Topics in Compan An Med 29 (2014) 96–101

Topical Review

A Review of the Genetics of Hypoadrenocorticism

Alisdair M. Boag, BSc, BVetMed, PhD, MRCVSa,n,
Brian Catchpole, BVetMed, PhD, PGCert(VetEd), FHEA, MRCVSb

Keywords: Hypoadrenocorticism is an uncommon disease in dogs and rare in humans, where it is known as
hypoadrenocorticism
Addison disease (ADD). The disease is characterized by a deficiency in corticosteroid production from
Addison
the adrenal cortex, requiring lifelong hormone replacement therapy. When compared with humans, the
genetics
MHC class II pathogenesis of hypoadrenocorticism in dogs is not well established, although the evidence supports a
DLA similar autoimmune etiology of adrenocortical pathology. Several immune response genes have been
CTLA4 implicated in determining susceptibility to Addison disease in humans, some of which are shared with
PTPN22 other autoimmune syndromes. Indeed, other types of autoimmune disease are common (approximately
autoimmunity 50%) in patients affected with ADD. Several lines of evidence suggest a genetic component to the
adrenal etiology of canine hypoadrenocorticism. Certain dog breeds are overrepresented in epidemiologic
canine studies, reflecting a likely genetic influence, supported by data from pedigree analysis. Molecular genetic
studies have identified similar genes and signaling pathways, involved in ADD in humans, to be also
a
Hospital for Small Animals, Royal (Dick) associated with susceptibility to canine hypoadrenocorticism. Immune response genes such as the dog
School of Veterinary Studies, University of leukocyte antigen (DLA) and cytotoxic T-lymphocyte–associated protein 4 (CTLA4) genes seem to be
Edinburgh, Midlothian, Scotland particularly important. It is clear that there are genetic factors involved in determining susceptibility to
b
Department of Pathology and Pathogen canine hypoadrenocorticism, although similar to the situation in humans, this is likely to represent a
Biology, Royal Veterinary College, University of complex genetic disorder.
London, Hatfield, UK & 2015 Published by Elsevier Inc.
n
Address reprint requests to: Alisdair M.
Boag, BSc, BVetMed, PhD, MRCVS, Royal
(Dick) School of Veterinary Studies,
University of Edinburgh, Easter Bush
Campus, Midlothian EH25 9RG, Scotland.
E-mail: alisdair.boag@ed.ac.uk (A.M. Boag)

Introduction to Hypoadrenocorticism enzyme (p450scc)7,11,12 have been demonstrated in dogs affected

Hypoadrenocorticism is an uncommon disease in dogs and is
rare in humans, where it is known as Addison disease (ADD). It is
characterized in both humans and dogs by a deficiency in cortico-
steroid production from the adrenal cortex, requiring lifelong
hormone replacement therapy. Hypoadrenocorticism is a chal-
lenging disease for dog owners, breeders, and veterinary surgeons,
often with waxing and waning nonspecific clinical signs that can
become severely life threatening. Anecdotally and based on post-
mortem data, it is likely that hypoadrenocorticism is underdiag-
nosed.1,2 For these reasons, there is interest in developing
genetic3-5 or serologic tests6,7 that might be employed in identify-
ing dogs at risk. These would be useful tools, both for diagnosis of
individuals in veterinary clinical practice and for informing selec-
tive breeding programs.
