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Original Studies |
Barbara Davis Center for Childhood Diabetes (L.Y., K.W.B., T.W., S.R.B., P.A.G., M.J.R., G.S.E.) and Clinical Immunology and Histocompatibility Laboratory (B.M.F.), University of Colorado, Denver, Colorado 80262; Stratton Veterans Affairs Medical Center (S.G., A.W.), Albany, New York 12208; and Roche Molecular Systems (H.A.E.), Alameda, California 95401
Address all correspondence and requests for reprints to: George S. Eisenbarth, M.D., Ph.D., Barbara Davis Center for Childhood Diabetes, University of Colorado Health Sciences Center, 4200 East 9th Avenue, Box B140, Denver, Colorado 80262. E-mail: george.eisenbarth{at}uchsc.edu
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Abstract |
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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We observed a family with 3 siblings with Addison’s disease. These 3 siblings all inherited a DRB110404 allele from their father, who was heterozygous for DRB110404 and DRB110401. To further evaluate this potential association, we studied all patients with Addison’s disease from whom we could obtain DNA through referral from colleagues, the type 1 diabetes Human Biologic Data Interchange (HBDI) family repository, and screening for expression of 21-hydroxylase autoantibodies of patients with type 1 diabetes (10, 11, 12, 13, 14, 15, 16, 17, 18). For many organ-specific autoimmune disorders, autoantibodies appear years before clinically recognized disease, and a series of relevant autoantigens have been isolated and cloned during the past decade (16, 19, 20, 21, 22, 23). With the cloned DNA for these autoantigens, it is frequently possible to develop specific and sensitive autoantibody radioassays (12, 24, 25, 26, 27). Not all patients expressing autoantibodies progress to overt disease. In particular, for type 1 diabetes, antiislet autoantibody-positive individuals with specific HLA alleles (e.g. DQB110602) infrequently progress to overt diabetes (28, 29, 30). Investigators have recently cloned and developed a recombinant autoantibody radioassay for autoantibodies reacting with the 21-hydroxylase enzyme (10, 12, 16, 17, 24, 25, 26). To identify individuals with Addison’s disease and to evaluate individuals with antiadrenal autoantibodies without Addison’s disease, we screened 957 patients with type 1 diabetes mellitus for 21-hydroxylase autoantibodies. Fifteen patients were positive and were studied. In addition, individuals with known Addison’s disease were similarly studied.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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DNA samples for HLA typing were obtained from nine individuals
with known Addison’s disease but not diabetic, nine individuals with
known Addison’s disease and diabetes, and three individuals found to
have Addison’s disease and diabetes after 21-hydroxylase autoantibody
screening (Fig. 1
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) and 241 normal
controls evaluated for the expression of 21-hydroxylase autoantibodies.
Of the 966 patients with diabetes, 9 had a known diagnosis of
Addison’s disease. Ten individuals had Addison’s disease without
diabetes. Of 957 screening serum samples of patients with type 1
diabetes (Fig. 1) analyzed for 21-hydroxylase autoantibodies, 725 were
collected at the Barbara Davis Center for Childhood Diabetes, and the
remaining 232 were provided by the HBDI Family Genetic Repository.
Samples were aliquoted and stored at -20 C. At the time of screening
the age of the 957 patients ranged from 0.7–71.2 yr (median, 16.6 yr).
Sera from 241 healthy control subjects (age range, 1–60 yr; median, 22
yr) without a family history of diabetes were also analyzed
for 21-hydroxylase autoantibodies.
Of the 15 (of 957) patients with type 1 diabetes found on screening to
have 21-hydroxylase autoantibodies (age range, 9–48 yr; median, 24
yr), we HLA-typed 14. In addition, approximately two thirds of the 942
patients (n = 666) with type 1 diabetes lacking 21-hydroxylase
autoantibodies were HLA typed. The HLA-typed group consisted of
sequential initial samples from families of the HBDI repository typed
by Dr. Erlich’s laboratory as well as samples from the Barbara Davis
Center after the institution of routine HLA DQ typing with
determination of autoantibodies. Over the past 4 yr, the HBDI, in
collaboration with the Juvenile Diabetes Foundation International, has
recruited families with 2 or more siblings with type 1 diabetes
mellitus from throughout the United States, and 578 patients with type
1 diabetes have been typed for HLA class II alleles. In addition, 9
patients with diabetes and known Addison’s disease and 9 patients with
a known diagnosis of Addison’s disease without diabetes were HLA typed
(Fig. 1, left).
Of multiplex families with Addison’s disease that we studied, one family was from HBDI family studies, one was from the Barbara Davis Center for Childhood Diabetes, one was from a prior family study at the Joslin Diabetes Center, and one family with four affected members in two generations was referred to us by Dr. Gates, Albany, NY.
