (5, 6), CTLA4 represents a candidate gene to confer susceptibility.

	Subjects and Methods

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Subjects

Patients with Hashimoto’s thyroiditis (n = 73) and those with Addison’s disease (n = 76) were analyzed and compared with 466 controls. Hashimoto’s thyroiditis was diagnosed by the presence of goitre, hypothyroidism, and elevated microsomal or thyroid peroxidase autoantibodies. Thyroid ultrasound showed a reduced echogenicity. The group included patients from our previous report (7) from Frankfurt, Germany, and Toronto, Canada (n = 18).

Addison’s disease was diagnosed by primary adrenocortical insufficiency without evidence for tuberculosis or adrenoleucodystrophy. The age of onset varied from 16–42 yr, and no neurological deficits could be detected. In 26 patients, thyroid (Graves’ disease or Hashimoto’s thyroiditis) or ß-cell (IDDM) autoimmune disease also was present. Patients were from Frankfurt/Main, Mannheim, or Berlin, Germany.

Healthy controls were randomly collected from Frankfurt/Main, Mannheim, or Berlin, Germany (n = 383), and Toronto, Canada (n = 83). There was no family history of type 1 diabetes, Graves’ disease, Hashimoto’s thyroiditis, or Addison’s disease. The distribution of CTLA4 alleles did not differ between controls from Canada or from Germany.

Methods

The CTLA4 exon 1 position 49 (codon 17) polymorphism was defined as described previously (8). Briefly, PCR was performed with oligonucleotides forward 5'-GCTCTACTTCCTGAAGACCT-3' and reverse 5'-AGTCTCACTCACCTTTGCAG-3', designed according to the published human CTLA4-cDNA sequence (9) using 0.2 µg genomic DNA, 1 U Taq polymerase (Gibco BRL, Eggenstine, FRG), 20 pmol of each primer, and 8 mmol deoxynucleotide triphosphates under the following conditions: initial denaturation for 4 min at 94 C, annealing for 45 sec at 58 C, extension for 45 sec at 72 C, denaturation for 45 sec at 94 C (30 cycles), and a final extension for 4 min at 72 C.

Single-strand conformation polymorphism analysis of CTLA4 polymorphisms. PCR products were screened for variants by single-strand conformation polymorphism. Aliquots of the PCR product (2 µL) were mixed with 2.3 µL deionized formamide, incubated for 5 min at 95 C, and loaded onto an 8% polyacrylamide gel. Gel electrophoresis was carried out at 10 mA (10 W, maximum 1000 V) for 2.5 h keeping constantly at 8 C on a Multiphor II apparatus and a Multitemp cooling system (LKB Pharmacia, Freiburg, Germany). Gels were silverstained to show variant conformational fragments, which corresponded to nucleotide substitutions as confirmed by restriction enzyme analysis. The restriction enzyme, BbvI, defined a G at position 49 (88/74-bp fragments) or an A (no digestion of the 162-bp fragment). DNA fragments were resolved in 2.0% agarose gels stained with SYBR Green I (Molecular Probes, Leiden, Netherlands).

Definition of HLA DQA1 and DQB1 alleles. Patients with Hashimoto’s thyroiditis (n = 66), Addison’s disease (n = 75), and controls (n = 230) were typed for HLA DQA1 and DQB1 alleles as previously described (7).

Statistical analysis. Patients and controls positive for an allele (phenotypic allele frequencies) were compared by the chi-square test with Yates’ correction and Fisher’s exact test where appropriate (one number < 5). P-values were multiplied by the numbers of alleles tested (p_corr). Statistical significance was defined at P < 0.05. Relative risks were calculated with Woolf’s formula.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
CTLA4 exon 1 polymorphisms in patients with Hashimoto’s thyroiditis

Significantly more patients were homozygous for Ala (22% vs. 15%) or heterozygous for Ala/Thr (53% vs. 46%) and less patients homozygous for Thr (25% vs. 39%, P < 0.04, Table 1). The gene frequency of Ala was higher in patients (49%) than in controls (38%, P < 0.02). Furthermore, the Ala phenotype was more frequent in patients (75%) than in controls (61%, P < 0.03, Table 1).

