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The Journal of Clinical Endocrinology & Metabolism Vol. 87, No. 6 2568-2574
Copyright © 2002 by The Endocrine Society

The Impact of the Human Genome on Endocrinology: Original Articles

AIRE Mutations and Human Leukocyte Antigen Genotypes as Determinants of the Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy Phenotype

Maria Halonen, Petra Eskelin, Anne-Grethe Myhre, Jaakko Perheentupa, Eystein S. Husebye, Olle Kämpe, Fredrik Rorsman, Leena Peltonen, Ismo Ulmanen and Jukka Partanen

Department of Molecular Medicine (M.H., P.E., L.P., I.U.), National Public Health Institute, FIN-00290 Helsinki, Finland; Hospital for Children and Adolescents (M.H., P.E., Ja.P.), Helsinki University Hospital, FIN-00290 Helsinki, Finland; Department of Pediatrics (A.-G.M.), Akershus Central Hospital, N-1474 Nordbyhagen, Norway; Division of Endocrinology (A.-G.M., E.S.H.), Institute of Medicine, Haukeland University Hospital, N-5021 Bergen, Norway; Department of Clinical Sciences (O.K., F.R.), University Hospital, SE-75185 Uppsala, Sweden; and Department of Tissue Typing (Ju.P.), FRC Blood Transfusion Service, FIN-00310 Helsinki, Finland

Address all correspondence and requests for reprints to: Maria Halonen, M.D., National Public Health Institute/Department of Molecular Medicine, Biomedicum, Haartmaninkatu 8, 00290 Helsinki, Finland. E-mail: . maria.halonen{at}ktl.fi

Abstract

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED, OMIM 240300) is a rare autoimmune disease caused by mutations in the autoimmune regulator (AIRE) gene on chromosome 21q22.3. This monogenic disease provides an interesting model for studies of other common and more complex autoimmune diseases. The most common components of APECED are chronic mucocutaneous candidiasis, hypoparathyroidism, and Addison’s disease, but several other endocrine deficiencies and ectodermal dystrophies also occur and the phenotype varies widely. The AIRE genotype also varies; 42 different mutations have been reported so far. To understand the complexity of the phenotype, we studied the AIRE and human leukocyte antigen (HLA) class II genotypes in a series of patients with APECED. The only association between the phenotype and the AIRE genotype was the higher prevalence of candidiasis in the patients with the most common mutation, R257X, than in those with other mutations. Addison’s disease was associated with HLA-DRB1*03 (P = 0.021), alopecia with HLA-DRB1*04- DQB1*0302 (P < 0.001), whereas type 1 diabetes correlated negatively with HLA-DRB1*15-DQB1*0602 (P = 0.036). The same HLA associations have previously been established for non-APECED patients. We conclude that mutation of AIRE per se has little influence on the APECED phenotype, whereas, in contrast to earlier reports, HLA class II is a significant determinant.

AUTOIMMUNE POLYENDOCRINOPATHY-CANDIDIASIS-ECTODERMAL DYSTROPHY (APECED) or autoimmune polyglandular syndrome type 1 (OMIM 240300) is a rare organ-specific autoimmune disease with monogenic, autosomal-recessive inheritance (1, 2). APECED is enriched among the Finns (incidence 1:25,000), Sardinians (1:14,400), and Iranian Jews (1:9,000) (2, 3, 4) but is also present in other populations (5, 6). The defective gene has been positionally cloned and named AIRE (7, 8). Numerous molecular features and in vitro experiments suggest that the corresponding protein is involved in transcriptional regulation (9, 10). The highest expression of the AIRE gene is seen in immunological tissues, particularly in the thymus. However, lower levels of expression of the mouse Aire gene can be detected in many tissues and cell types (11, 12, 13, 14). The link between autoaggression and the mutated AIRE protein remains elusive (15).