A large general population control group (31) was also available for analysis from the Diabetes Autoimmunity Study of the Young (DAISY) study. The DAISY screened for HLA alleles in 15,547 individuals from the general population. These newborns with cord blood were analyzed for DR"3/4" (DQ2/DQ8) heterozygotes and analyzed for DRB1 subtypes of the DR3/4 heterozygotes.
HLA typing was performed together with autoantibody studies after obtaining informed consent and institutional review board approval from the Joslin Diabetes Center and University of Colorado institutional review boards.
21-Hydroxylase (P450c21) autoantibody radioassay
Autoantibodies against 21-hydroxylase (Hyd21AA) were measured by a method previously described (12, 24), and the 21-hydroxylase complementary DNA clone was provided by Dr. Ake Lernmark. In brief, 21-hydroxylase complementary DNA was transcribed and translated in vitro with a commercially available kit (Promega Corp., Madison, WI). [35S]Methionine was incorporated, and 20,000 cpm of the labeled product were incubated with 2 µL serum overnight, followed by separation of bound from free radioactivity with protein A-Sepharose (Pharmacia Biotech, Piscataway, NJ) in 96- well filtration plates (Millipore Corp., Bedford, MA). Scintillation fluid was added directly to the 96-well plate for counting with a Top-Counter (Packard, Downers Grove, IL). Autoantibodies are reported as an index relative to those in a positive control sample. Positivity for anti-21-hydroxylase autoantibodies was defined as exceeding the highest index of 241 normal controls (an index >0.149).
HLA typing
HLA typing for HBDI and DAISY samples was performed in the laboratory of Dr. H. Erlich at Roche Molecular Systems, Inc. (Alameda, CA), using PCR amplification and oligonucleotide-specific probes (32). Additional HLA DQ and DR typing was performed in the laboratory of G. Eisenbarth and B. Freed at University of Colorado using oligonucleotide-specific probes (DQ2 = DQA110501, DQB110201 and DQ8 = DQA110301, DQB110302).
Other assays
Anti-GAD65 (GAA), ICA512/IA-2 (ICA512AA), and insulin (IAA) autoantibodies were determined with radioassays using recombinant proteins, as previously described (33). The upper limits of normal for GAA, ICA512AA, and IAA are index 0.032, index 0.071, and 42 nU/mL, respectively. In the report from the latest Immunology of Diabetes Workshop in Canberra, Australia, each of these assays (laboratory AR) were among the most sensitive and specific assays. ACTH and cortisol were measured by commercial laboratories.
Statistical analysis
Statistical analysis was performed using the 
2
test and Fisher’s exact test with Epistat (Richardson, TX)
software, and Life Table analysis with Prism software (Graph Pad
Software, San Diego, CA).
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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and 2). Where multiple samples
from autoantibody-positive patients were available, patients remained
positive for these antibodies. Autoantibody levels of the positive
patients on screening all exceeded an index of 0.3 (none of 241
controls had an index >0.15). With the finding of 21-hydroxylase
autoantibodies, patients with type 1 diabetes were evaluated for
adrenal insufficiency. We determined fasting cortisol, ACTH, and
cortisol post-Cortrosyn (Organon Inc., West Orange, NJ)
stimulation. To date, 3 patients, including 2 brothers with type 1
diabetes, have been found to have adrenocortical insufficiency after
detection of 21-hydroxylase autoantibodies.
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with the above three
individuals who were found to have adrenocortical insufficiency. The
patients in Table 1 include 12 patients with type 1 diabetes and 10
without diabetes (including 1 patient we have not been able to HLA
type). All but 1 of the patients with Addison’s disease and antibody
determination expressed 21-hydroxylase autoantibodies (19 of 20; for 2
patients there was no serum was available for antibody determination,
and most of these patients had Addison’s disease over 10 yr). Three
fourths (15 of 21) of the HLA-typed patients with Addison’s disease
were DR"3/4" (DQ2/DQ8) heterozygotes (Table 1), and 14 of 15 of these had the
relatively uncommon DRB110404 DR4 allele.
Table 2 summarizes allele frequencies,
haplotype frequencies, and genotype frequencies of patients with
Addison’s disease in comparison to normal controls and patients with
type 1 diabetes without Addison’s disease. All of the patients with
Addison’s disease expressed DQA110501, either on a DR3 haplotype with
DQA110501, DQB110201 (DQ2) or with DQA110501, DQB110301. DQ8 was not
significantly increased compared to patients with type 1 diabetes but
was increased compared to controls (Table 2). All but 1 of the DR4
haplotypes of the patients with Addison’s disease had the DRB110404
subtype (14 of 15 individuals in eight families). DRB110404 is greatly
enriched in the patients with Addison’s disease in comparison to
patients with type 1 diabetes, in whom only 27% of DR4, DQ8 haplotypes
are DRB110404 (P < 10-6) (31).
