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Original Studies |
Immunology and Immunogenetics Laboratory, Department of Internal Medicine and Endocrine and Metabolic Sciences (G.G., A.F., S.L., C.T., F.S., P.B.), University of Perugia, I-06126 Perugia, Italy; and Department of Molecular Medicine (G.G., M.G., C.B.S.), Karolinska Institute, S-17176 Stockholm, Sweden
Address correspondence and requests for reprints to: Carani B. Sanjeevi, M.D., Ph.D., Department of Molecular Medicine, Karolinska Hospital, CMM L8:03, S-171 76 Stockholm, Sweden. E-mail: sanjeevi.carani{at}molmed.ki.se
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Abstract |
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Introduction |
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In the majority of cases, Addison’s disease is a component of an autoimmune polyendocrine syndrome (APS) (4, 8, 9, 10). APS type I is a rare genetic disease resulting from a single autosomic recessive gene localized on chromosome 21 (11), the clinical onset of which is typically observed during childhood or adolescence. Conversely, APS type II is more frequently found in adult patients and is a complex multigenic disease, the mode of inheritance of which is still unclear. It is controversial whether isolated Addison’s disease is a distinct affection or represents only an early phase of APS II. Accordingly, we will refer to the multigenic form of the disease as to APS II-Addison’s disease.
Several endocrine autoimmune components of APS II (such as Addison’s disease, thyroid diseases, type 1 diabetes mellitus, or premature ovarian failure) share a common genetic background (12, 13). A long series of studies has shown that autoimmune Addison’s disease is associated with both class I and class II histocompatibility leucocyte antigen (HLA) alleles, and especially with HLA-B8 (14, 15, 16, 17), HLA-DRB1*03 (DR3), and HLA-DQA1*0501-DQB1*0201 (DQ2) (12, 13, 18, 19, 20, 21). The association with HLA-DR3-DQ2 seems to be stronger than that with HLA-B8, and the B8 allele is associated with APS II-Addison’s when part of the HLA-B8-DR3 haplotype (18). The association between APS II-Addison’s disease and the polymorphism of the 21-hydroxylase gene (CYP21), in the class III HLA gene region, is probably due to a linkage disequilibrium with HLA class II haplotypes (22). Although some endocrine diseases, such as type 1 diabetes and thyroid diseases, are associated with polymorphism of the CTLA-4 gene on chromosome 2 (23, 24, 25), APS II-Addison’s disease seems to be associated with the CTLA-4 Ala17 allele only in the presence of the HLA-DQA1*0501 allele (25). Furthermore, a recent study (26) showed an association between the CTLA-4 microsatellite gene polymorphism and APS II-Addison’s disease in only some populations (English) but not in others (Norwegian, Finnish, and Estonian). Thus, the strongest genetic association of APS II-Addison’s disease so far identified is with HLA-DR and DQ genes, and the HLA-DRB1*03-DQA1*0501-DQB1*0201 haplotype can be considered a genetic marker of disease risk.
Apart from the associations with classical HLA class I and class II alleles, susceptibility to autoimmune diseases has been linked to the genomic segment of chromosome 6 between the HLA-B and the B-associated transcript genes (27, 28, 29). The cloning and characterization of the major histocompatibility complex-class I chain-related MIC-A (30) and MIC-B (31) genes, localized between HLA-B and B-associated transcript genes, and the demonstration of their gene polymorphism (32, 33, 34, 35) warranted studies aimed at testing the association of these genes with autoimmune diseases (35, 36, 37). The exon 5 microsatellite polymorphism of the MIC-A gene consists of five alleles based on the number of GCT triplet repeat units (alleles A4, A5, A6, and A9) and the presence of an additional nucleotide insertion (allele A5.1) (32). The intron 1 microsatellite polymorphism of the MIC-B gene consists of 13 alleles based on the number of CA/TG repeat units (35).
In the present study, we evaluated the association of APS II-Addison’s disease with both MIC-A and MIC-B gene polymorphism. Our data are consistent with a primary association of autoimmune Addison’s disease with the exon 5 microsatellite polymorphism of the MIC-A gene.
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Materials and Methods |
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Genomic DNA was obtained from ethylenediaminetetraacetate-treated peripheral blood samples from 28 Italian subjects with autoimmune Addison’s disease (10 males and 18 females). Autoimmune Addison’s disease patients were identified by the presence of 21OHAb, as determined using a radiobinding assay with in vitro translated recombinant human 35S-21OH (3, 4, 5). DNA was purified using a standard phenol-chloroform extraction protocol, dissolved in sterile double-distilled water, and stored at 4 C.