Dogs have a high prevalence of spontaneous primary hypoa-
drenocorticism compared with other species. Adrenal gland path-
ology is similar to that seen in human autoimmune ADD, with
lymphocytic adrenalitis progressing to adrenocortical atrophy,1,8,9
as the adrenal cortex is destroyed by an immune-mediated
inflammatory process. The condition has been identified as an
inherited disease with a moderate-to-severe effect on dog health
and welfare affecting a wide range of popular breeds.10 Further
evidence of an autoimmune pathogenesis has been shown
recently, whereby circulating autoantibodies against the steroid
synthesis enzymes 21-hydroxylase11 and p450 side chain–cleavage
with hypoadrenocorticism, both of which are also seen in humans
with ADD.13-15
Secondary hypoadrenocorticism, resulting from nonadrenal
disease, is even less common than primary hypoadrenocorticism,
accounting for approximately 2%-4% of cases of hypoadrenocorti-
cism in referral populations.16,17 Reported causes of secondary
hypoadrenocorticism include head trauma18,19 and withdrawal of
steroid administration,20,21 although in most case reports, the
underlying cause is not identified.16,17,22 Given the limited infor-
mation available, secondary hypoadrenocorticism has not been
considered further in this review.
Comparative research into canine hypoadrenocorticism has
great potential for better understanding of genetic susceptibility
to autoimmune disease,23 and interest in using canine models of
human disease is increasing as part of the “One Biology, One
Health” strategy. Such comparative and collaborative research has
the potential to improve our understanding of both canine and
human diseases to the benefit of both species.8
Autoimmune Polyglandular Syndromes
In humans, AAD not only manifests as an isolated condition but
also occurs in association with other autoimmune disorders,
termed autoimmune polyglandular or polyendocrine syndrome
(APS).24 Approximately 50% of patients with ADD have a

http://dx.doi.org/10.1053/j.tcam.2015.01.001
1527-3369/& 2015 Topics in Companion Animal Medicine. Published by Elsevier Inc.
 A.M. Boag, B. Catchpole / Topics in Companion An Med 29 (2014) 96–101
Table 1
Criteria of Multiple Autoimmune Syndrome (MAS) Types in Humans. (Modified
With Permission From Betterle et al. 2002.28)
Type Inclusion Criteria
MAS type 1 At least 2 present: of chronic candidiasis, hypoparathyroidism,
or AAD
MAS type 2 AAD and either T1D or ATD
MAS type 3 ATD and other autoimmune disease(s) (excluding
AAD, hypoparathyroidism, and chronic candidiasis)
MAS type 4 Two or more organ-specific autoimmune diseases
(which do not fall into type 1, 2, or 3)
concurrent autoimmune disorder, most commonly autoimmune
thyroid disease (ATD) or type 1 diabetes (T1D).8,25 The prevalence
of autoimmune comorbidity in a recent Norwegian study26 was
66%, with 47% having ATD, 12% T1D, 11% vitiligo, 10% vitamin B12
deficiency, and 6.6% of women with premature ovarian failure.
Female AAD patients are reported to be more likely to be affected
with a concurrent immune-mediated disorder (72%) than men are
(42%).26 Owing to the range of autoimmune diseases exhibited by
these patients, there has been a recent move to rename APS as
multiple autoimmune syndrome (MAS).27
A standardized nomenclature has been adopted to classify
patients with autoimmune comorbidities, categorizing them
under APS/MAS types 1-4 (Table 1).28 Clinically, the classifications
MAS types 3 and 4 are not in common usage and are often
combined with MAS type 2.24
In the veterinary literature, there are relatively few published
reports of multiple endocrinopathies affecting dogs. There are a
number of case reports of dogs with concurrent hypoadrenocor-
ticism and hypothyroidism, including an 8-year-old female
boxer,29 a 9-year-old female Weimaraner,30 a 3-year-old male
Doberman,31 a 4-year-old female Great Pyrenees,32 a 6-year-old