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) in which patients, parents, and
unaffected siblings were available. In the 6 families (families 1–6)
with the haplotype DRB110404, DQ8 (including all of our known multiplex
Addison’s families), 13 of 19 family members with the identical
genotype DRB110404, DQ8/DRB110301, DQ2 had Addison’s disease. In
contrast, none of 28 family members without this genotype had
Addison’s disease (P < 10-6). Family 2
(described in the introduction) has 7 members with type 1 diabetes and
3 members with Addison’s disease. What is particularly striking
concerning family 2 with the 3 affected siblings is that the father is
homozygous for DR4, DQ8, but has DRB110404 on 1 haplotype and DRB110401
on the other. All 3 offspring who developed Addison’s disease
inherited the DRB110404 allele, whereas both the DRB110401 and
DRB110404 haplotypes were transmitted to multiple children with type 1
diabetes. For family 3, none of the family members has type 1 diabetes,
and none of the family members expresses islet autoantibodies reacting
with GAD65, ICA512/IA-2, or insulin. All 4 of the family members with
Addison’s disease express DRB110404, DQ8 with DQ2. In this family, the
DRB110404 bearing haplotype was introduced once, whereas the DR3, DQ2
haplotypes of the family consisted of 5 different haplotypes (a, c, d,
e, and h). Three of these DR3 haplotypes are found in the 4 members
with Addison’s disease (haplotypes could be traced as indicated
because of HLA class I typing, which is not shown). In family 5, there
are 2 identical twins who also have the genotype DRB110404, DQ8/DQ2,
and only 1 twin has Addison’s disease. The daughter of the twin
without Addison’s disease (this twin is also negative for Hyd21AA)
with the DRB110404, DQ8/DQ2 genotype developed Addison’s disease. In
family 6, the daughter who has the DRB110404, DQ8/DQ2 genotype, as did
her father with Addison’s disease, is metabolically normal, but she
has a high level of Hyd21AA. Family 7 is the only family in which a
parent with a DR4 haplotype did not transmit the DR4 haplotype to the
child with Addison’s disease. The DRB1 subtype of this haplotype was
DRB110403 and not DRB110404.
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summarizes the transmission of
HLA alleles from parents to Addisonian children for the 7 families. All
of the affected individuals with a DR4 haplotype had the DRB110404
allele. The haplotype DRB110404, DQ8 was always transmitted (11 of 11)
to affected offspring (P < 0.001). For all of these
familial patients with Addison’s disease and DRB110404, the DQ
haplotype of the other chromosome 6 was DQ2 (Table 1).
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summarizes HLA class II typing
and autoantibody expression for patients with type 1 diabetes who were
found to have 21-hydroxylase autoantibodies but do not have a diagnosis
of Addison’s disease. Similar to patients with Addison’s disease, 8
of the 11 patients are DR"3/4" (DQ2/DQ8) heterozygotes. In contrast
to the patients with a diagnosis of Addison’s disease, 9 of 11
non-Addisonian patients have DRB110401 or DRB110402. Two patients with
21-hydroxylase autoantibodies but not diagnosed with Addison’s disease
are DR"3/4" heterozygotes with DQB110404. The father (now deceased)
of 1 of these 2 patients had Addison’s disease. Twelve of 13
autoantibody-positive DR4 patients with Addison’s disease lacked
DRB110401 and DRB110402 and had DRB110404 vs. 2 of 11 DR4
non-Addisonian patients with DRB110404 (P <
0.001).
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). As would be predicted from the
analysis of patients with Addison’s disease (Table 3), a high
prevalence of 21-hydroxylase autoantibodies was found among DR"3/4"
DQ8/DQ2 heterozygous patients, followed by patients with
DQA10501/DQB110301, and, finally, patients homozygous for DQ2.
Approximately 5% of patients with type 1 diabetes and the first 2
genotypes expressed 21-hydroxylase autoantibodies.
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illustrates Life Table analysis of the age at which Addison’s disease
was diagnosed for all patients with 21-hydroxylase autoantibodies with
a DR4 allele. The Life Table is divided between patients with only
DRB110404 vs. those with DRB110401 or DRB110402. Consistent
with the association of DRB110404 with Addison’s disease, there is a
greater development of Addison’s disease by attained age for patients
with DRB110404 (P < 0.01, by log rank test).
