Addison’s Disease and Symmetrical Lupoid Onychodystrophy in Bearded Collies Provide Common Ground for Identifying Susceptibility Loci Underlying Canine Autoimmune Disorders

Hypoadrenocorticism or Addison’s disease (AD) is a life-threatening condition that afflicts multiple dog breeds and results from autoimmune destruction of the adrenal glands. Similarly, another canine autoimmune condition that causes pain and suffering is Symmetrical Lupoid Onychodystrophy (SLO).

Both AD and SLO are postulated to be complexly inherited and preliminary data suggest a common set of susceptibility genes working in concert with additional genes that determine expression of either disease. For the study of AD and SLO the investigators will focus on the Bearded Collie breed due to its relatively high prevalence of both conditions and a genomic structure favorable for identifying variations in the DNA.

The investigators will scan the entire canine genome using genetic markers coupled with whole genome sequencing to identify chromosomal regions that harbor genetic changes contributing to disease manifestation. The disease risk conferred by each of these genetic variants, or quantitative trait loci (QTL), will then be calculated to develop a tool for selecting sires and dams early in life, thereby allowing breeders to choose mating pairs that will produce offspring with a low likelihood of developing AD and SLO.

Co-sponsored with the AKC Canine Health Foundation, Grant Number: 02488

RESEARCHERS

Anita Oberbauer, PhD; University of California, Davis
Amount: $15,000

Identifying the Disease‐Defining Autoantibodies in Canine Addison’s Disease

Addison’s disease is a common and life‐threatening disorder in dogs in which the body’s immune system destroys the outer layer of the adrenal glands. The adrenal glands produce hormones that are critical for energy metabolism, immune system function, intestinal health, and kidney function. Symptoms of Addison’s disease can mimic other conditions, and as a result, many dogs remain undiagnosed for years.

About one‐third of dogs with Addison’s disease are diagnosed only after suffering an acute adrenal crisis, which can cause a wide range of complications that require emergency stabilization and hospitalization. Today, there is no way to predict which dogs will develop Addison’s disease before they become sick. If such a test were available, veterinarians would be able to evaluate high‐risk dogs before they show signs, helping to prevent disease‐related complications and potentially enabling earlier treatment.

In this study, the investigators will use a novel approach combining gene and protein sequencing to identify the antibodies that target the adrenal glands in Standard Poodles, Portuguese Water Dogs, and English Cocker Spaniels with Addison’s disease. These antibodies are produced by the immune system before the onset of clinical signs. The ability to identify these antibodies would therefore provide a test for early diagnosis.

This research will contribute to progress in developing an important clinical test for Addison’s disease that can help improve the lives of the many dogs at high risk of developing this life‐threatening condition.

Co-sponsored with the AKC Canine Health Foundation, Grant Number: 02428

For details and logistics of this project, to include eligibility criteria and how to enroll, please visit Dr. Friedenberg’s page for the Addison’s Disease – Autoantibody Study.

RESEARCHERS

Steven Friedenberg, DVM, PhD
University of Minnesota
Amount: $30,000

Genetic Analysis of Hypoandrenocorticism in Nova Scotia Duck Tolling Retrievers

Addison’s disease, also known as hypoadrenocorticism, is a deficiency of hormones that are produced by the adrenal glands and help regulate a dog’s metabolism, blood pressure, electrolyte balance and stress response. Though the disease is relatively uncommon in dogs, certain breeds—including Nova Scotia Duck Tolling Retrievers, Bearded Collies, Great Danes, Leonbergers, Portuguese Water Dogs, Standard Poodles and West Highland White Terriers—have a much higher risk than the general dog population.

Results

Researchers identified a region of the genome that is associated with the development of Addison’s disease in Nova Scotia duck tolling retrievers. Additionally, it appears that dogs that are homozygous (both chromosomes carrying the same genes) with respect to this region are at greater risk of developing Addison’s disease, even at a young age (under 2 years). Although additional genes are likely involved, this information is the first step toward understanding the genetics of this disease and developing a genetic test that will help eliminate Addison’s disease through informed breeding practices. This fellowship training grant also provided hands-on training for a veterinarian who is pursuing a research career.

Co-sponsored with the Morris Animal Foundation, Grant Number: D08CA-402

RESEARCHERS

Angela M. Hughes, DVM
University of California at Davis

Identifying Genes Regulating Addison’s Disease in the Portuguese Water Dog

Addison’s disease, or primary adrenocortical insufficiency, is characterized by destruction of the adrenal cortex, resulting in the inability to produce cortisone when stimulated with the hormone ACTH. In Portuguese Water Dogs (PWDs), this disease occurs with a frequency of 1-2 percent, and is a heritable autoimmune disease of low penetrance, caused by several interacting genes.

