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A Review of the Genetics of Hypoadrenocorticism
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 Addison genetics MHC class II DLA CTLA4 PTPN22 autoimmunity adrenal canine a
Hospital for Small Animals, Royal (Dick) School of Veterinary Studies, University of Edinburgh, Midlothian, Scotland
b
Department of Pathology and Pathogen Biology, Royal Veterinary College, University of London, Hatfield, UK
Hypoadrenocorticism is an uncommon disease in dogs and rare in humans, where it is known as Addison disease (ADD). The disease is characterized by a deficiency in corticosteroid production from the adrenal cortex, requiring lifelong hormone replacement therapy. When compared with humans, the pathogenesis of hypoadrenocorticism in dogs is not well established, although the evidence supports a similar autoimmune etiology of adrenocortical pathology. Several immune response genes have been implicated in determining susceptibility to Addison disease in humans, some of which are shared with other autoimmune syndromes. Indeed, other types of autoimmune disease are common (approximately 50%) in patients affected with ADD. Several lines of evidence suggest a genetic component to the etiology of canine hypoadrenocorticism. Certain dog breeds are overrepresented in epidemiologic 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 associated with susceptibility to canine hypoadrenocorticism. Immune response genes such as the dog leukocyte antigen (DLA) and cytotoxic T-lymphocyte–associated protein 4 (CTLA4) genes seem to be particularly important. It is clear that there are genetic factors involved in determining susceptibility to canine hypoadrenocorticism, although similar to the situation in humans, this is likely to represent a complex genetic disorder. & 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: [email protected] (A.M. Boag)
Introduction to Hypoadrenocorticism 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 corticosteroid production from the adrenal cortex, requiring lifelong hormone replacement therapy. Hypoadrenocorticism is a challenging 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 postmortem data, it is likely that hypoadrenocorticism is underdiagnosed.1,2 For these reasons, there is interest in developing genetic3-5 or serologic tests6,7 that might be employed in identifying dogs at risk. These would be useful tools, both for diagnosis of individuals in veterinary clinical practice and for informing selective breeding programs. Dogs have a high prevalence of spontaneous primary hypoadrenocorticism compared with other species. Adrenal gland pathology 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 http://dx.doi.org/10.1053/j.tcam.2015.01.001 1527-3369/& 2015 Topics in Companion Animal Medicine. Published by Elsevier Inc.
enzyme (p450scc)7,11,12 have been demonstrated in dogs affected 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 hypoadrenocorticism 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 information 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
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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 AAD and either T1D or ATD ATD and other autoimmune disease(s) (excluding AAD, hypoparathyroidism, and chronic candidiasis) Two or more organ-specific autoimmune diseases (which do not fall into type 1, 2, or 3)
MAS type 2 MAS type 3 MAS type 4
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 hypoadrenocorticism 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 hypoadrenocorticism, 2 of the 4 dogs had concurrent hypothyroidism.35 The largest case series of concurrent hypoadrenocorticism and hypothyroidism 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, hospitalbased 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 Hypoadrenocorticism 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
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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 hypoadrenocorticism 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 significant 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 inheritance, 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 Basset hound37 Bearded collie37,39 Border terrier39 Brussels Griffon39 English pointer39 German SH pointer37 Great Dane17 SCWT, soft-coated wheaten terrier.
