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The Journal of Clinical Endocrinology & Metabolism Vol. 85, No. 2 688-691
Copyright © 2000 by The Endocrine Society

Original Studies

Association Analysis of the Cytotoxic T Lymphocyte Antigen-4 (CTLA-4) and Autoimmune Regulator-1 (AIRE-1) Genes in Sporadic Autoimmune Addison’s Disease1

B. Vaidya, H. Imrie, D. R. Geatch, P. Perros, S. G. Ball, P. H. Baylis, D. Carr, S. J. Hurel, R. A. James, W. F. Kelly, E. H. Kemp, E. T. Young, A. P. Weetman, P. Kendall-Taylor and S. H. S. Pearce

Endocrine Group, Department of Medicine, University of Newcastle upon Tyne (B.V., H.I., D.R.G., S.G.B., P.H.B., R.A.J., P.K.-T., S.H.S.P.), Newcastle upon Tyne NE2 4HH; Department of Medicine, Freeman Hospital (P.P.), Newcastle upon Tyne NE7 7DN; Division of Medicine, North Tees General Hospital (D.C.), Stockton on Tees TS19 8PE; Department of Medicine, University College and Middlesex Hospital (S.J.H.), London W1N 8AA; Diabetes Care Centre, Middlesbrough General Hospital (W.F.K.), Middlesbrough TS5 5AZ; Division of Clinical Sciences, University of Sheffield (E.H.K., A.P.W.), Sheffield 55 7AU; Department of Medicine, Wansbeck General Hospital (E.T.Y.), Ashington NE63 9JJ, United Kingdom

Address correspondence and requests for reprints to: Dr. Simon Pearce, Department of Medicine, 4th Floor Leech Building, The Medical School, Newcastle upon Tyne, NE2 4HH, United Kingdom. E-mail: spearce{at}hgmp.mrc.ac.uk


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Although autoimmune Addison’s disease (AAD) may occur as a component of the monogenic autoimmune polyendocrinopathy type 1 syndrome (APS1), it is most commonly found as an isolated disorder or associated with the autoimmune polyendocrinopathy type 2 syndrome (APS2). It is likely that sporadic (non-APS1) AAD is inherited as a complex trait; however, apart from the major histocompatibility complex, the susceptibility genes remain unknown. We have examined polymorphisms at two non-major histocompatibility complex candidate susceptibility loci in sporadic (non-APS1) AAD: the cytotoxic T lymphocyte antigen-4 (CTLA-4) gene and the autoimmune regulator (AIRE-1) gene. DNA samples from AAD subjects (n = 90) and local controls (n = 144 for CTLA-4; n = 576 for AIRE-1) were analyzed for the CTLA-4A/G polymorphism in exon 1 of the CTLA-4 gene and for the common mutant AIRE-1 allele (964del13) in United Kingdom subjects with APS1, by using the restriction enzymes Bst71I and BsrBI, respectively. There was an association of the G allele at CTLA-4A/G in AAD subjects (P = 0.008 vs. controls), which was stronger in subjects with AAD as a component of APS2 than in subjects with isolated AAD. In contrast, the mutant AIRE-1 964del13 allele was carried in one each of the 576 (0.2%) control subjects and the 90 (1.1%) AAD subjects as a heterozygote (P = 0.254, not significant), suggesting that this common AIRE-1 gene abnormality does not have a major role in sporadic (non-APS1) AAD.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
AUTOIMMUNE Addison’s disease (AAD) is the most common cause of primary adrenal failure in developed countries, with an estimated prevalence of 100 per million (1, 2). It manifests either as an isolated (nonsyndromic) disorder or as a part of the autoimmune polyendocrinopathy syndromes (APSs). In the APS type 1 (APS1), which is also known as the autoimmune polyendocrinopathy, candidiasis and ectodermal dystrophy (APECED) syndrome, AAD occurs in association with autoimmune hypoparathyroidism and other organ-specific autoimmune disorders, such as type 1 diabetes, primary gonadal failure, pernicious anemia, and hypothyroidism (3, 4). APS1 is a monogenic disorder with strict autosomal recessive inheritance (5), and homozygous or compound heterozygous mutations in the autoimmune regulator (AIRE-1) gene have been recently demonstrated in APS1 subjects (6, 7, 8, 9, 10, 11, 12). In contrast, the genetic basis of isolated AAD and the APS type 2 (APS2) (an association of AAD with autoimmune thyroid disease and/or type 1 diabetes) (3) is thought to be distinct from APS1 (3, 13) and has been less clearly defined.