female Russian black terrier,33 and a 2-year-old female standard
poodle.34 In a case series of related Leonburgers with hypoadre-
nocorticism, 2 of the 4 dogs had concurrent hypothyroidism.35 The
largest case series of concurrent hypoadrenocorticism and hypo-
thyroidism was of 10 dogs that had thyroid function testing
performed after being diagnosed with hypoadrenocorticism due
to poor response to steroid replacement therapy.36
Concurrent endocrinopathies in dogs are mentioned in 2 large
retrospective studies. In 1 report of 187 cases of hypoadrenocorticism,
28 (15%) had at least one other endocrinopathy, 16 (8.6%) had
hypothyroidism, 14 (7.5%) diabetes, 3 (1.6%) hypoparathyroidism,
and 2 (1%) had azoospermia.16 In the second of these studies, which
included data from 225 dogs with hypoadrenocorticism, 11 (4.9%) had
a concurrent endocrinopathy noted, 10 had hypothyroidism, 2 had
diabetes, and 1 had hypoparathyroidism.17 A cross-sectional analysis
of dogs with hypoadrenocorticism found an odds ratio for concurrent
hypothyroidism of 4.65 (95% CI; 3.04-7.12); however, the author
advised caution in interpretation owing to potential measurement
bias.37 An examination of concurrent autoimmune diseases in Italian
greyhounds has shown 9% prevalence in a retrospective, hospital-
based analysis and approximately 2%-4% of individuals affected in a
cross-sectional breeder-based analysis; half of this population had
more than one concurrent autoimmune disorder.38 Hypoadrenocor-
ticism was the third most prevalent problem, with immune-mediated
hemolytic anemia and a systemic lupus erythematous–like disease
more common; thyroiditis was less commonly noted.38
These findings suggest that concurrent autoimmune diseases
might be more common in the canine population than previously
recognized. The underlying genetic associations discussed later in
this review might explain these findings in dogs, as in the
situation in humans, autoimmune susceptibility genes are likely
97
to be common to several immune-mediated diseases, including
AAD, ATD, and T1D.
Epidemiology of Canine Hypoadrenocorticism
The incidence of AAD in the human population is estimated to
be approximately 0.4-1 per 100,000 people per year,26,28 giving a
reported prevalence of approximately 40-144 per 1,000,000, but
with wide geographic variance. The estimated prevalence of
canine hypoadrenocorticism is greater, with cross population
estimates between 0.3% and 1.1%.37,39 The incidence of hypoadre-
nocorticism has been estimated at approximately 0.5 per 1000
dogs per year.16 The age of onset is typically between 2 and 6
years;, however, the diagnosis can be made at almost any age with
a range of 3 months to 14 years reported.17,40 ADD is more
common in women than in men,28 and there might be a similar
sex bias in dogs, with bitches having a higher incidence of
disease17,37; though this is not always consistent with some
breed-specific studies showing equal sex split.5,41-43
A wide range of breeds are affected with hypoadrenocorticism,
but the most commonly diagnosed breed classification in larger
studies is the crossbreed.16,17,37,41 In these analyses, there is signifi-
cant overrepresentation and underrepresentation of certain breeds,
as shown in Tables 2 and 3. Table 4 shows data from a study by
Kelch,37 detailing breed-specific incidence estimates in a US referral
population. Some breed-specific studies of hypoadrenocorticism
have reported higher prevalence estimates, including standard
poodles (10%),5 Portuguese water dogs (PWDs) (minimum of
1.5%),44 and bearded collies (3.4%).45 There are also family-based
case series reported in the literature including lines of Leonbergers,35
Nova Scotia duck tolling retrievers (NSDTRs),46 soft-coated wheaten
terriers,43 and Pomeranians.47 These breed-specific differences
strongly suggest a genetic predisposition to hypoadrenocorticism.