Disease duration ranged from 0–31 yr (age at diagnosis of Addison’s disease: median, 31 years; range, 8–65 yr). All the patients underwent routine analyses to evaluate the function of adrenal cortex (such as plasma levels of cortisol, aldosterone, renin activity, and ACTH), and all patients were treated with 25–50 mg/day cortisone acetate and 0.1–0.2 mg/day fludrocortisone. The patients enrolled in our study were selected from a total group of 59 Addison’s disease patients diagnosed at the Department of Internal Medicine and Endocrine and Metabolic Sciences, University of Perugia (Perugia, Italy), including 42 cases of autoimmune Addison’s disease (4). The following criteria were used, as described previously (4): 1) presence of 21OHAb; 2) absence of CT signs of infiltrative adrenalitis; 3) normal plasmatic concentrations of very long chain fatty acids; and 4) residence in Umbria, a geographically delimited region of central Italy. A total of 14 autoimmune patients was not enrolled in the study (and DNA samples were not collected) because of one of the following reasons: 1) death before collection of DNA samples; 2) patient’s refusal to accept blood sampling for genetic analysis; 3) loss of contact with the patient because of a change of residence; or 4) belonging to a different ethnic group.
Of the 28 autoimmune Addison’s disease patients enrolled in the study,
15 had hypothyroidism, 3 had Graves’ disease, 4 had type 1 (insulin
dependent) diabetes mellitus, 1 had vitiligo, 1 had atrophic gastritis,
and 9 females had premature ovarian failure (APS type II cases). Using
radiobinding assays with in vitro-translated autoantigen
(38, 39), glutamic acid decarboxylase antibodies (GAD65Ab) and
IA-2/ICA512 antibodies (IA-2/ICA512Ab) were detected in four and two
subjects with type 1 diabetes, respectively. The cDNA for human GAD65
(40) was a kind gift from Dr. Åke Lernmark (University of Washington,
Seattle, WA) and that for ICA512bdc (39) from Dr. George S. Eisenbarth
(Barbara Davis Center for Childhood Diabetes, Denver, CO). Using
similar radiobinding assays, side-chain cleavage antibodies (sccAb) and
17
-hydroxylase antibodies (17OHAb) were found in five and four
females with premature ovarian failure, respectively. The cDNA for
human sccAb (41) and that for human 17OH (42) were a kind gift
from Dr. Walter Miller (Department of Pediatrics and Metabolic Research
Unit, University of California, San Francisco, CA). Thyroid peroxidase
(TPO) autoantibodies (TPOAb), as determined using an immunoradiometric
assay with recombinant human 125I-TPO (Radim,
Angleur, Belgium), were found in 14 of the 28 patients with autoimmune
Addison’s disease.
In none of the 28 patients was a diagnosis of APS type I made. Ten subjects had isolated Addison’s disease, with no clinical or laboratory signs of other organ-specific autoimmune diseases. These latter 10 subjects were found negative for GAD65Ab, IA-2/ICA512Ab, TPOAb, sccAb, and 17OHAb.
A total of 75 unrelated and healthy control subjects residing in Umbria (45 males and 30 females; age: median, 33 yr; range, 7–62 yr) was also included in our study. None of the healthy control subjects resulted positive for 21OHAb.
MIC-A and MIC-B genotyping
The transmembrane (TM) region of the MIC-A gene (exon 5) and the intron 1 of the MIC-B gene were amplified by the PCR using primers labeled at the 5' end with the fluorescent reagent 6-HEX (Amersham Pharmacia Biotech). For MIC-A genotyping, PCR primers were 5'-CCTTTTTTTCAGGGAAAGTGC-3' and 5'-CCTTACCATCTCCAGAAACTGC-3' (32). For MIC-B genotyping, PCR primers were 5'-AATAGCCATGAGAAGCTATGTGGGGGAG-3' and 5'-CTACCTCCTTGCCAAACTTGCTGTTTGTG-3' (35). After amplification, the number of the GCT triplet repeat units in the TM region of the MIC-A gene (32) and the number of CA/TG repeats in the intron 1 of the MIC-B gene (35) were determined using an ABI prism automated DNA sequencer. For the MIC-A gene polymorphism, alleles were designated as A4, A5, A6, and A9 according to the number of repetitions of GCT in the TM domain of MIC-A. The MIC-A5.1 allele consists of five repetitions of GCT with one additional nucleotide insertion (G). For the MIC-B gene polymorphism, 13 alleles were designated as MICB-CA-14 to MICB-CA-28 according to the number of CA/TG repeats in intron 1 (35). However, the MICB-CA-14 allele was absent in our population of Italian subjects, and, accordingly, only 12 MIC-B alleles were taken into consideration.
