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MHC2TA Single Nucleotide Polymorphism and Genetic Risk for Autoimmune Adrenal Insufficiency

Department of Clinical Pathology and Cytology (M.G.), Karolinska University Hospital, SE-141 86 Stockholm, Sweden; Department of Internal Medicine (G.G., C.T., A.B., A.F.), Section of Internal Medicine and Endocrine and Metabolic Sciences, University of Perugia, 06126 Perugia, Italy; Division of Biomedicine (K.J.), Department of Clinical Medicine, University of Örebro, SE-701 82 Örebro, Sweden; Stanford Genome Technology Center (B.G.), Stanford University, Palo Alto, California 94305; Department of Clinical and Experimental Medicine and Surgery (A.D.B.) F. Magrassi, A. Lanzara, Second University of Naples, 10-81100 Naples, Italy; Chair of Endocrinology (F.P.G.), University of Milan, Ospedale San Luca, Istituto Auxologico Italiano Istituto di Ricovero e Cura a Carattere Scientifico, 7–20122 Milan, Italy; Medicina Interna I (M.T.), Department of Clinical and Biological Sciences, University of Torino, ASO San Luigi, 185-10149 Orbassano, Italy; and Department of Medical and Surgical Sciences (C.B.), University of Padova, 2-35122 Padova, Italy

Address all correspondence and requests for reprints to: Alberto Falorni, M.D., Ph.D., Department of Internal Medicine, Section of Internal Medicine and Endocrine and Metabolic Sciences, Via E. Dal Pozzo, 06126 Perugia, Italy. E-mail: falorni{at}dimisem.med.unipg.it.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Context: The polymorphism of class II HLA genes modulates the genetic risk for several endocrine autoimmune diseases. The constitutive class II expression on antigen-presenting cells is under the control of the MHC class II transactivator, encoded by the MHC2TA gene, which is mapped to chromosome 16p13. The MHC2TA –168 AG single nucleotide polymorphism (rs3087456) has been suggested to confer susceptibility to some autoimmune diseases.

Design: With the aim of testing whether this MHC2TA single nucleotide polymorphism is independently associated with autoimmune Addison’s disease (AAD) and/or modulates the genetic risk conferred by DRB1-DQA1-DQB1 haplotypes, we analyzed DNA samples from 128 AAD patients and 406 healthy control subjects from continental Italy.

Results: Frequency of allele G of MHC2TA was significantly increased among AAD patients (39% alleles), compared with 29% in healthy controls (P = 0.003). Similarly, the frequency of AG+GG genotypes was significantly higher among AAD patients than among healthy control subjects, in both a codominant (P = 0.012) and a G-dominant model (P = 0.018). Multivariate logistic regression analysis showed that MHC2TA AG+GG continued to be positively associated with genetic risk for AAD (P = 0.028, odds ratio = 1.72, 95% confidence interval = 1.06–2.78), after correction for DRB1*03-DQA1*0501-DQB1*0201, DRB1*04 (not 0403)-DQA1*0301-DQB1*0302 and DRB1*0403. Similar results were obtained when the number of G alleles was included in the model (P = 0.004; odds ratio = 1.65, 95% confidence interval = 1.17–2.32).

Conclusions: Our study provides the first demonstration of the association of the polymorphism of the MHC2TA gene with genetic risk for AAD that appears to be independent from the well-known association with the polymorphism of HLA class II genes.

	Introduction

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ENDOCRINE AUTOIMMUNE DISEASES, such as thyroid autoimmune diseases, autoimmune Addison’s disease (AAD), type 1 diabetes mellitus, autoimmune premature ovarian failure, autoimmune hypophysitis, or autoimmune hypoparathyroidism, share a common genetic background (1). With the exception of the autoimmune polyendocrine syndrome type 1 (APS I), which is caused by mutations of the AIRE gene (2), located on chromosome 21, all the other clinical manifestations of endocrine autoimmunity are positively associated with the polymorphism of class II HLA genes DRB1, DQA1, and DQB1.

The constitutive as well as the interferon--inducible class II expression on antigen-presenting cells is under the control of the class II transactivator (CIITA), the master regulator for HLA-D gene expression (reviewed in Ref. 3). In humans, CIITA exhibits cell-specific, cytokine-inducible, and differentiation-specific expression and is expressed in the same cells that express class II molecules, such as B cells, monocytes, dendritic cells, and activated T cells (4). The CIITA gene, named MHC2TA, has been mapped to chromosome 16p13 and is characterized by the presence of several single nucleotide polymorphisms (SNPs) in both the promoter type III (responsible for constitutive CIITA expression in B cells) and the coding sequence (5, 6). One such SNP, the –168 AG in the human type III promoter (position –168 from translation start or –155 from transcription initiation, rs3087456) has recently been suggested to confer susceptibility to rheumatoid arthritis and multiple sclerosis (7). Polymorphisms in the CIITA gene have been shown to be weakly associated with multiple sclerosis also in another report (8). However, the results of other studies (6, 9, 10) do not appear to support the hypothesis of a significant association between MHC2TA gene polymorphism (and more specifically, the –168 AG SNP) and the development of human autoimmune diseases.

Primary adrenal insufficiency is classified as AAD in the presence of adrenal cortex autoantibodies and/or steroid-21-hydroxylase autoantibodies (11), but occasionally these markers have also been detected in patients with clear signs of posttuberculosis Addison’s disease (12). To optimize the criteria for the etiological classification of primary adrenal insufficiency, the Italian Addison Network (IAN) has recently developed a comprehensive flow chart that takes into consideration autoantibody levels, imaging datam, and biochemical parameters (IAN Study 1) (13). The accurate reclassification of patients affected by AAD enabled the demonstration that both DRB1*03-DQA1*0501-DQB1*0201 and DRB1*04-DQA1*0301-DQB1*0302 are positively associated and DRB1*0403 is negatively associated with genetic risk for AAD (IAN Study 2) (14).

With the aim of testing whether MHC2TA-168 AG SNP is independently associated with AAD and/or modulates the genetic risk conferred by DRB1-DQA1-DQB1 haplotypes, we analyzed a large set of genomic DNA samples from AAD patients and healthy control subjects from continental Italy, enrolled by the Italian Addison Network. The results of our study indicate that MHC2TA-168 AG SNP is positively associated with genetic risk for AAD, independently from HLA class II gene polymorphism.

	Subjects and Methods

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Subjects

Genomic DNA was obtained from 128 AAD patients and 406 healthy control subjects. IAN includes 14 endocrinological centers located in nine regions of continental Italy (13). Between January 1998 and December 2005, IAN has enrolled 322 patients with primary adrenal insufficiency. According to a recent update of diagnostic criteria for the etiological classification of primary adrenal insufficiency (13) and based on the combined use of immunological, biochemical, and clinical data, 220 cases (68%) were reclassified as AAD. Of these 220 cases, DNA was available for the present study from 128. Of these 128 patients (median age at diagnosis: 32 yr, range 8–69 yr; male to female ratio: 0.83), 65 (51%) had other autoimmune diseases. APS I was excluded in all cases on the basis of clinical manifestations, and no APS I patient was included in our study.

Blood samples collected during routine analyses, between March 1994 and December 2001, were available from 406 unrelated healthy control subjects (median age: 30 yr, range 5–62 yr; male to female ratio: 1.14) with no family history of endocrine autoimmune diseases. All patients and healthy individuals gave their informed consent for the study, and the study was approved by the local ethics committee.

HLA-DR and -DQ genotyping

HLA-DR and -DQ genotyping was performed by sequence-specific oligonucleotide-dot blot analysis with modifications of a previously described method (15), and using sequence-specific oligonucleotides, 3'-end-labeled with digoxigenin (Roche Diagnostics S.p.A., Monza, Italy). A chemiluminescent signal was generated by using alkaline phosphatase-labeled anti-digoxigenin (Roche Diagnostics S.p.A.) and disodium 3(4-methoxyspiro{1,2-dioxetane-3,2'-(5'-chloro)tricyclo[3.3.1.1^3,7]decan}-4-yl)phenyl phosphate (CSPD) (Roche Diagnostics S.p.A.). Chemiluminescence was measured in a microplate scintillation and luminescence counter (TopCount NXT; Packard Instrument Company, Meriden, CT). Each membrane contained 10 control samples with known HLA genotype.

HLA-DRB1*04 subtyping was performed by PCR-SSP with sequence-specific primers, according to the method described by Zetterquist and Olerup (16).

Genotyping of MHC2TA –168 AG (rs3087456) SNP by 5' nuclease assay for allelic discrimination

The –168 AG SNP of the MHC2TA gene (rs3087456) was selected for genotyping. Taq-Man MGB biallelic discrimination system was used as described earlier (17, 18). Probes and oligonucleotides were synthesized in 40x concentrations by Applied Biosystems (Foster City, CA) using the Assay-by-Design ordering system (Table 1). PCRs were performed on ABI prism Sequence Detection System 7000 (Applied Biosystems). The 25-µl PCR contained 1x of the TaqMan Universal PCR Master Mix, No AmpErase UNG, 1x of the assay probe and primer mix, and 25 ng of genomic DNA and was performed on 96-well optical PCR plates. Each genotyping plate contained no DNA template controls, and random samples were run as duplicates to confirm the successful genotyping process. SDS version 2.0 software was used to analyze real-time data and end-point fluorescence. Genotyping data were exported from SDS software into Excel data sheets for further analysis.

The odds ratio (OR) was calculated according to Woolf (19) and Miettinen (20). Differences in allele/haplotype/genotype frequencies between patients and healthy control subjects were tested by the ² method. Yates’ correction or the Fisher’s exact test was used when necessary. For the HLA haplotyping and DRB1*04 subtyping, the probability values were corrected for the number of comparisons, according to the number of HLA-DRB1,-DQA1,-DQB1 alleles or haplotypes observed. For the MHC2TA gene polymorphism analysis, both a codominant model and a G-dominant model were applied.

The association of the dichotomous variables presence/absence of DQA1*0501-DQB1*0201, DRB1*0403, DQA1*0301-DQB1*0302, and MHC2TA AG+GG with AAD, and its dependence on other variables such as sex and age at diagnosis, was tested by multivariate logistic regression analysis using SPSS for Windows (SPSS Inc., Chicago, IL). In a separate analysis, MHC2TA AG+GG was substituted by the number of G alleles (0, homozygous AA; 1, heterozygous A/G; 2, homozygous G/G).

Deviations from the Hardy-Weinberg equilibrium were tested by comparison of observed and expected genotype frequencies. Although class II gene loci and MHC2TA gene locus are located on different chromosomes, pairwise linkage disequilibrium was also tested by using a permutation test using the EM algorithm. A P value <0.05 was considered significant in all tests.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Allele G of MHC2TA –168 was found significantly increased in the group of AAD patients, being detected in 39% AAD alleles and in 29% of healthy control alleles (P = 0.003) (Table 2). Thus, allele G was detected in 49% of healthy control subjects and in 62% of Addison patients (in either heterozygous or homozygous combination). The frequency of the AG+GG genotypes was significantly higher among AAD patients than among healthy control subjects, in both the codominant model (P = 0.012) and in the G-dominant model [P = 0.018; OR = 1.66, 95% confidence interval (CI) = 1.11–2.49]. This association was not influenced by the presence/absence of other autoimmune diseases as allele G frequency was similar in isolated Addison’s and in Addison’s plus other autoimmune diseases (40 vs. 39%, respectively).

View this table: [in this window] [in a new window]   TABLE 2. Genotype and allele frequencies for the MHC2TA –168 AG SNP (rs3087456) in AAD

Among DRB1*04 subtypes, both DRB1*0401 and *0402 were more frequent among patients than among healthy control subjects, but the differences did not reach the statistical significance after correction of the P value. Similarly DRB1*0404 was not significantly more frequent among AAD patients than among healthy control subjects. DRB1*0403 was absent among 30 AAD DRB1*04-positive patients, but was the most frequent DRB1*04 allele detected in healthy controls (28% of DRB1*04-positive individuals) (P < 0.003).

Pairwise linkage disequilibrium analysis, with a permutation test using the EM algorithm, showed no significant linkage disequilibrium between MHC2TA AG or GG and DRB1*03-DQA1*0501-DQB1*0201 or DRB1*04-DQA1*0301-DQB1*0302 in either the patient or the control group. None of the tested variables showed significant deviations from Hardy-Weinberg equilibrium in any group.

To define better the independent contribution of MHC2TA to genetic susceptibility for AAD, we then performed multivariate logistic regression analysis. When the variables found associated at the univariate analysis were included as variables in the model, they were all found independently associated with AAD, after correction for age and sex (Table 3). Thus, MHC2TA AG+GG continued to be positively associated with genetic risk for the disease (P = 0.028, OR = 1.72, 95% CI = 1.06–2.78), even after correction for DRB1*03-DQA1*0501-DQB1*0201, DRB1*04 (not 0403)-DQA1*0301-DQB1*0302 and DRB1*0403. The association of the MHC2TA SNP with AAD was also confirmed when the multivariate logistic regression analysis took into consideration the number of G alleles (0, homozygous AA; 1, heterozygous A/G; 2, homozygous G/G) (P = 0.004; OR = 1.65, 95% CI = 1.17–2.32). In addition, the correction for age and sex in the multivariate analysis also excludes the possibility that the association of MHC2TA with AAD was influenced by a different sex distribution among patients and healthy control subjects.

	Discussion

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Primary adrenal insufficiency occurs in approximately 1/7000 to 1/8000 subjects in Europe (21, 22). Around 70% of cases have an autoimmune origin and are classified as AAD (13), with an estimated prevalence of AAD in the general population of 1/10,000 to 1/11,000. AAD represents a major component of the so-called autoimmune polyglandular syndromes, and clinical or biochemical features of other endocrine or nonendocrine autoimmune diseases can be detected in over 50% of AAD patients (11). It is not surprising that AAD shares common genetic markers with other endocrine autoimmune diseases, namely the HLA-DRB1*03-DQA1*0501-DQB1*0201 and the DRB1*04-DQB1*0301-DQB1*0302 haplotypes. However, given the frequency of the "high-risk" HLA haplotypes in the general population (approximately 20% of individuals are positive for HLA-DRB1*03-DQA1*0501-DQB1*0201 and/or DRB1*04-DQB1*0301-DQB1*0302 in central Italy), only a small minority of positive individuals will develop the clinical signs of AAD. Accordingly, other genes (as well as environmental factors) must play a role in modulating the risk conferred by HLA class II genes. One such genetic factor is the DRB1*0403 allele that confers dominant protection from AAD even when part of the high-risk DRB1*04-DQA1*0301-DQB1*0302 haplotype (IAN Study 2) (14). Other MHC and non-MHC genes, such as MHC class I-chain related A (23, 24), CTLA-4 (25) and vitamin D receptor (26) may also modulate the genetic risk conferred by DR and DQ haplotypes. Thus, genetic studies are deemed important for both unraveling the molecular mechanisms of the pathogenesis of endocrine autoimmune diseases and identifying novel markers for the discrimination of subjects genetically at high risk for AAD.

Modulation of the expression of HLA class II determinants in antigen-presenting cells may represent a critical factor in the activation and maintenance of the organ-specific autoimmune process. All the classical and nonclassical class II promoters contain three elements denominated S, X, and Y boxes (27). The regulatory factor X (RFX) binds to the X1 and S boxes, whereas the Y element is bound by the heterotrimer nuclear factor Y (NF-Y)/CCAAT binding factor (28), and X2 by cAMP response element binding protein (29). However, RFX and NF-Y are expressed constitutively, and their presence alone is not sufficient for the interferon--inducible and developmental expression of MHC II genes. Rather, the interaction of the NF-Y/cAMP response element-binding protein/RFX factors determines the formation of a platform for the allocation and action of the CIITA transactivator, which does not bind the DNA itself, but interacts with other DNA-binding proteins, directing the initiation and elongation of MHC class II transcription (30, 31).

The role of CIITA as a master regulator of HLA-D expression provides a sound rationale for the study of MHC2TA gene polymorphism and its association with the development of human autoimmune diseases. So far, SNPs have been identified in the promoter type III (the –168 AG SNP analyzed in our present study), in the coding region and in an intronic region at nucleotide 485 (5, 6), with no demonstrable linkage disequilibrium among them (5). The four SNPs identified in the coding region of MHC2TA are either silent (at nt 2509, 2536, and 2791) or responsible for a conservative alanine to glycine substitution at amino acid 500, which provides a weak rationale for a role of these polymorphisms in genetic predisposition for human autoimmune diseases. The more recently identified SNP in an intronic region at nucleotide 485 has been demonstrated in only 3% of Japanese healthy subjects (6), and only the study of several hundred AAD patients would exclude an association between this specific SNP and human diseases. Accordingly, we have chosen to test the association of the –168 AG SNP with AAD.

In our study with 128 AAD patients and 406 healthy subjects from continental Italy, we demonstrate the presence of the –168 A/G substitution in 49% of healthy individuals, with a G allele frequency of 29%. These frequencies are in line with those reported in other Caucasian populations (5, 7, 10), whereas a lower frequency of the G allele has been observed in the Japanese population (6). On the other hand, we found the G allele in 62% of patients with AAD, representing 45% of heterozygous subjects and 17% of homozygous subjects.

In a Swedish study from Swanberg et al. (7), the presence of the MHC2TA G allele was significantly increased in patients with multiple sclerosis or rheumatoid arthritis. A subsequent study in a German population (10) failed to confirm this association, opening a controversy on the actual role of the MHC2TA gene polymorphism in genetic predisposition for human autoimmune diseases. More recently, Koizumi et al. (6) have studied the polymorphism of the MHC2TA gene in 100 Japanese patients with systemic lupus erythematosus and in 100 Japanese healthy control subjects, but have failed to demonstrate any significant association of the tested SNPs with this human disease. Our study provides the first data on the association of the MHC2TA gene polymorphism with an organ-specific, endocrine autoimmune disease, such as AAD. Our data can be interpreted to indicate that the presence of the –168 AG substitution is positively associated with genetic risk for AAD, with an estimated OR of 1.65–1.7. The significant association observed at the univariate analysis was confirmed in the multivariate logistic regression analysis, which demonstrated that the significant increase of the G allele among Italian AAD patients was not dependent on the presence of DRB1*0301-DQA1*0501-DQB1*0201, DRB1*04-DQB1*0301-DQB1*0302, or DRB1*0403. This conclusion is further supported by the absence of significant linkage disequilibrium between the MHC2TA SNP in the promoter type III region and the studied HLA class II haplotypes.

At present, we cannot rule out the possibility that the observed association between MHC2TA –168 SNP and AAD is a consequence of linkage disequilibrium with a yet unidentified predisposing gene on chromosome 16. However, in vitro stimulation experiments (7) have shown that the MHC2TA –168 G/G genotype is associated with the reduced induction of HLA-DRA and HLA-DQA1 genes by inflammatory stimuli, and it has been speculated that this MHC2TA-associated reduction of expression of MHC molecules may influence the risk for the development of autoimmune and inflammatory diseases (7). Although this hypothesis has not yet been substantiated, our demonstration that MHC2TA gene polymorphism is associated with genetic risk for AAD paves the way to further genetic studies with other human endocrine autoimmune diseases.

	Acknowledgments

 
In addition to the authors, the following members of the Italian Addison Network contributed to the collection of data and blood samples from patients with primary adrenal insufficiency: B. Ambrosi (Milan), A. Angeli (Orbassano), G. Arnaldi (Ancona), E. Arvat (Turin), A. Baccarelli (Milan), L. Barbetta (Milan), P. Beck-Peccoz (Milan), A. Bellastella (Naples), A. Bizzarro (Naples), M. Boscaro (Ancona), F. Cavagnini (Milan), C. Dal Prà (Padova), F. Dotta (Siena), E. Ghigo (Turin), R. Giordano (Turin), S. Laureti (Perugia), R. Libè (Milano), F. Loré (Siena), M. Mannelli (Florence), F. Mantero (Padova), G. Mantovani (Milan), P. Paccotti (Orbassano), R. Perniola (Lecce), F. Santeusanio (Perugia), C. Tiberti (Rome), P. Toja (Milan), M. Torlontano (S. Giovanni Rotondo), V. Toscano (Rome), V. Trischitta (S. Giovanni Rotondo), and R. Zanchetta (Padova).

	Footnotes

 
First Published Online July 18, 2006

Abbreviations: AAD, Autoimmune Addison’s disease; APS I, autoimmune polyendocrine syndrome type I; CI, confidence interval; CIITA, class II transactivator; IAN, Italian Addison Network; NF-Y, nuclear factor Y; OR, odds ratio; RFX, regulatory factor X; SNP, single nucleotide polymorphism.

Received April 20, 2006.

Accepted July 11, 2006.

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