In addition to breed-specific prevalence and risk, evidence of a
genetic component to hypoadrenocorticism is seen in a number of
pedigree analysis studies. High estimates of heritability are seen in
a number of breeds, including of 0.76 for bearded collies,45 0.75 for
standard poodles,5 0.49 in PWDs,48 and 0.98 for NSDTRs.42 The
study of PWDs analyzed the effect of inbreeding, revealing that the
more inbred the individual, the more likely they were to develop
hypoadrenocorticism.48 The analyses for standard poodles, PWDs,
and NSDTRs supported an autosomal recessive mode of inheri-
tance, although data from 2 of these studies are also consistent
with a more complex pattern of inheritance, as seen in human
AAD and APS/MAS type 2.45,48
Genetics of ADD and APS/MAS in humans
Although AAD, the most common form of adrenal deficiency in
humans, is a complex genetic disorder, there are other disease
Table 2
Breeds Significantly Overrepresented for Hypoadrenocorticism in Epidemiologic
Studies
Breeds Significantly Overrepresented for Hypoadrenocorticism
Airedale37 Poodle—unspecified37
Basset hound37 Poodle—standard17,39
Bearded collie37,39 Portuguese water dogs17,39
Border terrier39 Rottweiler17
Brussels Griffon39 SCWT17
English pointer39 Springer spaniel37
German SH pointer37 St Bernard41
Great Dane17 WHWT17,37
SCWT, soft-coated wheaten terrier.
98 A.M. Boag, B. Catchpole / Topics in Companion An Med 29 (2014) 96–101
Table 3
Breeds Significantly Underrepresented for Hypoadrenocorticism in Epidemiologic
Studies
Breeds Significantly Underrepresented for Hypoadrenocorticism
Boxer37 Pit bull terrier37
Cocker spaniel37 Pomeranian37
Dalmatian37 Shetland sheepdog37
Golden retriever17 Shih Tzu37
Labrador retriever37 Yorkshire terrier17,37
Lhasa Apso17,37
etiologies and pathologies that have been described,28 a subset of
which have a genetic basis.
Congenital adrenal hyperplasia is the most common form of ADD
diagnosed in children younger than 2 years,49 which is caused by
mutation(s) in enzymes of the steroid synthesis pathway. Mutations
affecting CYP21A2 (21-hydroxylase) account for more than 90% of
affected individuals, with mutations in CYP11B1 (11-β-hydroxylase),
CYP17A1 (17-α-hydroxylase), HSD3B2 (3-β-hydroxysteroid dehydro-
genase), and POR (P450 oxidoreductase) accounting for most of the
remaining cases.50 A single nucleotide polymorphism (SNP) in
CYP21A2 associated with susceptibility to hypoadrenocorticism has
recently been described in West Highland white terriers (WHWTs),
though further investigations are needed to confirm this link.51
APS/MAS type 1 (Table 1) is a rare disease, occurring in
approximately 1 in 80,000 humans.28 However, APS/MAS1 has
an increased prevalence in some ethnic groups, including Iranian
Jews, Finns, and Sardinians.49 The genetic basis of this syndrome
has been identified to mutations in the autoimmune regulator
(AIRE) gene, with 4 different mutations being of primary impor-
tance, depending on ethnicity.28 AIRE is an important transcription
factor that regulates expression of tissue-specific antigens by
thymic epithelial cells,52 which is important in negative selection
of developing T cells (central tolerance).53 Disruption of the AIRE
gene alters the profile of self-antigens presented in the thymus,
thus affecting thymic selection. Subsequently, autoreactive T cells
migrate into the periphery,54 where they are involved in eliciting
an autoimmune reaction, leading to the clinical signs of APS/MAS
type 1.49 A missense mutation in the AIRE gene has been found to
be associated with hypoadrenocorticism in Border Collies.51
Although further work is required to better characterize the
biological significance of this association, this raises the possibility
that mutations in the canine AIRE gene might be involved in
susceptibility to autoimmune disease in some dog breeds.