HLA-DR and -DQ genotyping
The polymorphic second exon of the DQA1, DQB1, and DRB1 genes was amplified by PCR. The amplified products were manually dotted onto nylon membranes (Amersham Pharmacia Biotech) under denaturing conditions. The membranes were hybridized with sequence-specific oligonucleotides, 3'end-labeled with 32P-dCTP, and washed in stringency conditions before exposure to x-ray film, as described previously (43). The membranes were stripped of the labeled probe under alkaline conditions and reused for probing with other oligonucleotides.
Statistical analysis
The odds ratio (OR) was calculated according to Woolf (44) and
Miettinen (45). When all the patients or the controls were negative for
a particular allele or haplotype, Haldane’s (46) correction was used.
Differences in allele/haplotype frequencies between the Addison’s
disease and control groups were tested by the
2 method. Yates’ correction or the Fisher’s
exact test were used when necessary. The test of the strongest HLA
association, comparing MIC-A and HLA class II alleles/haplotypes, was
performed according to Svejgaard and Ryder (47). The probability values
were corrected (Pc) for the number of comparisons, according to the
alleles, haplotypes, or genotypes observed among healthy subjects: 5
for MIC-A alleles, 12 for MIC-B alleles, 15 for MIC-A genotypes, 16 for
HLA-DRB1, 8 for HLA-DQA1, 17 for HLA-DQB1, 19 for HLA-DQA1-DQB1
haplotypes, and 26 for HLA-DRB1-DQA1-DQB1 haplotypes. A Pc value less
than 0.05 was considered significant. The absolute risk for autoimmune
Addison’s disease was calculated according to the prevalence of
Addison’s disease in Umbria (117 cases per million inhabitants) (2)
and the frequency of adrenal autoimmunity in Addison’s disease
patients (70%) (4).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The frequencies of exon 5 microsatellite alleles of the MIC-A gene
in Italian APS II-Addison’s disease patients and healthy control
subjects are shown in Table 1
. Most
Addison’s disease patients were positive for the MIC-A5.1 allele
(79%), as compared with only 36% healthy subjects (OR = 6.52,
Pc = 0.0015). The allele frequency (number of A5.1 alleles per
total number of MIC-A locus alleles) for MIC-A5.1 in our population of
APS II-Addison’s disease patients was 61% (34 of 56), which is almost
3-fold higher than that observed in healthy controls (31 of 150; 21%)
(Pc < 0.0005). The association of MIC-A5.1 with autoimmune
Addison’s disease was not dependent on the concomitant presence of
other autoimmune diseases because 8 of 10 (80%) subjects with isolated
Addison’s disease were also carrying this allele. This frequency was
similar to that observed in the subgroup of APS II patients (14 of 18;
78%). Also the frequency of MIC-A4-positive subjects was higher in the
presence of APS II-Addison’s disease, but the difference with healthy
subjects did not reach statistical significance. Conversely, MIC-A6 and
MIC-A9 were negatively associated with autoimmune Addison’s disease
[OR = 0.13, Pc = 0.002 and OR = 0.33, Pc = not
significant (NS), respectively]. The allele frequency for MIC-A6 in
APS II-Addison’s patients was 7% (4 of 56) as compared with 37% (56
of 150) in healthy subjects (Pc < 0.0005).
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None of the intron 1 microsatellite alleles of the MIC-B gene was
significantly and positively associated with APS II-Addison’s disease
after correction of P values (Table 2). The highest OR associated with a
MIC-B allele was that of MICB-CA-25 (OR = 3.09, P
= 0.037, Pc = NS). Only 14% (4 of 28) APS II-Addison’s disease
patients were positive for the MICB-CA-25 allele in the absence of
MIC-A5.1, which is almost identical to the prevalence observed in
healthy subjects (10 of 75; 13%). However, the concomitant presence of
both MIC-A5.1 and MICB-CA-25 was significantly more frequent in APS
II-Addison’s disease patients (7 of 28; 25%) than in healthy subjects
(3 of 75; 4%) (OR = 8.0, P = 0.0039, Pc =
0.047). A strongly negative association with APS II-Addison’s disease
was observed for the MICB-CA-17 allele, which was absent in affected
subjects but present in more than 25% healthy individuals (OR =
0.10 after Haldane’s correction, P = 0.0025, Pc =
0.03).