The factors contributing to the complexity of the APECED phenotype are unknown. The most common components of APECED are chronic mucocutaneous candidiasis, hypoparathyroidism, and adrenocortical failure (2). Other components of proven or probable autoimmune origin are gonadal atrophy, type 1 diabetes, pernicious anemia, autoimmune hepatitis, alopecia, vitiligo, and hypothyroidism. The pathomechanisms of the ectodermal dystrophies enamel hypoplasia, punctate nail dystrophy, and atrophy and calcification of the tympanic membrane are unknown. The spectrum of the phenotype is broad. The number of components varies from 0 to 9 and the age at first manifestation from some months to adulthood. Furthermore, there is great variation in the sequence in which the different components appear. Intrafamilial variation in the clinical picture suggests that factors other than the specific AIRE mutations are involved. Additionally, some population-based differences are evident. In the Iranian Jewish patients, candidiasis and Addison’s disease are less common, whereas in the Finnish patients, diabetes mellitus is more common than in the other ethnic groups (4, 15).

One of the features that indicates the autoimmune nature of APECED is the presence of circulating autoantibodies. Patients with the disease have autoantibodies of several types in their sera; one type is targeted against steroidogenic hydroxylases (16, 17) and another against pteridine-dependent hydroxylases functioning in the catalysis of neurotransmitter synthesis (18). Various other autoantibodies have been found (19), but their role in the pathogenesis of APECED is unknown. Many autoantibodies are important in reflecting ongoing autoimmune tissue inflammation and thus indicating or predicting functional failure (20, 21, 22).

By October 2001, altogether 42 mutations resulting in APECED have been identified in the AIRE gene (23). They vary from changes in single nucleotides to gross deletions. The most prevalent Finnish mutation R257X is present in 89% of the Finnish and in 33% of the non-Finnish disease chromosomes (10). Other common mutations, enriched in certain populations, have also been identified. Because the functions of the AIRE protein are still unresolved, the mechanisms by which the different mutations disturb the physiological function of the protein are unknown. However, recent data indicate that mutations in different regions of the gene have different effects on the intracellular targeting and transcriptional regulation functions of the AIRE protein (9, 10).

Certain alleles in the genes of human leukocyte antigen (HLA) class I (HLA A, B, Cw) and class II (DR, DQ, DP) are strongly associated with many common autoimmune diseases, such as type I diabetes and autoimmune thyroiditis; hence, they may also be assumed to play a role in APECED. Several studies based on the associations between serologically specified HLA determinants and the phenotype of APECED have been performed, but no definite associations have been observed. In a study of 17 APECED patients, no significant association was found between HLA-DR3 and Addison’s disease (24). In another study of 32 patients, associations were observed between some of the disease components and HLA-A alleles but not HLA-DR alleles (25). In a more recent study of 16 APECED patients, no significant association was observed between the disease components and HLA-DRB1 or DQB1 (26). In a study of 47 APECED patients, a lower frequency of high-risk alleles for type 1 diabetes was observed in patients with glutamic acid decarboxylase (GAD) autoantibodies predisposing to the development of type 1 diabetes (27). Betterle et al. (5) reported an increased frequency of the DR3 allele in 17 patients with autoimmune polyglandular syndrome type 1.

To better understand the genetic determinants of the phenotype variability of APECED, we analyzed the genotype-phenotype associations of APECED in a large, well-characterized group of patients. Several definite associations were observed between specific APECED mutations and phenotypes. Furthermore, HLA class II alleles were found to modify the APECED phenotype.

Subjects and Methods

Patient selection

We studied 104 index patients and their affected siblings from 12 different countries (Table 1Go). The clinicians responsible filled in our questionnaire with clinical details for each patient. All but a few of the Finnish patients have been followed by J. Perheentupa for over 30 yr. In Norway, Sweden, Italy, and Germany, one clinician in each country collected all the clinical information. For the rest of the patients, individual clinicians filled in our questionnaire for the patients from whom they had provided us with blood for the mutation analysis.


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  		Table 1. The nationalities of the APECED patients

 
DNA extraction

Genomic DNA was extracted from 10- to 20-ml blood samples (28). The samples were drawn in accordance with the Helsinki Declaration, and the study was approved by the Ethics Committee of Helsinki University.

Mutation analysis

The 14 exons and the exon-intron boundaries of the AIRE gene were analyzed by PCR and ABI 377 sequencing as described earlier (10). The haplotypes at the AIRE locus (21q22.3) were analyzed using the microsatellite markers JA1, D21S1912, PFKL, and D21S171 (29).

HLA allele typing

The HLA-DRB1 and DQB1 alleles of the non-Finnish samples were determined with Inno-LiPA DQB and LiPA HLA-DRB1 kits (Innogenetics N.V., Gent, Belgium) according to the manufacturer’s instructions. The DQA1 PCR-SSP kit (DynAl A.S., Oslo, Norway) was used for typing the DQA1 alleles. The Finnish samples were analyzed as described earlier, and the data have been included in previous studies on the role of certain autoantibodies in the development of type 1 diabetes (27, 30).

Autoantibody analysis

Serum titers for autoantibodies against 21-, 17-, tryptophan, phenylalanine and tyrosine hydroxylases, SOX9, aromatic L-amino acid and glutamic acid 65 decarboxylases, and side chain-cleaving enzyme were determined from 60 Scandinavian patients. Detection was based on the antigens produced by in vitro transcription and translation (21).

Statistical analyses

We used Fisher’s exact test with two-sided exact significance. The tests were performed in a 2 x 2 contingency table, and each HLA allele was tested against the presence of a certain phenotype or autoantibody. Similarly, the significance of the phenotype differences in patient groups carrying different mutations were tested, using the Fisher’s exact test.

Results

Clinical phenotype

In the index patients, the three most common components of the phenotype were mucocutaneous candidiasis, hypoparathyroidism, and Addison’s disease (Table 2Go). Vitiligo was more common (23%) than in previous reports. The mean age of the patients was 29.4 yr (SD 12.9; range 6.8–64.2). The sequence in which the components occurred was characteristic, i.e. mucocutaneous candidiasis and hypoparathyroidism appeared early, and Addison’s disease was manifested later (Fig. 1Go). The mean number of disease components was 4.4, ranging from 1 to 9. In most families (95%), the phenotype of the affected siblings differed by one or more components.


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  		Table 2. Prevalences of the disease components among the 104 index patients with APECED

 


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  		Figure 1. Prevalences of disease components among our group of patients as a function of age. The ages were known for the majority of the patients.

 
Disease mutations

Thirteen different mutations were found in 104 APECED families (Table 3Go and Fig. 2Go). Some of the patients and their mutations have been described earlier (6, 10). We identified a novel mutation, a cytosine nucleotide 62-to-thymine transition changing alanine to valine at amino acid position 21. This mutation was found in both Swedish and North American patients. The major Finnish mutation R257X was found in the great majority of all the chromosomes (57%), i.e. 66 families (64%) carried this mutation. The second most common mutation (18.3% of the chromosomes) was the 13-bp deletion 967–979, the major Norwegian and British mutation. The remaining patients had several mutations (Table 3Go). In 12 of 208 (5.8%) chromosomes, no mutation was found in the analyzed region of the AIRE gene.


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  		Table 3. The frequencies of the 13 different AIRE mutations

 


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  		Figure 2. The effects of the 13 mutations summarized in Table 3Go on the amino acid sequence of the AIRE protein. The arrows refer to missense mutations, the dotted line segments to early stop codons, and the arrow at mutation 13 to a delayed stop codon. Mutations 3 (R203X) and 4 (R257X) cause deletion of both plant homeodomain type (PHD) zinc finger domains as well as part of the SAND domain. The other nonsense mutations delete the second PHD domain only. Two of the missense mutations probably disrupt the structure of the homogeneously staining region (HSR) domain, whereas the third affects the first of the PHD domains.

 
The major Finnish mutation, R257X, was also the most common mutation among the Swedish patients with APECED, being present in 13 of 20 (65%) Swedish disease alleles. Six of these patients were homozygotes. In addition, one of the patients carried the adenine 1163><1164 insertion previously found in two of the Finnish alleles. Another patient carried the 967–979 deletion. The novel missense mutation, A21V, was detected in three of the alleles of the Swedish patients as well as in one of the alleles of a North American patient. Although the haplotypes of the linked microsatellite markers JA1, D21S1912, and PFKL could not be completely constructed because of lack of parental DNA, we confirmed that the patients with the novel A21V mutation did not share the same haplotype. In one of the Swedish patients, no mutations could be detected in the exons or exon-intron boundaries of the AIRE gene.

AIRE genotype vs. phenotype

The patients homozygous for R257X (n = 52) were compared with the patients heterozygous for this mutation (n = 14) as well as with those carrying some other APECED mutations (n = 35) to test whether any phenotypic features were associated with the mutation (Table 4Go). In patients carrying at least one R257X allele, the incidence of Addison’s disease as well as mucocutaneous candidiasis was higher than in the others. The difference was statistically significant (P < 0.001) only for candidiasis, which was present in 64 of the 66 patients (97%) with at least one R257X allele vs. 25 of the other 35 (71.4%). The patients (10 of the 101) without a nonsense mutation (Table 3Go, mutations numbers 3, 4, 6–12) also had a significantly lower (P = 0.002) prevalence of candidiasis than the other patients.


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  		Table 4. Prevalences of the disease components in patients grouped according to the presence or absence of the mutant allele R257X

 
HLA vs. phenotype

The most common alleles in our index patient group were HLA DRB1*01 (15.9%) and *04 (17.8%). As compared with the allele frequencies in the Finnish, Swedish, and Norwegian populations, the distribution of HLA alleles was typical (data not shown). Addison’s disease was positively associated with the DRB1* 03 allele (P = 0.021; relative risk 8.8) (Table 5Go). Only 1 of the 19 (5.3%) patients with DRB1*03, in contrast to 28 of the 85 (33%) patients without this allele, had not developed Addison’s disease. Alopecia was also positively associated with DRB1*04 (P < 0.001; relative risk 4.8) and DQB1*0302 (P = 0.001; relative risk 6.6). The most common protective alleles for type 1 diabetes, DRB1*15 and DQB1*0602, appeared similarly protective in the APECED patients (P = 0.036 and P = 0.035, respectively). None of the 24 patients with DRB1*15 or the 25 patients with DQB1*0602 had diabetes, in contrast to 13 of the 80 (16.3%) DRB1*15-negative patients and 13 of the 79 (16.4%) DQB1*0602-negative patients (relative risk zero). No significant positive association was found between diabetes and HLA. The two main susceptibility alleles, DRB1*03 and 04, were present in 8 of the 13 (61.5%) diabetic APECED patients, in contrast to the 39 of the 91 (42.9%) nondiabetic patients. In addition, several other associations were found (Table 5Go), but because these were weaker and there are no definitive prior data on these associations in non-APECED patients, their true significance is not known.


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  		Table 5. Associations of disease components of the index patients with HLA alleles

 
HLA vs. autoantibodies

We tested whether certain HLA alleles predispose to the presence of particular autoantibodies (Table 6Go). The 17-hydroxylase autoantibodies were possibly negatively associated with the DRB1*15 allele (P = 0.05). Only 5 of the 18 (28%) DR15-positive individuals had developed autoantibodies against the 17-hydroxylase, in contrast to the 24 of the 42 (57%) DR15-negative individuals.


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  		Table 6. Prevalences of autoantibodies in our subgroup of patients of Scandinavian origin

 
Discussion

We demonstrate here that direct associations between the APECED phenotype and the AIRE mutations may exist between the R257X mutation and the high frequency of mucocutaneous candidiasis. However, this observation requires confirmation because it could be owing to the differences in clinical observation. So far, there seems to be no evident molecular mechanism to explain the association. R257X is a nonsense mutation that either leads to the carboxy-terminally truncated AIRE protein (Fig. 2Go) or may undergo the nonsense-mediated mRNA decay (31) and a total loss of function. When all the patients carrying a nonsense mutation that had possibly lost all function were grouped together, a significant, although smaller, increase in the frequency of candidiasis was observed. Our finding is in agreement with the hypothesis that the lower prevalences of candidiasis (18%) and Addison’s disease (22%) and the common missense mutation Y85C in the Iranian Jewish patients may be connected. Although our series of patients is multinational and relatively large, the majority had the R257X mutation. More extensive exploration of the phenotype-genotype associations would necessitate analysis of a larger group of patients with the rare mutation types. It is also necessary to consider the possible impact of environmental factors. Despite the observed phenotype-genotype association, it seems evident that the allelic heterogeneity of the AIRE gene explains very little of the interfamilial variation of the phenotype.

Our study of the associations between the APECED phenotype and the HLA types was stimulated by the wide phenotypic variation, which cannot be explained solely on the basis of the diversity of mutations in the AIRE gene. There is increasing evidence of the genetic complexity that underlies monogenic diseases. Although the mode of inheritance of many diseases is clearly monogenic, the clinical phenotype of these diseases may be modified by other genes (32, 33, 34). For example, cystic fibrosis patients with meconium ileus have been found to share a common modifier locus on chromosome 19q13 (35). On the other hand, the pathology of the major autoimmune diseases has been suggested to result from complex interactions between environmental and genetic factors, including the HLA alleles (36, 37).

The autoimmune components of APECED, when occurring as isolated diseases or components of the autoimmune polyglandular syndrome type 2, have a complex etiology involving several associations with the HLA genotypes. Autoimmune Addison’s disease is associated with HLA-DR3 and DR4 (24, 38, 39). In addition to the HLA class II association, other loci from the major histocompatibility complex region such as complement C4, CYP21A, and the tumor necrosis factor B are also associated with Addison’s disease (40, 41, 42). However, some of these associations may be explained by linkage disequilibrium. Moreover, various susceptibility loci have been found in other chromosomes (43). The strongest genetic associations of type 1 diabetes are between diabetes and the HLA alleles (44). The two main susceptibility HLA haplotypes for type 1 diabetes are DRB1*04-DQA1*0301-DQB1*0302 and DRB1*03-DQA1*0501-DQB1*0201 (45, 46), whereas the strongest protective HLA haplotype is DRB1*1501-DQA1*0102-DQB1*0602 (47). The non-MHC genes associated with diabetes include the insulin and CTLA-4 genes (48, 49). Vitiligo and alopecia may also be associated with HLA alleles, but the data are inconsistent (50). Against this background and the wide spectrum of APECED phenotype, it is very likely that genetic complexity also exists in APECED. Despite the negative reports, HLA remains one of the primary candidates for involvement.

According to our study, the individual HLA class II alleles may significantly modify the APECED phenotype. The most definite and interesting associations with the HLA alleles were found for Addison’s disease, alopecia, and diabetes mellitus. Importantly, we observed the same associations that have been established for these diseases in the absence of APECED. Interestingly, patients carrying the DRB1*03 allele had a significantly higher prevalence of Addison’s disease. This and the DRB1*04 allele have been shown to be associated with non-APECED autoimmune Addison’s disease. Furthermore, alopecia was strongly associated with the DRB1* 04 allele, as is known with idiopathic alopecia totalis and universalis (50). In our study, the severity of the alopecia was not determined; it varied from transient alopecia areata to alopecia universalis. Moreover, the major protective haplotype for type 1 diabetes, DRB1*15-DQB1*0602, was also found to be protective in the APECED patients. However, it is of note that no alleles were found to predispose to the diabetes of APECED. The protective DR15 haplotype is known to dominate the predisposing haplotypes, and the present results agree with this state of affairs: APECED patients with DR15 did not have type 1 diabetes. The relevance of the other observed associations with HLA may be difficult to assess because they are not supported by similar observations in non-APECED patients.

To test whether the presence of a certain HLA allele can predispose APECED patients to the formation of certain autoantibodies, we studied associations between HLA allele and the presence of serum antibodies in the 60 index patients whose autoantibody data were available. Only a tendency toward an association appeared, suggesting that in APECED the HLA alleles do not have a strong influence on autoantibody formation. This finding contrasts with those of isolated diseases, in which HLA alleles are often associated with presence of autoantibodies.

The HLA associations in APECED connect the underlying pathogenetic mechanisms with those of non-APECED Addison’s disease, alopecia areata, and type 1 diabetes. The role of the HLA-DRB1*03 allele in all forms of Addison’s disease may reflect a likeness in the pathogenesis. The alopecia areata of APECED and the severe idiopathic form of alopecia share similarities in pathogenesis (22). This is further supported by our finding that both forms are associated with HLA-DRB1*04. However, further studies are still necessary to identify the similarities in pathogenesis. The pancreatic ß-cell destruction in the islets of Langerhans has a complicated pathogenesis that is probably explained by alternative molecular pathways, some of which could be shared with the diabetes of APECED. The immunoreactivity against GAD in APECED patients suggests that, because GAD reactivity is not diabetes specific, there may be pathogenetic differences from the common type 1 diabetes (51). Although the protective role of DRB1*15-DQB1*0602 in APECED would point to a common pathogenesis, there seems to be no association with any susceptibility haplotype. Even though some associations connect the components of APECED with the HLA polymorphisms, many susceptibility alleles seem not to influence the APECED phenotype. This may be explained by the relatively small number of patients and consequent low power for establishing or excluding associations. Another explanation may be that although the different disease forms have certain aspects in common, major differences also exist in the pathogenic pathways.

The HLA associations appear to be weaker in APECED than in the common autoimmune diseases, suggesting that HLA genes play a minor role in the pathogenesis of APECED. However, it should be remembered that a normal population distribution of the HLA alleles is found among APECED patients. Consequently, when small subgroups are analyzed statistically, even though the susceptibility alleles are involved in the pathogenesis, the associations appear weak.

In conclusion, we have shown here that there may be some association between the type of mutation in the AIRE gene and the APECED phenotype: for example, the frequency of mucocutaneous candidiasis is lower in the patients without the R257X allele. We also provide evidence that the phenotype of APECED is modified by other genetic elements besides the AIRE gene alleles. The different HLA class II alleles seem to predispose to or protect from particular components of the phenotype. The same allelic associations have previously been found in idiopathic alopecia, isolated Addison’s disease, Addison’s disease as part of autoimmune polyglandular syndrome type 2, and isolated type 1 diabetes, suggesting similarities in the pathogeneses. In the future, the characterization of other modifying factors will be clinically important in understanding the development of APECED in affected individuals.

Acknowledgments

We warmly thank all the APECED patients for donation of the DNA samples and collaboration. Anne Vikman, Elina Honkavaara, and Katri Miettinen are thanked for excellent technical assistance. Prof. Seppo Sarna is thanked for providing help with the statistical analyses. Drs. Joel Zlotogora, Olov Ekwall, Håkan Hedstrand, Jan Gustafsson, P. Heidemann, J. Solyom, D. Lewis, K. O. Schwab, M. Silink, P. E. Mullis, M. Pohl, Beckers, E. Oblinger, Steinert, J. Hurst, G. B. Kletter, C. S. Smith, P. G. Voorhoeve, G. Weber, L. Mathivon, and S. de Muinck Keizer-Schrama are warmly thanked for providing the clinical data, making it possible to complete this study.

Footnotes

This work was supported by the Academy of Finland, Ulla Hjelt Fond of the Foundation for Pediatric Research, Emil Aaltonen Foundation, Finnish Medical Foundation, Maud Kuistila Foundation, Clinical Research Fund of Finnish Red Cross Blood Transfusion Service, Sigrid Juselius Foundation, and Helsinki Biomedical Graduate School.

Abbreviations: AIRE, Autoimmune regulator gene; APECED, autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy; GAD, glutamic acid decarboxylase; HLA, human leukocyte antigen.

Received November 28, 2001.

Accepted February 5, 2002.

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