In contrast to the previous examples of monogenic disorders,
AAD and APS/MAS type 2 are complex genetic diseases, with
several susceptibility genes and additional environmental factors
contributing to disease.8 This is common to many autoimmune
diseases, including other immune-mediated endocrinopathies
such as T1D and ATD.55 A genetic predisposition to autoimmunity
is exemplified in first-degree relatives of human patients with
autoimmune vitiligo, who are at an increased risk of not only
developing vitiligo themselves but also developing ATD, system-
atic lupus erythematosus (SLE), AAD, or pernicious anemia.56 A
similarly increased prevalence of AAD, celiac disease, lymphocytic
thyroiditis, pernicious anemia, ulcerative colitis, SLE, and rheuma-
toid arthritis is seen in parents of children with T1D.57 Several
large-scale genome-wide association studies have been under-
taken to better understand the genetic basis of the various human
autoimmune endocrinopathies, with similar genes identified as
playing a role in several conditions.58
The major susceptibility locus associated with immune-
mediated endocrinopathies, including AAD, is the major histo-
compatibility complex (MHC),59 discussed in more detail later.
Two other genes have been consistently shown to be involved in a
range of autoimmune diseases, namely protein tyrosine phospha-
tase nonreceptor 22 (PTPN22), which is involved in intracellular
T-cell receptor (TCR) signaling,24,60 and cytotoxic T-lymphocyte–
associated protein 4 (CTLA4),24,61 an important regulator of T-cell
activation. Associations with other genes have also been
described, more specifically for ADD, including MIC-A and MIC-
B,62,63 vitamin D receptor,64 and CYP27B1.65,66
Genetics of Canine Hypoadrenocorticism
A candidate gene analysis of genes linked with ADD has been
performed in NSDTRs—microsatellite markers we used to assess
association with canine hypoadrenocorticism.67 Of the genes ana-
lyzed (AIRE, CD28, CTLA4, and PTPN22), most did not show any
significant association except for CTLA4, which demonstrated a
weak association.67 A genome-wide microsatellite analysis of PWDs
demonstrated a relatively strong association with the dog leukocyte
antigen (DLA) region of the dog genome on chromosome 1244 and
of a marker close to CTLA4 on chromosome 37. This genome-wide
genetic association study was the first to highlight the MHC region
and CTLA4 as having potential importance in susceptibility to
hypoadrenocorticism within the breeds that were analyzed.
MHC class II
MHC class II molecules are vital components of the adaptive
immune system, both in selection of the T-cell repertoire in primary
lymphoid tissues and clonal activation of T cells in the periphery, by
facilitating interaction between antigenic peptides and the TCR
expressed on CD4 þ T cells.55,68 Genetic variation in the genes
encoding MHC class II proteins, which can alter the repertoire of
peptide epitopes presented,69 has been associated with a wide range
of autoimmune diseases across several species.55,58,70-72 A strong
association with MHC class II has been seen in AAD and APS/MAS
type 2 in humans, with HLA-DR3 and HLA-DR4 identified as major
susceptibility haplotypes in several studies.73,74
Owing to selective breeding, there is extensive interbreed
variation but often minimal intrabreed diversity in DLA class II
alleles and haplotypes,75,76 with the result that most pedigree
breeds have a distinct set of DLA haplotypes (incorporating DRB1,
DQA1, and DQB1 loci) expressed and a high degree of homo-
zygosity. Similar to the situation in humans, DLA genes have also
been linked to susceptibility to various types of autoimmune
disease,77-79 including endocrinopathies such as hypothyroid-
ism80-82 and diabetes mellitus.83 Associations between DLA class
II and other types of disease include canine arthritis,77 necrotizing
meningoencephalitis in pugs,78 IMHA,79 anal furunculosis,84 pan-
creatic acinar atrophy,85 and inflammatory hepatitis.86
Table 4
Breed-Specific Incidence Estimates of Naturally Occurring Canine Hypoadrenocor-
ticism Seen in Veterinary Referral Hospitals in 1989-1991, United States and
Canada. Expressed as the Number of Cases of a Particular Breed with Hypoadre-
nocorticism/1000 Dogs of that Breed/3 yr. (Reproduced With Permission From
Kelch 1996.37)
Breed Number of Breed-Specific
Cases Incidence Estimate
German shepherd 9 1.2
Great Dane 10 7.6
Labrador retriever 9 0.9
Mixed 58 1.7
Poodle 35 4.9
Rottweiler 7 2.2
West Highland white terrier 12 12.0
All other breeds 118 1.4
 A.M. Boag, B. Catchpole / Topics in Companion An Med 29 (2014) 96–101 99

Specific associations with hypothyroidism recognized to date are
DLA-DRB1n012:01/DQA1n001:01/DQB1n002:01 in Doberman
Pinchers,81 DLA-DRB1n012:01/DQA1n001:01/DQB1n002:01 in giant
Schnauzers, and an association with DLA-DQA1n001:01 identified in
a larger mixed-breed population.80 Diabetes in dogs has been
associated with 3 risk haplotypes in a mixed population of dogs,
DLA-DRB1n009/DQA1n001/DQB1n008, DLA-DRB1n002/DQA1n009/
DQB1n001, and DLA-DRB1n015/DQA1n006/DQB1n023.83
A variant of the diabetes-associated haplotype DLA-
DRB1n015:02/DQA1n006:01/DQB1n023:01 has been associated
with risk of hypoadrenocorticism in NSDTRs,3 although this
finding has been questioned by another study that failed to
demonstrate any association over a larger DLA block.87 However,
it is possible that the lack of association with the extended
haplotype in the latter study is because of a low level of variation
within NSDTRs compared with SNP-based typing, which would
also potentially decrease the power of the analysis.87,88
A more recent analysis across several breeds reported signifi-
cant associations with variants of DLA-DRB1n015/DQA1n006/
DQB1n023 in 3 of the 8 breeds analyzed, namely Cocker paniels,
Springer spaniels, and Standard poodles.89 However, DLA-
DRB1n015/DQA1n006/DQB1n023 was not significantly associated
with hypoadrenocorticism in Labrador retrievers (odds ratio ¼
1.4; 95% CI: 0.84-2.55; P ¼ 0.18) compared with control dogs.
Cocker spaniels and bearded collies both demonstrated a signifi-
cant association with a variant of DLA-DRB1n009:01/
DQA1n001:01/DQB1n008, related to a diabetes risk haplotype.
Labradors and WHWTs were found to have significant associa-
tions between hypoadrenocorticism and DLA-DRB1n001:01/
DQA1n001:01/DQB1n002:01, a haplotype also associated with
increased risk of hypothyroidism.
A significant effect of DLA-DRB1n001:01/DQA1n001:01/
DQB1n002:01 homozygosity was shown for both Labradors and
WHWTs, with a greater effect in the former. It is unlikely that this
related only to DLA-DRB1n001:01/DQA1n001:01/DQB1n002:01,
indeed homozygosity for DLA-DRB1n015:02/DQA1n006:01/
DRB1n023:01 has been shown to influence disease susceptibility
and earlier onset in NSDTRs.3 Furthermore, being homozygous for
DLA-DRB1n006:01/DQA1n004:01/DQB1n013:03 has been associ-
ated with increased odds of inflammatory hepatitis in Dober-
mans86 and homozygosity has been associated with altered
disease susceptibility in human multiple sclerosis90 and exper-
imental diabetes in rodents.91
The fact that the same or related DLA haplotypes are found to
be significantly associated with hypoadrenocorticism in breed-
specific and multibreed analyses, especially when those are also
associated with diabetes and hypothyroidism, supports the prop-
osition that DLA represents a common genetic risk factor for
autoimmunity. Given the large number of other immune response
genes in the MHC region of potential interest (e.g., TNFA, MICA,
and MICB), and the extensive linkage disequilibrium in this region
of the dog genome, further research is required to fully address the
specific role of DLA in hypoadrenocorticism, both at the genetic
and functional levels.
Genes Associated With T-cell Signaling Pathways
One of the hallmarks of genetic susceptibility to autoimmune
disease in humans is the link with genes critical to T-cell activation
(Fig). MHC, as discussed previously, is a clear example of this, but
other genes including CTLA4, an important regulator of T-cell
activation, and PTPN22, a regulator of T-cell signaling which affects

PTPN22

Fig. T-cell activation. (A) Two signals are required for activation of naïve T cells. Antigen presentation is detected through the T-cell receptor (“recognition” signal) binding to
the peptide/MHC class II (pMHC) complex, this is in part mediated by PTPN22 and co-stimulation via CD28 (“danger” signal). (B) Both signals lead to downstream signaling
pathways, including activation of nuclear factor of activated T cells (NFAT), which moves to the nucleus, binding to sensitive promoter sites, including those for IL-2, IL-2R
(required for proliferation or clonal expansion) and CTLA4 (required for regulation). (C) The CTLA4 gene is transcribed into mRNA and is subsequently translated into CTLA4
protein. (D) CTLA4 protein traffics to the cell surface, where it interacts with CD80/CD86, displacing CD28 and removing CD80/86 from the APC. This binding also leads to
inhibitory downstream signaling from the CTLA4 receptor, moderating T-cell activation. This is an important process for regulating T-cell responses to antigen. APC, antigen-
presenting cell.
100 A.M. Boag, B. Catchpole / Topics in Companion An Med 29 (2014) 96–101
responsiveness of the TCR, have been shown to be involved across
a range of human diseases.
Several studies in humans have linked CTLA4 polymorphisms
with ADD.92,93 A recent European-wide meta-analysis demon-
strated a significant association between ADD and a particular SNP
in exon 1, within the signal peptide of the coding sequence.94
There are also several studies linking PTPN22 with AAD.95-97
A recent genome-wide candidate gene analysis of hypoadre-
nocorticism in 3 breeds found CTLA4 and PTPN22 to be signifi-
cantly associated with hypoadrenocorticism in springer spaniels
and cocker spaniels, respectively.4 Markers associated with
PTPN22 have also previously been linked to diabetes in poodles98
and with atopic dermatitis in WHWTs.99,100
Canine CTLA4 has been sequenced and demonstrates a similar
4 exon gene structure and a high degree of sequence identity with
the equivalent gene in other species.101 The promoter region of
canine CTLA4 has been characterized,102,103 with 20 SNPs and
3 insertions/deletions identified in a 1.5-kb region upstream of the
start codon, segregating into 17 distinct haplotypes. Significant
allele, haplotype, and genotype associations were found between
the CTLA4 promoter region and diabetes mellitus in dogs.102 The
association of a CTLA4 marker with hypoadrenocorticism in
Springer spaniels had been further examined in a recent study
by Short et al.103 Significant risk and protective associations were
found with CTLA4 promoter variation in Cocker spaniels and
Springer spaniels; haplotypes previously associated with diabetes
in Border terriers are also associated with hypoadrenocorticism in
Cocker spaniels.103 Functional assessment of CTLA4 promoter
variation will further elucidate the significance of these genetic
associations.
Conclusions
Hypoadrenocorticism is a heterogeneous disease, and although
a lack of glucocorticoid production is a consistent feature, the
etiology and pathogenesis of disease in an individual animal or in
individual breeds of dogs are not well investigated. The evidence
from epidemiologic studies highlights breed-specific predisposi-
tions, and results of inheritance studies and molecular genetic
studies allow a genetic basis of disease to be inferred. It is clear
that there is a great degree of overlap in underlying genetic risk
factors when comparing breeds and likely between different
autoimmune conditions, mirroring the situation in humans. How-
ever, the immunologic consequences of inheriting susceptibility
genes and the environmental factors that trigger progression of
autoimmune disease in genetically susceptible individuals require
further research. An increased understanding of the molecular
mechanisms involved in disease progression opens up the possi-
bility for genetic tests to be established to identify dogs at
increased risk of developing hypoadrenocorticism and develop-
ment of new therapeutic interventions.
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