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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There is essentially universal agreement that isolated Addison’s disease and Addison’s disease as part of the APS-II syndrome are strongly associated with the DR3 haplotype with DQ2 (DQA110501, DQB110201) (1, 2, 7, 8, 9). A recent report has suggested that in contrast to type 1 diabetes, Addison’s disease is not associated with DQ8 (DQA110301, DQB110302) when individuals with type 1 diabetes are excluded from analysis (36). Our study is not large enough to prove that in the absence of diabetes, DRB110404, DQ8 is associated with Addison’s disease, but in the patients studied, we do not see an apparent difference in the HLA haplotypes of patients with and without type 1 diabetes mellitus (8 of 12 DRB110404 DQ8/DQ2 with diabetes vs. 6 of 9 without diabetes vs. 11% of patients with type 1 diabetes and 0.7% of the general population). As many as 50% of patients with Addison’s disease as part of the APS-II syndrome develop diabetes (37, 38, 39), and selection against diabetes may increase the presence of haplotypes such as DQA110501, DQB110301, which are relatively infrequent in patients with type 1 diabetes.
The current study evaluated patients with isolated Addison’s disease and APS-II patients (none with APS-I). For the families analyzed, the DR4 haplotype DRB110404, DQ8 haplotype was always (n = 11) transmitted from parents with this haplotype to patients with Addison’s disease. This included transmission to five patients without type 1 diabetes (and without antiislet autoantibodies). This transmission is markedly different from the expected 50% transmission if the haplotype did not contribute to risk for Addison’s disease (P < 0.001). In the 6 families with a DR4 haplotype that were HLA typed (including all multiplex Addison’s disease families available), 68% (13 of 19) of the family members with the genotype DRB110404, DQ8/DRB110301, DQ2 had Addison’s disease.
As part of the DAISY study we have typed cord blood from more than 15,000 general population newborns, and our distribution of HLA alleles is consistent with studies of U.S. populations (31). The genotype DRB110404, DQ8 with DRB1103 occurs in 0.7% of newborns in Colorado. In addition, less than 15% of patients with type 1 diabetes are DQ8/DQ2 heterozygotes with the DRB110404 allele (31). In contrast, two thirds of the patients with Addison’s disease expressed this genotype.
The great majority (9 of 11) of 21-hydroxylase autoantibody-positive diabetic patients who did not have Addison’s disease expressed either DRB110401 (7 of 11) or DRB110402 (2 of 11) vs. only 1 individual (of 15) among DR4 patients with Addison’s disease who expressed DRB10401 (or 0402) (P < 0.0002). This leads to the hypothesis that progression to overt Addison’s disease among 21-hydroxylase-positive patients may differ depending upon expression of DRB110401 or DRB110402 vs. DRB110404. Protection or lack of susceptibility with DRB110401- or DRB110402-containing haplotypes with concomitant expression of 21-hydroxylase autoantibodies is not absolute. One DQ8 patient (of 15) with Addison’s disease had DRB110401/DQ8. Further follow-up is necessary to ascertain whether Addison’s disease is delayed rather than prevented in the remaining 21-hydroxylase autoantibody-positive patients with DRB110401 or DRB110402.
Differences between DRB1104 alleles appear to be critical for the development of another autoimmune disease, rheumatoid arthritis (40, 41). DRB110404 differs from DRB110401 and DRB110402 in only two and three amino acids, respectively. Thus, one hypothesis is that the unique amino acids of DRB110401 and DRB110402, by the peptides they bind and/or their influence on the T cell repertoire, prevent Addison’s disease, or DRB110404 may increase the risk of Addison’s disease. An alternate hypothesis for the decreased prevalence of Addison’s disease with DRB110401 or DRB110402 compared to DRB110404 is that the alleles DRB110404, DQ8 are in linkage dysequilibrium with an additional "Addisonian" gene not usually present for haplotypes with DRB110401 and DRB110402. Of note, the gene coding for 21-hydroxylase is within the major histocompatibility complex and therefore linked to DR and DQ (42).
A high index of suspicion is warranted for autoimmune polyendocrine syndrome disorders in patients with type 1 diabetes and with specific DR and DQ genotypes, such as DRB110404, DQ8 with DQ2. Approximately 1 of 200 individuals in Colorado are born with the genotype DRB110404, DQ8/DQ2, which is present in more than half of the patients we studied with Addison’s disease. With a reported prevalence of Addison’s disease of approximately 1 in 20,000 (43), approximately 1 in 200 of such DRB110404, DQ8/DRB110301,DQ2 individuals are likely to develop Addison’s disease, a 100-fold enrichment. Our data suggest that DRB1 typing will aid in the prediction of Addison’s disease among patients with 21-hydroxylase autoantibodies.
Addison’s disease is readily diagnosed and readily treated when diagnosed (5). Nevertheless, the disease can be fatal and has been occasionally diagnosed at autopsy. If genetic screening for a series of preventable disorders is implemented in the future, screening for Addison’s disease is a candidate for a component of such programs. Further prospective studies are needed to define the utility and drawbacks of such screening.
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Acknowledgments |
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Footnotes |
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Received July 31, 1998.
Revised October 7, 1998.
Accepted October 12, 1998.
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References |
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