There are reports of concordance of AAD and APS2 in monozygotic twins, and the clustering of the component disorders of APS2 in some families suggests a role for genetic susceptibility in their pathogenesis (1, 14, 15, 16, 17, 18). Thus, in common with other organ-specific autoimmune diseases, such as type 1 diabetes and autoimmune thyroid disease, it is likely that sporadic (non-APS1) AAD is inherited as a complex trait, with many loci conferring variable degrees of susceptibility in different populations (19). There are already well-defined major histocompatibility complex (MHC) associations for sporadic (non-APS1) AAD (13, 20, 21, 22, 23, 24); however, the non-MHC susceptibility genes for AAD remain largely unknown.

The cytotoxic T lymphocyte antigen-4 (CTLA-4) gene on chromosome 2q33 encodes a costimulatory molecule, which is an important negative regulator of T-cell activation (25). This locus is linked to and associated with both type 1 diabetes (designated IDDM12) and Graves’ disease (26, 27, 28, 29, 30, 31). In addition, CTLA-4 gene polymorphisms are associated with other autoimmune disorders, such as autoimmune hypothyroidism, coeliac disease, rheumatoid arthritis, myasthenia gravis, and multiple sclerosis (30, 32, 33, 34, 35, 36, 37). Recently, the G allele of a diallelic polymorphism (CTLA-4A/G) in exon 1 of the CTLA-4 gene has been shown to be associated with AAD, but only in a subgroup of patients carrying the HLA DQA110501 allele (32). In another study, an association was found between the 106-bp allele of a microsatellite polymorphism (CTLA-4[AT]n) within the 3' untranslated region of the CTLA-4 gene in a subset of European AAD patients from the United Kingdom. (36). Thus, it is possible that CTLA-4 is a susceptibility locus for AAD, at least in certain subsets of patients, although this awaits confirmation.

The AIRE-1 gene, which is mutated in APS1 (6, 7, 8, 9, 10, 11, 12), encodes a 545-amino acid protein that has two plant homeodomain (PHD)-type zinc-finger domains, suggesting a role as a transcription factor (6, 7). AIRE-1 messenger RNA is expressed in lymphoid tissues including thymus, lymph node and spleen, and possibly in other tissues including the adrenal cortex (6, 7). The pattern of AIRE-1 gene expression, together with its mutation in APS1 patients, suggests that it may have a critical role in the development of a normal immune response. Because homozygous or compound heterozygous mutations of AIRE-1 causes AAD in the context of APS1, AIRE-1 is, therefore, a candidate susceptibility gene for sporadic (non-APS1) AAD. In the United Kingdom population, we have found that one particular mutant AIRE-1 allele, a 13-bp deletion at nucleotide 964 in exon 8 (964del13), accounts for more than 70% of APS1 alleles (8). Although the parents of APS1 subjects, who carry one mutant AIRE-1 allele, are generally normal (5), this does not exclude a role for heterozygous AIRE-1 gene abnormalities in non-APS1 AAD or APS2, as susceptibility alleles at other loci are likely to be required for the development of these genetically complex disorders (19, 38). To determine whether this common British mutant AIRE-1 allele, 964del13, and the CTLA-4A/G polymorphism have a role in the pathogenesis of AAD, we have examined a United Kingdom cohort of sporadic (non-APS1) AAD subjects for these genetic polymorphisms.