Poodle—unspecified37 Poodle—standard17,39 Portuguese water dogs17,39 Rottweiler17 SCWT17 Springer spaniel37 St Bernard41 WHWT17,37
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Table 3 Breeds Significantly Underrepresented for Hypoadrenocorticism in Epidemiologic Studies Breeds Significantly Underrepresented for Hypoadrenocorticism Boxer37 Cocker spaniel37 Dalmatian37 Golden retriever17 Labrador retriever37 Lhasa Apso17,37
Pit bull terrier37 Pomeranian37 Shetland sheepdog37 Shih Tzu37 Yorkshire terrier17,37
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 dehydrogenase), 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 importance, 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, systematic lupus erythematosus (SLE), AAD, or pernicious anemia.56 A similarly increased prevalence of AAD, celiac disease, lymphocytic thyroiditis, pernicious anemia, ulcerative colitis, SLE, and rheumatoid arthritis is seen in parents of children with T1D.57 Several large-scale genome-wide association studies have been undertaken 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 immunemediated endocrinopathies, including AAD, is the major histocompatibility 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 phosphatase 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 MICB,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 analyzed (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 homozygosity. 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 hypothyroidism80-82 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 pancreatic acinar atrophy,85 and inflammatory hepatitis.86 Table 4 Breed-Specific Incidence Estimates of Naturally Occurring Canine Hypoadrenocorticism Seen in Veterinary Referral Hospitals in 1989-1991, United States and Canada. Expressed as the Number of Cases of a Particular Breed with Hypoadrenocorticism/1000 Dogs of that Breed/3 yr. (Reproduced With Permission From Kelch 1996.37) Breed
Number of Cases
Breed-Specific Incidence Estimate
German shepherd Great Dane Labrador retriever Mixed Poodle Rottweiler West Highland white terrier All other breeds
9 10 9 58 35 7 12 118
1.2 7.6 0.9 1.7 4.9 2.2 12.0 1.4
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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 DLADRB1n015:02/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 significant 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, DLADRB1n015/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 significant 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 associations between hypoadrenocorticism and DLA-DRB1n001:01/ DQA1n001:01/DQB1n002:01, a haplotype also associated with increased risk of hypothyroidism.
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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 associated with increased odds of inflammatory hepatitis in Dobermans86 and homozygosity has been associated with altered disease susceptibility in human multiple sclerosis90 and experimental diabetes in rodents.91 The fact that the same or related DLA haplotypes are found to be significantly associated with hypoadrenocorticism in breedspecific and multibreed analyses, especially when those are also associated with diabetes and hypothyroidism, supports the proposition 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, antigenpresenting cell.
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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 demonstrated 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 hypoadrenocorticism in 3 breeds found CTLA4 and PTPN22 to be significantly 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 predispositions, 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. However, 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 possibility for genetic tests to be established to identify dogs at increased risk of developing hypoadrenocorticism and development of new therapeutic interventions. References 1. Frank CB, Valentin SY, Scott-Moncrieff JCR, et al. Correlation of Inflammation with adrenocortical atrophy in canine adrenalitis. J Comp Pathol 149:268–279, 2013 2. Chase K, Lawler DF, McGill LD, et al. Age relationships of postmortem observations in Portuguese water dogs. Age 33:461–473, 2010 3. Hughes AM, Jokinen P, Bannasch DL, et al. Association of a dog leukocyte antigen class II haplotype with hypoadrenocorticism in Nova Scotia Duck Tolling Retrievers. Tissue Antigens 75:684–690, 2010 4. Short AD, Boag A, Catchpole B, et al. A candidate gene analysis of canine hypoadrenocorticism in 3 dog breeds. J Hered 104:807–820, 2013 5. Famula TR, Belanger JM, Oberbauer AM. Heritability and complex segregation analysis of hypoadrenocorticism in the standard poodle. J Small Anim Pract 44:8–12, 2003