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Among HLA class II haplotypes, only DRB1*03-DQA1*0501-DQB1*0201
(DR3/DQ2) was significantly increased in Italian APS II-Addison’s
disease patients (OR = 4.77, P = 0.0019, Pc =
0.049) (Table 3). The absolute risk for
autoimmune Addison’s disease resulted in 1 per 4201 among subjects
carrying the DRB1*03-DQA1*0501-DQB1*0201 (DR3/DQ2) haplotype. The
association of DR3/DQ2 with autoimmune Addison’s disease was not
dependent on the concomitant presence of other autoimmune diseases
because 5 of 10 (50%) subjects with isolated Addison’s disease were
also carrying this haplotype. Furthermore, the association of APS
II-Addison’s disease with the HLA-DR3/DQ2 haplotype seemed to be
dependent on the presence of the MIC-A5.1 allele: only 1 of 28 (3.6%)
APS II-Addison’s disease patients were positive for HLA-DR3/DQ2 in the
absence of MIC-A5.1 (Table 4). This
prevalence is even lower than that observed in healthy subjects (8 of
75; 11%). The frequency of the MIC-A5.1 allele was only slightly, and
not significantly, increased among Addison’s disease patients in the
absence of the HLA-DR3/DQ2 haplotype (Table 4). The test of the
strongest HLA association, performed according to Svejgaard and Ryder
(47), confirmed that both MIC-A5.1 and HLA-DR3/DQ2 were associated with
APS II-Addison’s disease (Table 5,
comparisons 1, 2, 3, and 5). In addition, this analysis demonstrated
that the combined association of MIC-A5.1 and DR3/DQ2 (Table 5,
comparison 8) was associated with the highest OR for APS II-Addison’s
and the lowest Pc value. No significant linkage disequilibrium between
MIC-A5.1 and HLA-DR3/DQ2 was present in the Italian population studied
(Table 5, comparison 10). Thus, the test of the strongest HLA
association revealed an interaction between the MIC-A and the HLA class
II gene polymorphism. Only the concomitant presence of MIC-A5.1 and
HLA-DR3/DQ2 was significantly and positively associated with APS
II-Addison’s disease. This combination was associated with an absolute
risk of 1 per 1740.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The function of the MIC-A gene product is little understood, and it is still unclear how the gene polymorphism may affect biological significance. Nevertheless, our study shows that polymorphism of the MIC-A gene marks the genetic risk for autoimmune Addison’s disease. According to the population-based prevalence in Umbria (2) and the frequency of autoimmune Addison’s disease (4), we calculated the absolute risk to develop the disease to be, in central Italy, 1 per 1,131 in subjects carrying the genotype A5.1/A5.1 and less than 1 per 61,000 in the presence of the A6/A6 genotype.
The MIC-A gene transcript is expressed mostly in epithelial cells, and
no expression has been found in B- or T-lymphocytes (30, 48). MIC-A is
characterized by an unusual distribution of amino acid substitutions in
the putative ligand binding site (34), which is consistent with the
hypothesis of a lateral interaction with the T-cell or natural
killer antigen receptors. More specifically, MIC-A may present
invariant ligands, such as glycolipids or carbohydrates, to 
T-cell receptors (30, 34, 49). The strong association of APS
II-Addison’s disease with MIC-A5.1 is of particular interest because
this allele may encode for a soluble molecule. The presence of an
additional nucleotide causes a frameshift mutation, which results in 15
amino acid changes and in a less hydrophobic transmembrane segment. The
role of a putative deficiency of membrane-bound MIC-A molecules in the
pathogenesis of APS II-Addison’s disease remains totally unknown at
this stage.
Addison’s disease is frequently associated with other endocrine autoimmune diseases in the autoimmune polyendocrine syndromes. Genetic risk to APS I does not seem to be linked to the class II HLA region (50). Because none of our autoimmune Addison’s disease patients had an APS I, we cannot provide data on the association of the MIC gene polymorphism with this syndrome. APS II is strongly associated with the class II HLA gene polymorphism (12, 13). To date, there is no sound evidence that isolated autoimmune Addison’s disease has different genetic associations than APS II. In addition, classification of isolated Addison’s disease can be done only after exclusion of clinical and laboratory signs of other endocrine autoimmune diseases, and a patient with isolated Addison’s disease can develop an APS II subsequently. Accordingly, patients with non-APS I autoimmune Addison’s disease can be studied as a single population.