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

Ninety-one subjects with AAD were identified sequentially as they presented to the local endocrine clinics in the North East of England. Two of these subjects were concordant monozygotic twins, of which only one was included in the subsequent analysis. All had a maximum serum cortisol of less than 550 nmol/L within 1 h of synthetic ACTH (250 µg) administration. All subjects had a diagnosis of autoimmune primary adrenal failure; secondary adrenal failure, infective or infiltrative causes were excluded. Evidence of another autoimmune condition was present in 49 subjects: hypothyroidism, 26; Graves’ disease, 12; primary gonadal failure, 5; vitiligo, 5; pernicious anemia, 7; type 1 diabetes, 4; rheumatoid arthritis, 2; coeliac disease, 1; autoimmune hepatitis, 1; hemolytic anemia, 1; and alopecia universalis, 1. Overall, 41 subjects had APS2, with AAD coexisting with either type 1 diabetes mellitus or autoimmune thyroid disease. There were 25 males and 65 females with a mean age at the onset of AAD of 38 yr (range, 15–83). None of the AAD subjects had autoimmune hypoparathyroidism or candidiasis. Thirty-two of these patients were included in the earlier report studying the microsatellite CTLA-4[AT]n polymorphism (36). Samples from local healthy subjects (n = 144 for CTLA-4, n = 576 for AIRE-1) made up the control population. All patients and controls were Caucasian and were derived from a genetically homogeneous population from the well-defined and stable population within the North East of England. Studies were carried out with the approval of the regional and district ethical committees.

Methods

CTLA-4A/G polymorphism analysis.Genomic DNA was obtained from venous blood from each subject using the Nucleon BACCII kit (Nucleon Biosciences, Glasgow, Scotland). The CTLA-4A/G polymorphism was amplified from genomic DNA using the primers 5'-CCACGGCTTCCTTTCTCGTA-3' and 5'AGTCTCACTCACCTTTGCAG-3', followed by digestion with the restriction enzyme Bst71I (Promega Corp., Southampton, UK), as described previously (28). Bst71I cuts the 328-bp PCR product only if G allele is present at position 49, resulting in 244- and 84-bp fragments, which were resolved on a 2.5% agarose gel.

AIRE-1 964del13 mutation analysis.Genomic DNA was used as a template for PCR with oligonucleotide primers to produce a 229-bp amplicon that encompassed exon 8 of the AIRE-1 gene. The primer sequences were 5'-CACCCCAGCCCAGTCTGCATG-3' and 5'-CTTCAGGGTCAGTGGGTGGAG-3'. PCR was performed with 200 ng template DNA, 50 pmol of each primer, 200 µM dNTPs, 1 mM magnesium chloride, 50 mM potassium chloride, 10 mM tris HCl (pH 8.3), and 1 U Taq DNA polymerase (Life Technologies, Inc., Paisley, UK) in a final volume of 50 µL. After an initial denaturation at 94 C for 5 min, 35 cycles of PCR amplification were performed, with each cycle consisting of 30 s at 93 C, 30 s at 63.5 C, and 30 s at 72 C. This exon 8 AIRE-1 amplicon was then digested overnight with the restriction enzyme BsrBI (New England Biolabs, Inc., Beverly, MA), which yields two fragments of 140- and 89-bp in the presence of wild-type sequence but a single fragment of 216-bp in the presence of the 964del13 mutation. These fragments were resolved by electrophoresis on a 2.3% agarose gel. Mutations were confirmed by direct DNA sequencing, as described previously (8).

Statistical analysis

Comparison of the prevalence of the alleles of the CTLA-4A/G polymorphism and the mutant AIRE-1 allele between patient and control groups was performed using a one-tailed Fisher’s exact test on 2 x 2 contingency tables. Odds ratios (ORs) were calculated with Woolf’s method.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Association analysis of the CTLA-4A/G polymorphism

There was a significantly increased frequency of the G allele at the CTLA-4A/G polymorphism in AAD subjects compared with controls [P = 0.008 vs. controls; OR = 1.64; 95% confidence interval (CI), 1.11–2.40] (Table 1Go). Analysis in 49 subjects with isolated AAD also showed a tendency toward increased frequency of the G allele (P = 0.040) (Table 1Go). This contrasts to the finding in subjects with AAD as part of APS2, where there was a more marked excess of the G allele at CTLA4-A/G, compared with controls (P = 0.022; OR = 1.73; 95% CI, 1.05–2.84). There was no heterogeneity between the genotypes of the isolated AAD subjects and those with APS2 (P = 0.428). There was no difference in CTLA-4A/G genotype distribution between males and females with AAD (P = 0.370).