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Bednarek J, Furmaniak J, Wedlock N, et al. Steroid 21-hydroxylase is a major autoantigen involved in adult onset autoimmune Addison’s disease. FEBS Lett 309:51–55, 1992 14. Falorni A, Laureti S, Santeusanio F. Autoantibodies in autoimmune polyendocrine syndrome type II. Endocrinol Metab Clin North Am 31:369–389, 2002[vii] 15. Betterle C, Volpato M, Pedini B, et al. Adrenal-cortex autoantibodies and steroid-producing cells autoantibodies in patients with Addison’s disease: comparison of immunofluorescence and immunoprecipitation assays. J Clin Endocrinol Metab 84:618–622, 1999 16. Feldman EC, Nelson RW. Hypoadrenocorticism (Addison’s disease). Canine and Feline Endocrinology and Reproduction. 3 ed: Elselvier; 394–439, 2004 17. Peterson ME, Kintzer PP, Kass PH. Pretreatment clinical and laboratory findings in dogs with hypoadrenocorticism: 225 cases (1979-1993). J Am Vet Med Assoc 208:85–91, 1996 18. Platt SR, Chrisman CL, Graham J, et al. 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Melendez L, Greco DS, Turner JL. Concurrent hypothyroidism and hypoadrenocorticism in 10 dogs. ACVIM Annual Congress 1996, 1996. 37. Kelch WJ. Canine hypoadrenocorticism (canine Addison’s disease): history, contemporary diagnosis by practicing veterinarians, and epidemiology. Knoxville: University of Tennessee; 1996 38. Pedersen NC, Liu H, Greenfield DL, et al. Multiple autoimmune diseases syndrome in Italian Greyhounds: preliminary studies of genome-wide diversity and possible associations within the dog leukocyte antigen (DLA) complex. Vet Immunol Immunopathol 145:264–276, 2012
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39. Bellumori TP, Famula TR, Bannasch DL, et al. Prevalence of inherited disorders among mixed-breed and purebred dogs: 27,254 cases (1995-2010). J Am Vet Med Assoc 242:1549–1555, 2013 40. Greco DS. Hypoadrenocorticism in Small Animals. Clin Tech Small Anim Pract 22:32–35, 2007 41. Thompson AL, Scott-Moncrieff JCR, Anderson JD. Comparison of classic hypoadrenocorticism with glucocorticoid-deficient hypoadrenocorticism in dogs: 46 cases (1985-2005). J Am Vet Med Assoc 230:1190–1194, 2007 42. Hughes AM, Nelson RW, Famula TR, et al. Clinical features and heritability of hypoadrenocorticism in Nova Scotia Duck Tolling Retrievers: 25 cases (19942006). J Am Vet Med Assoc 231:407–412, 2007 43. Haviland RL, Toaff-Rosenstein RL, Reeves MP, et al. Clinical features of hypoadrenocorticism in soft-coated wheaten terriers: 72 cases (1979-2011). J Vet Intern Med 26:756, 2012 44. Chase K, Sargan D, Miller K, et al. Understanding the genetics of autoimmune disease: two loci that regulate late onset Addison’s disease in Portuguese Water Dogs. Int J Immunogenet 33:179–184, 2006 45. Oberbauer AM, Benemann KS, Belanger JM, et al. Inheritance of hypoadrenocorticism in Bearded Collies. Am J Vet Res 63:643–647, 2002 46. Burton S, DeLay J, Holmes A, et al. Hypoadrenocorticism in young related Nova Scotia duck tolling retrievers. Can Vet J 38:231–234, 1997 47. Mooney ET, Hammond TN, Mahony OM. Early-onset hypoadrenocorticism in a kindred of Pomeranians. J Vet Intern Med. 26:255-256, 2012 48. Oberbauer AM, Bell JS, Belanger JM, et al. Genetic evaluation of Addison’s disease in the Portuguese Water Dog. BMC Vet Res 2:15, 2006 49. Ten S, New M, Maclaren N. Clinical review 130: Addison’s disease 2001. J Clin Endocrinol Metab 86:2909–2922, 2001 50. Krone N, Arlt W. Genetics of congenital adrenal hyperplasia. Best Pract Res Clin Endocrinol Metab 23:181–192, 2009 51. Short AD, Catchpole B, Boag AM, et al. Putative candidate genes for canine hypoadrenocorticism (Addison’s disease) in multiple dog breeds. Vet Rec 175:430, 2014 52. Zumer K, Saksela K, Peterlin BM. The mechanism of tissue-restricted antigen gene expression by AIRE. J Immunol 190:2479–2482, 2013 53. Shi Y, Zhu M. Medullary thymic epithelial cells, the indispensable player in central tolerance. Sci China Life Sci 56:392–398, 2013 54. Liston A, Lesage S, Wilson J, et