Several studies have shown that the risk for APS II-Addison’s disease is increased in the presence of HLA-DR3/DQ2 (12, 13, 18, 19, 20, 21). On the other hand, controversial data on the association between HLA-DR4/DQ8 and Addison’s disease are available (13, 18, 20, 51). In a recent study (51), the risk for autoimmune Addison’s disease seemed to be linked to the DRB1*0404 subtype. However, in that study (51), many Addison’s disease cases were identified by screening type 1 diabetic subjects for presence of 21OHAb. In addition, several cases of familial Addison’s disease were also included. In our study, genotyping was performed in sporadic, unselected cases of APS II-Addison’s disease. HLA-DR4/DQ8 was not significantly increased in our Addison’s disease patients from central Italy as compared with healthy subjects, and our results support the hypothesis that only HLA-DR3/DQ2 is a class II marker of autoimmune adrenal insufficiency in the general population. This conclusion is in line with other studies of Italian Addison’s disease patients (21). However, it must be noted that DR4/DQ8 is infrequent in the Italian population (only 9% of our healthy control subjects were found positive for this haplotype). Accordingly, the results of different studies may be influenced not only by a different selection of the patients but also by a different prevalence of at-risk haplotypes in the general population.
Our study demonstrates that MIC-A gene polymorphism complements HLA-DR/DQ polymorphism in determining the genetic risk to APS II-Addison’s disease. Indeed, only the concomitant presence of both MIC-A5.1 and HLA-DR3/DQ2 was positively associated with this organ-specific autoimmune disease. At this stage, it is still unknown whether MIC-A gene polymorphism is associated with Addison’s disease because of a linkage disequilibrium with still unidentified gene(s) or because of a pathogenic role of the gene products in the development of adrenal autoimmunity.
No linkage disequilibrium between the MIC-A and MIC-B genes has so far
been shown (33, 35). This may be due to a recombination hot spot
between the MIC-A and the MIC-B genes (52). In Behçet’s disease,
a discrepancy between the association with MIC-A gene polymorphism (36)
and the absence of an association with MIC-B gene polymorphism (35) was
observed. In our study, the presence of MICB-CA-25 increased the risk
for Addison’s disease in subjects carrying the MIC-A5.1 allele.
Furthermore, a strongly negative association with MICB-CA-17 was also
observed. The absence of a linkage disequilibrium between MIC-A and
MIC-B genes, also documented in our population of Italian subjects, is
consistent with the hypothesis that the association of MIC-A
polymorphism with Addison’s disease is not due to a linkage with genes
located centromeric to the MIC-B gene (e.g., in the HLA
class III region). This hypothesis is also supported by the absence of
linkage disequilibrium between MIC-A and HLA-DR/DQ gene polymorphism
(Table 5
).
The HLA-B gene is located only 46 kb telomeric to the MIC-A gene (30). The analysis of HLA homozygous cell lines (36) revealed strong linkage disequilibrium between MIC-A and HLA-B loci. MIC-A5.1 is in linkage with HLA-B7 and -B8, and MIC-A6 with B51 and B44. It has previously been shown that HLA-B8 is associated with autoimmune Addison’s disease when part of the HLA-DR3/B8 haplotype (18). Because of the high frequency of MIC-A5.1 in Addison patients, higher than any other frequency of class I or class II alleles so far recorded, we hypothesize that MIC-A gene polymorphism is primarily associated with APS II-Addison’s disease. This hypothesis is indirectly supported by the fact that no HLA-DR or -DQ allele was negatively associated with Addison’s disease, in contrast to the negative association with MIC-A6. The high frequency of the negatively associated MIC-A6 and MICB-CA-17 alleles in the general population may, in part, explain the low prevalence of the disease.
The test of the strongest HLA association revealed an interaction between MIC-A5.1 and HLA-DR3/DQ2. Thus, only the concomitant presence of both MIC-A5.1 and HLA-DR3/DQ2 was strongly and significantly associated with risk for APS II-Addison’s disease.
In conclusion, our study demonstrates that MIC-A gene polymorphism marks the genetic risk for APS II-Addison’s disease. According to our data, the combination of MIC-A5.1 and HLA-DR3/DQ2 is now to be seen as the most important genetic marker, so far identified, for this disease. Future studies will be aimed at better characterizing the role of MIC-A and MIC-B gene polymorphism in the pathogenesis of Addison’s disease, as well as of other organ-specific autoimmune diseases.
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Footnotes |
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Received March 22, 1999.
Revised June 22, 1999.
Accepted July 2, 1999.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-hydroxylase/17,20 lyase): cloning of
human adrenal and testis cDNA indicates the same gene is expressed in
both tissues. Biochemistry. 84:407–411.
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