CTLA4 exon 1 polymorphisms in patients with Addison’s disease

Eighteen percent of patients with Addison’s disease were homozygous for Ala, 52% were heterozygous (Ala/Thr), and 30% were homozygous for Thr. The patients with Addison’s disease and other autoimmune endocrine disorders did not differ from the controls or the whole group.

Patients with Addison’s disease selected for the presence of HLA DQA1¹0501 (n = 53, 71% of all HLA DQA1 typed patients) were significantly more positive for the Ala allele: 40 (75%) patients, compared with 59 (58%) DQA1¹0501+ controls, P < 0.05. Also, the gene frequencies of Ala were borderline significantly higher in DQA1¹0501+ patients, compared with controls selected for the same DQA1 allele (P = 0.05, Table 2).

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
The CTLA4 gene has been implicated in several endocrine autoimmune disorders. The CTLA4 Ala¹⁷ is associated with IDDM and Graves’disease, whereas linkage was observed for IDDM (1, 8). Because this CTLA codon 17 polymorphism is only diallelic, it is less sensitive in association or linkage studies. A closely linked microsatellite polymorphism of the CTLA4 gene has a variability of 21 alleles and is situated in the 3'-untranslated region as an (AT)_n repeat. The 106-bp allele of this microsatellite shows a particular association with Graves’ disease, both in Japan (10) and in Great Britain (11). The latter report also finds this allele increased in patients with autoimmune hypothyroidism caused by Hashimoto’s thyroiditis.

We extend our recent report of the CTLA4 codon 17 dimorphism (8) to Hashimoto’s thyroiditis, where 75% of patients have at least one Ala-containing allele. The presence of particular HLA DQ alleles does not affect this association. In contrast, patients with Addison’s disease and the predisposing HLA DQA1¹0501 carry, significantly more often, at least one CTLA4 Ala¹⁷ allele.

This suggests that susceptibility to Addison’s disease may, at least in a subgroup defined by HLA DQ risk alleles, be influenced by CTLA4 genotypes. A similar interaction between HLA DRB1¹04 genotype and the CTLA4 Ala¹⁷ allele has been observed by us in patients with rheumatoid arthritis (12).

Our genetic findings may reflect differences between thyroid and ß-cell or adrenal autoimmunity: whereas Graves’ disease and Hashimoto’s thyroiditis show a stronger association with the CTLA4 Ala¹⁷ allele, the role of this marker seems to be weaker in IDDM and Addison’s disease. This may relate to current concepts of the immune pathogenesis of those disorders.

Macrophage activation, subsequent to a T-helper 1 response, is thought to mediate organ-specific autoimmunity in IDDM, whereas the antibody formation in Graves’ disease is believed to result from a T-helper 2 action, (reviewed in Ref.6). Cytokine profiles of thyroid tissue derived from Graves’ disease patients have been reported to show a pattern consistent with a T-helper type 2 response, i.e. an increase of interleukin 4 and interleukin 10 levels (13).

Because T-lymphocytes are thought to be the prime mediators of thyroid and also adrenal autoimmunity, the CTLA4 phenotype may affect T cell function in the pathogenesis of both thyroid autoimmunity and Addison’s disease. B7, the natural ligand of the CTLA4 molecule, is not expressed by thyrocytes but by antigen-presenting cells within the thyroid. Intrathyroidal macrophages have a higher density of B7–2 on their surfaces, compared with peripheral monocytes (14). This makes it likely that thyroidal cofactors lead to a higher expression level of B7–2.

Although the exon 1 alanine/threonine substitution of the CTLA4 gene is not known to be of functional relevance, this polymorphism may be linked to the (AT)_n microsatellite that is situated in the 3' untranslated region and could affect RNA stability (10).

Further study of the expression of this gene will provide more evidence of how antigen polymorphism and immune dysregulation contribute to endocrine autoimmunity.

	Footnotes

 
¹ This work was supported by the Deutsche Forschungsgemeinschaft (DFG Ba 976/2–3, to K.B.), the Mount Sinai Hospital Department of Medicine Research Fund, and the W. Garfield Weston Foundation (to P.G.W.).

Received March 28, 1997.

Revised July 28, 1997.

Accepted August 21, 1997.

	References

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