al. Aire regulates negative selection of organspecific T cells. Nat Immunol 4:350–354, 2003 55. Vyse TJ, Todd JA. Genetic analysis of autoimmune disease. Cell 85:311–318, 1996 56. Alkhateeb A, Fain PR, Thody A, et al. Epidemiology of vitiligo and associated autoimmune diseases in Caucasian probands and their families. Pigment Cell Res 16:208–214, 2003 57. Hemminki K, Li X, Sundquist J, et al. Familial association between type 1 diabetes and other autoimmune and related diseases. Diabetologia 52:1820–1828, 2009 58. Pearce SH, Merriman TR. Genetic progress towards the molecular basis of autoimmunity. Trends Mol Med 12:90–98, 2006 59. Forabosco P, Bouzigon E, Ng MY, et al. Meta-analysis of genome-wide linkage studies across autoimmune diseases. Eur J Hum Genet 17:236–243, 2008 60. Criswell LA, Pfeiffer KA, Lum RF, et al. Analysis of Families in the Multiple Autoimmune Disease Genetics Consortium (MADGC) Collection: the PTPN22 620W allele associates with multiple autoimmune phenotypes. Am J Hum Genet 76:561–571, 2005 61. Gough SC, Walker LS, Sansom DM. CTLA4 gene polymorphism and autoimmunity. Immunol Rev 204:102–115, 2005 62. Gambelunghe G, Falorni A, Ghaderi M, et al. Microsatellite polymorphism of the MHC class I chain-related (MIC-A and MIC-B) genes marks the risk for autoimmune Addison’s disease. J Clin Endocrinol Metab 84:3701–3707, 1999 63. Park YS, Sanjeevi CB, Robles D, et al. Additional association of intra-MHC genes, MICA and D6S273, with Addison’s disease. Tissue Antigens 60:155–163, 2002 64. Pani MA, Seissler J, Usadel K-H, et al. Vitamin D receptor genotype is associated with Addison’s disease. Eur J Endocrinol 147:635–640, 2002 65. Jennings CE, Owen CJ, Wilson V, et al. A haplotype of the CYP27B1 promoter is associated with autoimmune Addison’s disease but not with Grave’s disease in a UK population. J Mol Endocrinol 34:859–863, 2005 66. Lopez ER, Zwermann O, Segni M, et al. A promoter polymorphism of the CYP27B1 gene is associated with Addison’s disease, Hashimoto’s thyroiditis, Graves’ disease and type 1 diabetes mellitus in Germans. Eur J Endocrinol 151:193–197, 2004 67. Hughes AM, Bannasch DL, Kellett K, et al. Examination of candidate genes for hypoadrenocorticism in Nova Scotia Duck Tolling Retrievers. Vet J 187:212–216, 2011 68. Tsai S, Santamaria P. MHC class II polymorphisms, autoreactive T-Cells, and autoimmunity. Front Immunol 4:321, 2013 69. Chao CC, Sytwu HK, Chen EL, et al. The role of MHC class II molecules in susceptibility to type I diabetes: identification of peptide epitopes and characterization of the T cell repertoire. Proceedings of the National Academy of Sciences of the United States of America 96:9299-9304, 1999. 70. Gregersen PK, Behrens TW. Genetics of autoimmune diseases—disorders of immune homeostasis. . Nature Publishing Group; 7:917–928, 2006 71. Wahren-Herlenius M, Dörner T. Immunopathogenic mechanisms of systemic autoimmune disease. Lancet 382:819–831, 2013 72. Jones EY, Fugger L, Strominger JL, et al. MHC class II proteins and disease: a structural perspective. Nat Rev Immunol 6:271–282, 2006 73. Myhre AG, Undlien DE, Løvås K, et al. Autoimmune adrenocortical failure in Norway autoantibodies and human leukocyte antigen class II associations related to clinical features. J Clin Endocrinol Metab 87:618–623, 2002
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74. Gombos Z, Hermann R, Kiviniemi M, et al. Analysis of extended human leukocyte antigen haplotype association with Addison’s disease in three populations. Eur J Endocrinol 157:757–761, 2007 75. Kennedy LJ, Barnes A, Happ GM, et al. Evidence for extensive DLA polymorphism in different dog populations. Tissue Antigens 60:43–52, 2002 76. Kennedy LJ, Barnes A, Happ GM, et al. Extensive interbreed, but minimal intrabreed, variation of DLA class II alleles and haplotypes in dogs. Tissue Antigens 59:194–204, 2002 77. Ollier WE, Kennedy LJ, Thomson W, et al. Dog MHC alleles containing the human RA shared epitope confer susceptibility to canine rheumatoid arthritis. Immunogenetics 53:669–673, 2001 78. Greer KA, Wong AK, Liu H, et al. Necrotizing meningoencephalitis of Pug dogs associates with dog leukocyte antigen class II and resembles acute variant forms of multiple sclerosis. Tissue Antigens 76:110–118, 2010 79. Kennedy LJ, Barnes A, Ollier WER, et al. Association of a common dog leucocyte antigen class II haplotype with canine primary immune-mediated haemolytic anaemia. Tissue Antigens 68:502–508, 2006 80. Kennedy LJ, Quarmby S, Happ GM, et al. Association of canine hypothyroidism with a common major histocompatibility complex DLA class II allele. Tissue Antigens 68:82–86, 2006 81. Kennedy LJ, Huson HJ, Leonard J, et al. Association of hypothyroid disease in Doberman Pinscher dogs with a rare major histocompatibility complex DLA class II haplotype. Tissue Antigens 67:53–56, 2006 82. Wilbe M, Sundberg K, Hansen IR, et al. Increased genetic risk or protection for canine autoimmune lymphocytic thyroiditis in Giant Schnauzers depends on DLA class II genotype. Tissue Antigens 75:712–719, 2010 83. Kennedy LJ, Davison LJ, Barnes A, et al. Identification of susceptibility and protective major histocompatibility complex haplotypes in canine diabetes mellitus. Tissue Antigens 68:467–476, 2006 84. Kennedy LJ, O’Neill T, House A, et al. Risk of anal furunculosis in German shepherd dogs is associated with the major histocompatibility complex. Tissue Antigens 71:51–56, 2008 85. Tsai KL, Starr-Moss AN, Venkataraman GM, et al. Alleles of the major histocompatibility complex play a role in the pathogenesis of pancreatic acinar atrophy in dogs. Immunogenetics 65:501–509, 2013 86. Dyggve H, Kennedy LJ, Meri S, et al. Association of Doberman hepatitis to canine major histocompatibility complex II. Tissue Antigens 77:30–35, 2011 87. Safra N, Pedersen NC, Wolf Z, et al. Expanded dog leukocyte antigen (DLA) single nucleotide polymorphism (SNP) genotyping reveals spurious class II associations. Vet J 189:220–226, 2011 88. Wilbe M, Jokinen P, Truvé K, et al. Genome-wide association mapping identifies multiple loci for a canine SLE-related disease complex. Nat Genet 42:250–254, 2010 89. Massey J, Boag A, Short AD, et al. MHC class II association study in eight breeds of dog with hypoadrenocorticism. Immunogenetics 65:291–297, 2013 90. Barcellos LF, Oksenberg JR, Begovich AB, et al. HLA-DR2 dose effect on susceptibility to multiple sclerosis and influence on disease course. Am J Hum Genet 72:710–716, 2003 91. Yokoi N, Hidaka S, Tanabe S, et al. Role of major histocompatibility complex class II in the development of autoimmune type 1 diabetes and thyroiditis in rats. Genes Immun 13:139–145, 2012 92. Kemp EH, Ajjan RA, Husebye ES, et al. A cytotoxic T lymphocyte antigen-4 (CTLA-4) gene polymorphism is associated with autoimmune Addison’s disease in English patients. Clin Endocrinol 49:609–613, 1998 93. Vaidya B, Imrie H, Geatch DR, et al. Association analysis of the cytotoxic T lymphocyte antigen-4 (CTLA-4) and autoimmune regulator-1 (AIRE-1) genes in sporadic autoimmune Addison’s disease. J Clin Endocrinol Metab 85:688–691, 2000 94. Brozzetti A, Marzotti S, Tortoioli C, et al. Cytotoxic T lymphocyte antigen-4 Ala17 polymorphism is a genetic marker of autoimmune adrenal insufficiency: Italian association study and meta-analysis of European studies. Eur J Endocrinol 162:361–369, 2010 95. Velaga MR, Wilson V, Jennings CE, et al. The codon 620 tryptophan allele of the lymphoid tyrosine phosphatase (LYP) gene is a major determinant of Graves’ disease. J Clin Endocrinol Metab 89:5862–5865, 2004 96. Skinningsrud B, Husebye ES, Gervin K, et al. Mutation screening of PTPN22: association of the 1858T-allele with Addison’s disease. Eur J Hum Genet 16:977–982, 2008 97. Roycroft M, Fichna M, McDonald D, et al. The tryptophan 620 allele of the lymphoid tyrosine phosphatase (PTPN22) gene predisposes to autoimmune Addison’s disease. Clin Endocrinol (Oxf) 70:358–362, 2009 98. Short AD, Catchpole B, Kennedy LJ, et al. Analysis of candidate susceptibility genes in canine diabetes. J Hered 98:518–525, 2007 99. Roque JB, O’Leary CA, Duffy DL, et al. Atopic dermatitis in West Highland white terriers is associated with a 1.3-Mb region on CFA 17. Immunogenetics 64:209–217, 2012 100. Roque JB, O’Leary CA, Kyaw-Tanner M, et al. PTPN22 polymorphisms may indicate a role for this gene in atopic dermatitis in West Highland white terriers. BMC Res Notes 4:571, 2011 101. Chen L, Flies DB. Molecular mechanisms of T cell co-stimulation and coinhibition. Nat Rev Immunol 13:227–242, 2013 102. Short AD, Saleh NM, Catchpole B, et al. CTLA4 promoter polymorphisms are associated with canine diabetes mellitus. Tissue Antigens 75:242–252, 2010 103. Boag AM, Short A, Threlfall A, et al. Hypoadrenocorticism In Cocker Spaniels Is Associated With Polymorphisms In The Cytotoxic T-Lymphocyte-Antigen 4 Promoter. J Vet Intern Med 28:1052, 2014
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 Addison genetics MHC class II DLA CTLA4 PTPN22 autoimmunity adrenal canine a
Hospital for Small Animals, Royal (Dick) School of Veterinary Studies, University of Edinburgh, Midlothian, Scotland
b
Department of Pathology and Pathogen Biology, Royal Veterinary College, University of London, Hatfield, UK
Hypoadrenocorticism is an uncommon disease in dogs and rare in humans, where it is known as Addison disease (ADD). The disease is characterized by a deficiency in corticosteroid production from the adrenal cortex, requiring lifelong hormone replacement therapy. When compared with humans, the pathogenesis of hypoadrenocorticism in dogs is not well established, although the evidence supports a similar autoimmune etiology of adrenocortical pathology. Several immune response genes have been implicated in determining susceptibility to Addison disease in humans, some of which are shared with other autoimmune syndromes. Indeed, other types of autoimmune disease are common (approximately 50%) in patients affected with ADD. Several lines of evidence suggest a genetic component to the etiology of canine hypoadrenocorticism. Certain dog breeds are overrepresented in epidemiologic 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 associated with susceptibility to canine hypoadrenocorticism. Immune response genes such as the dog leukocyte antigen (DLA) and cytotoxic T-lymphocyte–associated protein 4 (CTLA4) genes seem to be particularly important. It is clear that there are genetic factors involved in determining susceptibility to canine hypoadrenocorticism, although similar to the situation in humans, this is likely to represent a complex genetic disorder. & 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: [email protected] (A.M. Boag)
Introduction to Hypoadrenocorticism 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 corticosteroid production from the adrenal cortex, requiring lifelong hormone replacement therapy. Hypoadrenocorticism is a challenging 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 postmortem data, it is likely that hypoadrenocorticism is underdiagnosed.1,2 For these reasons, there is interest in developing genetic3-5 or serologic tests6,7 that might be employed in identifying dogs at risk. These would be useful tools, both for diagnosis of individuals in veterinary clinical practice and for informing selective breeding programs. Dogs have a high prevalence of spontaneous primary hypoadrenocorticism compared with other species. Adrenal gland pathology 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 http://dx.doi.org/10.1053/j.tcam.2015.01.001 1527-3369/& 2015 Topics in Companion Animal Medicine. Published by Elsevier Inc.
enzyme (p450scc)7,11,12 have been demonstrated in dogs affected 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 hypoadrenocorticism 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 information 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
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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 AAD and either T1D or ATD ATD and other autoimmune disease(s) (excluding AAD, hypoparathyroidism, and chronic candidiasis) Two or more organ-specific autoimmune diseases (which do not fall into type 1, 2, or 3)
MAS type 2 MAS type 3 MAS type 4
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 hypoadrenocorticism 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 hypoadrenocorticism, 2 of the 4 dogs had concurrent hypothyroidism.35 The largest case series of concurrent hypoadrenocorticism and hypothyroidism 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, hospitalbased 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 Hypoadrenocorticism 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
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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 hypoadrenocorticism 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 significant 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 inheritance, 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 Basset hound37 Bearded collie37,39 Border terrier39 Brussels Griffon39 English pointer39 German SH pointer37 Great Dane17 SCWT, soft-coated wheaten terrier.
Poodle—unspecified37 Poodle—standard17,39 Portuguese water dogs17,39 Rottweiler17 SCWT17 Springer spaniel37 St Bernard41 WHWT17,37
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Table 3 Breeds Significantly Underrepresented for Hypoadrenocorticism in Epidemiologic Studies Breeds Significantly Underrepresented for Hypoadrenocorticism Boxer37 Cocker spaniel37 Dalmatian37 Golden retriever17 Labrador retriever37 Lhasa Apso17,37
Pit bull terrier37 Pomeranian37 Shetland sheepdog37 Shih Tzu37 Yorkshire terrier17,37
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 dehydrogenase), 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 importance, 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, systematic lupus erythematosus (SLE), AAD, or pernicious anemia.56 A similarly increased prevalence of AAD, celiac disease, lymphocytic thyroiditis, pernicious anemia, ulcerative colitis, SLE, and rheumatoid arthritis is seen in parents of children with T1D.57 Several large-scale genome-wide association studies have been undertaken 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 immunemediated endocrinopathies, including AAD, is the major histocompatibility 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 phosphatase 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 MICB,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 analyzed (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 homozygosity. 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 hypothyroidism80-82 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 pancreatic acinar atrophy,85 and inflammatory hepatitis.86 Table 4 Breed-Specific Incidence Estimates of Naturally Occurring Canine Hypoadrenocorticism Seen in Veterinary Referral Hospitals in 1989-1991, United States and Canada. Expressed as the Number of Cases of a Particular Breed with Hypoadrenocorticism/1000 Dogs of that Breed/3 yr. (Reproduced With Permission From Kelch 1996.37) Breed
Number of Cases
Breed-Specific Incidence Estimate
German shepherd Great Dane Labrador retriever Mixed Poodle Rottweiler West Highland white terrier All other breeds
9 10 9 58 35 7 12 118
1.2 7.6 0.9 1.7 4.9 2.2 12.0 1.4
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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 DLADRB1n015:02/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 significant 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, DLADRB1n015/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 significant 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 associations between hypoadrenocorticism and DLA-DRB1n001:01/ DQA1n001:01/DQB1n002:01, a haplotype also associated with increased risk of hypothyroidism.
99
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 associated with increased odds of inflammatory hepatitis in Dobermans86 and homozygosity has been associated with altered disease susceptibility in human multiple sclerosis90 and experimental diabetes in rodents.91 The fact that the same or related DLA haplotypes are found to be significantly associated with hypoadrenocorticism in breedspecific and multibreed analyses, especially when those are also associated with diabetes and hypothyroidism, supports the proposition 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, antigenpresenting cell.
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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 demonstrated 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 hypoadrenocorticism in 3 breeds found CTLA4 and PTPN22 to be significantly 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 predispositions, 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. However, 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 possibility for genetic tests to be established to identify dogs at increased risk of developing hypoadrenocorticism and development of new therapeutic interventions. References 1. Frank CB, Valentin SY, Scott-Moncrieff JCR, et al. Correlation of Inflammation with adrenocortical atrophy in canine adrenalitis. J Comp Pathol 149:268–279, 2013 2. Chase K, Lawler DF, McGill LD, et al. Age relationships of postmortem observations in Portuguese water dogs. Age 33:461–473, 2010 3. Hughes AM, Jokinen P, Bannasch DL, et al. Association of a dog leukocyte antigen class II haplotype with hypoadrenocorticism in Nova Scotia Duck Tolling Retrievers. Tissue Antigens 75:684–690, 2010 4. Short AD, Boag A, Catchpole B, et al. A candidate gene analysis of canine hypoadrenocorticism in 3 dog breeds. J Hered 104:807–820, 2013 5. Famula TR, Belanger JM, Oberbauer AM. Heritability and complex segregation analysis of hypoadrenocorticism in the standard poodle. J Small Anim Pract 44:8–12, 2003
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