Using both new and existing data, we propose to identify regions of the PWD genome that contain genes regulating the frequency of Addison’s disease. Within those large regions we propose to identify the specific DNA sequence variants that are associated with Addison’s.

Results

To date we have obtained DNA from about 90 Addisonian PWDs, as well as a number of unaffected PWDs, for which no family history of Addison’s is reported. We have already identified two genomic regions, on canine chromosomes 12 and 37, that appear to be associated with the disease. To identify candidate genes, we will make selections using the newly available canine genome sequence, as well as the more detailed human genome sequence. Once affected gene disease frequency is identified, our long term hope is that prognostic tests can be developed that will aid breeders in selecting the most genetically compatible dogs for future.

Co-sponsored with the AKC Canine Health Foundation, Grant Number: 00589B

RESEARCHERS

Elaine Ostrander, PhD
National Human Genome Research Institute

Establishing a Genetic Linkage Between Addison’s Disease and DNA Markers

Statistical evaluation of the dogs’ pedigrees suggests a single locus of large Addison’s disease is a late onset disorder caused by deterioration of the adrenal gland cortex. Although Addison’s disease occurs in the general canine population, some breeds show a greater prevalence as noted by owners and breeders: Bearded Collies, Standard Poodles, Leonbergers, Portuguese Water Dogs, and West Highland White Terriers.

Results

We have demonstrated that for Standard Poodles and Bearded Collies, Addison’s disease is highly heritable. Effect significantly influences the expression of Addison’s in the Standard Poodle and that this locus acts as an autosomal recessive. Similar findings characterize Addison’s for the Bearded Collie although the level of significance is less robust.

The specific objectives of this grant are to expand our pedigree, phenotypic, and DNA databases for all possible Bearded Collies, Standard Poodles, Leonbergers, Portguese Water Dogs and West Highland White Terriers as related to Addison’s disease and to continue our genome scan of the DNA to identify a genetic marker linked to the single locus suggested by the pedigree analyses.

Co-sponsored with the AKC Canine Health Foundation, Grant Number: 00225

RESEARCHERS

Anita M. Oberbauer, PhD
University of California, Davis

Preclinical Detection of Hypoadrenocorticism (Addison’s Disease) in Dogs

Development and Evaluation of Laboratory Techniques for the Diagnosis of Immune-Mediated Canine Adrenal Disease

Addison’s disease in the dog has been well studied. It is very similar to the disease in humans. Signs include anorexia, vomiting, weakness, pain, diarrhea, lethargy, the inability to handle stress, and, in severe cases, cardiac arrest. Since there is no early diagnostic test available and clinical signs are nonspecific, more than one-third of affected dogs are presented in a life-threatening condition. Of these dogs, many are misdiagnosed and consequently die.

Results

The results of this study provide the basis for the development of a commercially available diagnostic test that can be used prior to onset of life-threatening clinical signs. Such a test, which measures antibodies against adrenal tissue, is already available in human medicine. The researchers developed a test that is able to detect antibodies in some dogs that already have the disease and in dogs that are believed to be at higher risk (based on pedigree analysis). Completely healthy dogs tested negative, as expected. The test developed is very difficult to produce and cannot be offered commercially yet. They continue working on this project to solve these issues. If successful, the health and welfare of dogs with adrenal dysfunction should be improved by early diagnosis and by more fully understanding the disease.

Co-sponsored with the AKC Canine Health Foundation, Grant Number: 0002273

RESEARCHERS

Marcus Rick, VetMed
Michigan State University

Characterizing the Inheritance of Addison’s Disease and Linked DNA Markers

Addison’s disease is a late onset disorder caused by the deterioration of the adrenal gland. Addison’s occurs in the domestic dog at approximately 0.1 percent, with some breeds showing a greater prevalence. Notably, the Bearded Collie, the West Highland White Terrier, the Standard Poodle, the Portuguese Water Dog, and the Leonberger are considered to have unacceptable rates of Addison’s disease. Breeders have noted a familial tendency of Addison’s disease suggesting a genetic basis to the disorder.

Results

Our laboratory has determined that Addison’s is highly heritable in Bearded Collies. Further, although Addison’s is not fully governed by a single locus in the Bearded Collie, it does appear to be regulated by a single gene of large effect.

The specific objectives of this study are to develop a genetic marker associated with an Addison’s locus in the Bearded Collie; such a genetic marker will provide a useful tool to aid breeders in making health-based breeding decisions. The second objective is to determine if Addison’s disease in the Standard Poodle, West Highland White Terrier, Portuguese Water Dog and Leonberger also has a genetic basis and if so, whether there is a common genetic defect across all these breeds.

Co-sponsored with the AKC Canine Health Foundation, Grant Number: 0002226

RESEARCHERS

Anita M. Oberbauer, PhD
University of California at Davis