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  		Table 1. Frequency of the CTLA-4A/G polymorphism in AAD subjects and in controls

 
Association analysis of the 964del13 AIRE-1 gene allele

One of 576 (0.2%) normal control samples was found to be a heterozygous carrier of the 964del13 AIRE-1 mutation, confirming that 964del13 is an infrequently carried AIRE-1 allele in our normal population. Of the 90 unrelated subjects with AAD, 1 (1.1%) was found to be a heterozygous carrier of the 964del13 AIRE-1 gene allele (P = 0.254 vs. control alleles, not significant). This man presented with adrenal failure and positive adrenal antibodies at the age of 47 yr. He has no other endocrinopathy, and has never had an episode of candidiasis. His serum ionized calcium concentration is normal.


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
Defining the susceptibility loci for complex disorders can be notoriously difficult (19, 38), however, association studies such as this one may be sensitive in detecting loci with small effects (38). Furthermore, association studies may be particularly useful in disorders such as AAD where it is impossible to collect sufficient families with multiple affected members to perform conventional familial linkage studies. In this study, we have shown that the G allele of the CTLA-4A/G polymorphism confers susceptibility to AAD (OR = 1.64, P = 0.008). Furthermore, we observed a stronger association with the G allele in AAD in subjects with APS2 (OR = 1.73, P = 0.022), compared with those with isolated AAD. In an earlier study, Donner et al. (32) showed an association of AAD with the G allele of the CTLA-4A/G polymorphism that was only present in a subgroup of patients carrying the HLA DQA110501 allele. Our finding, of a stronger allelic association in APS2 subjects, suggests that the effect observed by Donner et al. (32) may reflect the presence of an excess of the HLA DQA110501 (DR3/DQ2 haplotype)-associated autoimmune thyroid diseases and type 1 diabetes in this subgroup of patients (24, 39, 40). We previously found an association of the 106-bp allele of CTLA-4[AT]n polymorphism, which is in linkage disequilibrium with the G allele of CTLA-4A/G, in a cohort of 39 English AAD patients but not in AAD subjects from the Norwegian, Finnish, or Estonian populations (36). Our results are consistent with these initial findings and confirm in a larger cohort of subjects that CTLA-4 is a susceptibility locus for AAD in our United Kingdom population.

The consistency of allelic associations between the CTLA-4 gene polymorphisms CTLA-4[AT]n and CTLA-4A/G and different autoimmune diseases (26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37) suggests that one of these polymorphisms may have a functional role in the pathogenesis of autoimmunity. The CTLA-4[AT]n polymorphism lies within the 3' untranslated region of exon 4 of the CTLA-4 gene, and it has been suggested that the larger size of the linked 106-bp allele compared to the more common 88-bp allele could adversely affect the stability of the messenger RNA transcript, leading to reduced levels of cell-surface CTLA-4 (26). A functional role of the CTLA-4A/G polymorphism, which encodes a threonine to alanine change within the signal peptide of CTLA-4, is generally discounted, and CTLA-4A/G is thought simply to be in linkage disequilibrium with the true susceptibility polymorphism. The association of A allele rather than the G allele of this polymorphism in coeliac disease (33), and the finding that linkage of Graves’ disease to this region is not confined to G allele carriers (31), support this idea. However, it is also possible that this signal peptide polymorphism determines a subtle alteration in the subcellular localization of the mature CTLA-4 protein or affects the interaction of the nascent peptide with chaperonins, leading to a functionally important difference in the folding of the mature protein. Additional investigation will be necessary to distinguish between these possibilities.

The finding that only 1 of 90 unrelated AAD patients had the 964del13 AIRE-1 allele (not significant vs. controls) contrasts to the presence of this mutant allele in more than 70% of APS1 subjects (8) in our population. Although APS1 is a monogenic disorder, with no MHC linkage or association (3, 13), this does not per se exclude the AIRE-1 gene from having a role in sporadic (non-APS1) AAD or APS2. Thus, we confirm that the common United Kingdom APS1 mutation does not make a major contribution to the etiology of isolated AAD and APS2.


   Acknowledgments
 
We thank Kath Brown and Elaine Farrell for collecting patient samples.


   Footnotes
 
1 Supported by the Wellcome Trust. Back

Received May 5, 1999.

Revised July 22, 1999.

Accepted November 1, 1999.


   References
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 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals