Great Dane Club of America Research
     
The GDCA has been a regular contributor to research that involves health and welfare issues that affect the Great Dane. The GDCA has a non-profit 501(c) charity, THE CHARITABLE TRUST, to which you can contribute towards health and welfare research, or you can send donations directly to the AKC-CHF, which has a DONOR ADVISED FUND through a partnership with the GDCA that contributes specifically to Great Dane related research.

SUMMARY OF RECENT RESEARCH UNDERWRITTEN:

The GDCA through the Charitable Trust has been sponsoring health clinics, to include an echocardiogram clinic, at the National Specialty each year beginning in 2007. Reports of such clinics are publically available at the Health & Welfare section of the parent club website.

A Charitable Trust sponsored grant ($40,000) to Dr. Leigh Anne Clark (Clemson University) resulted in 2009 in the identification of the Harlequin gene. Publication is pending. Further information concerning this and other coat color research is publically available at the Health & Welfare section of the parent club website.

A Charitable Trust sponsored research grant ($5000) was awarded to Dr. Robert Loechel (VetGen) in 2008 to identify the gene(s) specific to this breed that result in vWD. Sequencing candidate genes, however more Great Danes afflicted with vWD are needed to complete the study.

A Charitable Trust donation of $5000 was made to the Rabies Challenge Study by Dr. Ron Schultz from UW Madison. CT allocated in 2007.

Currently unfunded but still active is: research ongoing on Addison’s disease, osteosarcoma, O.C.D, primary orthostatic tremor, autoimmune disease (CHF#305), research on H.O.D., coat color research, as well as a work seeking to provide a commercial gene test for the genetic cause of von Willebrand’s Disease in our breed. For all these studies our parent website has recently updated pages on how to participate and relevant results.

CHF Grant#700-A Widescale Genome Profiling in Great Danes with Dilated Cardiomyopathy.(Mark A. Oyama, UPenn)--DAF sponsored 2008: An ACORN grant ($12,960) to study alteration in regulation of cardiac-related genes in the Great Dane resulted in measuring the gene activity of over 18,000 genes in 3 Great Danes that were euthanized for advanced DCM. This gene activity was compared to 3 healthy large-breed dogs that were euthanized for non-cardiac causes. Analysis revealed that 24 genes are significantly down-regulated and 298 genes are up-regulated in DCM Great Danes. Researcher recommends these genes should be further investigated as they may represent the primary abnormality in affected dogs. The gene found with the greatest level of down-regulation is triadin. Triadin is important in muscle tissue due to its ability to help regulated calcium movement. Calcium is the primary trigger for contraction of the heart muscle. In humans, abnormalities in calcium movement lead to poor contractility and abnormal heart rhythms. Proposal in process to further study the role of triadin in Great Dane DCM. These studies would concentrate on directly measuring the amount of triadin in the heart muscle as well as isolating the calcium-channel that triadin is attached to. These studies could help confirm that triadin deficiency is an important feature of Dane DCM.

CHF Grant#900-A: Immunological Treatment of Canine Dilated Cardiomyopathy Using a T-Lymphocyte Modulator. (Imulan Bio Therapeutics, LLC)--DAF sponsored 2008: A pilot study (ACORN grant--no publication anticipated) to research the potential use of a TCR (T-cell receptor peptides) therapeutic vaccine resulted in improved cardiac function in the majority of the dogs (Great Danes & Dobermans) enrolled in the study, suggesting that TCR vaccination represents a new biologic approach for cardiovascular medicine. Expanded clinical trials are recommended by the researchers.

CHF GRANT#789 IDENTITIFICATION OF CANDIDATE GENES CAUSATIVE FOR DILATED CARDIOMYOPATHY IN THE DOG (KEITH MURPHY: TAMU)—DAF SPONSORED 2007-2009 (Total Grant Amount $111,527): A publication is not expected from this extensive research project that utilized whole genome scanning and a SNIP array to search for candidate genes in a large population of unrelated Danes (all identified by echocardiogram as suffering from DCM), as the project failed to identify any candidate genes. Two chromosomes identified as possibly having a DCM association will be further researched as available Great Danes are added to the study, which will be continued by the researcher using university funding.

CHF Grant#778 ROLE OF REGULATORY T CELLS IN DOGS WITH OSTEOSARCOMA (Barbara Biller: CSU) DAF sponsored 2008. T-regulatory cells (T-regs) are increased in many dogs with cancer and by decreasing the percentage of these cells, in theory the dogs should then be better able to mount an immune response (and so suppress the tumor). The effect of two forms of chemotherapy, doxorubicin and carboplatin, on the percentage of T-regs is being studied, and the disease-free interval and survival time of the patients is now being followed .

CHF Grant#1018-A COMPARATIVE GENE DISCOVERY FOR CANINE CRYPTORCHIDISM (MAX ROTHSCHILD: LUS) DAF sponsored ACORN grant. 2007: FINAL REPORT RECEIVED: Specific candidate genes isolated. Investigators can now apply for a larger & more long-term grant in hopes of some definitive answers to the question of cryptorchidism in dogs.

CHF Grant#613 The Prognostic Significant of Chromosome Aneuploidy in Canine Lymphoma (Matthew Breen) DAF sponsored 2007-2010: FINAL REPORT PENDING. ABSTRACT: Lymphoma is the most common life-threatening cancer in dogs, accounting for up to 24 percent of all canine malignancies. A large proportion of canine lymphomas are responsive to chemotherapy, increasing both the length and quality of an affected dog's life. However, there is considerable difference in the response to therapy working and overall survival time. This shows that there is a need to develop more improved forms of classification. In human lymphoma, the use of cytogenetics has been used to show the presence of frequent chromosome abnormalities that have both diagnostic and predictive importance. In previous studies the researchers have identified frequent chromosome abnormalities in canine lymphoma, including copy number changes (aneuploidy) of dog chromosomes 6, 15, 16, and 18. Objective: In this project the researchers will use molecular cytogenetics to study a collection of lymphoma specimens, taken from dogs that were all treated with the same chemotherapy procedure as part of a clinical trial. This approach will allow us to determine if these frequent copy number abnormalities are able to predict response. This project hopes to increase the sophistication of diagnosis and life expectancy for canine lymphoma

CHF Grant#1005-A: A Pilot Study of Intravenous Levetiracetam for Emergency Treatment of Seizures in Dogs. (Ned Patterson) DAF sponsored 2007-2010: FINAL REPORT PENDING. ABSTRACT: Epilepsy is the most common neurological disorder in dogs and about 20-30 percent of dogs do not respond to standard treatments. Of these "refractory" cases many end up needing emergency treatment of repeated or long lasting seizures. Levetiracetam (LEV) is an anti-epileptic drug that is approved for oral use in people and has been used in the oral form in epileptic dogs with some success. In 2006 an intravenous (IV) formulation was approved for people. We have tested the IV formulation in normal dogs for which it was well tolerated both IV and for intra-muscular injections. In this study we propose to test whether one IV injection of LEV will improve the emergency treatment of seizures in dog patients in our intensive care unit. All dogs will receive our standard treatment for the emergency treatment of seizures with one-half of the enrolled dogs receiving one IV dose of LEV, and one-half of the enrolled dogs receiving an equivalent dose of a sterile IV solution as a comparison group. Objective 1: A prospective, double masked, controlled clinical study to determine if the administration of parenteral Levetiracetam (Keppra) at a dose of 30 mg/kg improves the treatment of cluster seizures (acute repetitive seizures) and status epilepticus in dogs.

CHF Grant#225 Establishing a Genetic Linkage Between Addison's Disease and DNA Markers (Anita Oberbauer: UCDavis). DAF Sponsored 2005. Abstract: 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. We have demonstrated that for Standard Poodles and Bearded Collies, Addison's disease is highly heritable. Statistical evaluation of the dogs' pedigrees suggests a single locus of large 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. (Note the Great Dane was added to this approved grant).

The following is a historical list of GDCA supported research projects:

Hip Dysplasia
Active Grant No. 1836: Identifying the Genetic Cause of Canine Hip Dysplasia
George Brewer, MD; University of Michigan 
Sponsors: Alaskan Malamute Club of America, Great Dane Club of America, Orthopedic Foundation for Animals, Rottweiler Health Foundation, Samoyed Club of America Research and Education Foundation 
Abstract: Canine Hip Dysplasia is the number one genetic health problem in dogs, with a significant frequency in over 100 breeds. The mode of inheritance may be polygenic (due to more than one gene) which has discouraged some studies of the genetic cause. However, with the proper approach, a polygenic disease can also be solved, and a DNA test or tests can be offered to help get rid of the disease. We propose a comprehensive approach studying 12 breeds and 11 additional candidate genes (beyond 2 already ruled out). Using multiple breeds increases the chance a given candidate gene will score a "hit." When a hit occurs, we will develop a DNA test to detect affected and carriers. In those breeds where the candidate gene search fails, we will do a genome-wide scan to establish linkage, which may allow us to offer a linked marker test, but in the longer run, will lead to gene discovery through homologous mapping. In the end, we expect to have a DNA test for hip dysplasia in most breeds.

Cancer
Completed Grant No. 1626: Significance of Tumor Suppressor Genes in Canine Cancer 
Jaime Modiano, VMD, PhD
AMC Cancer Research Center 
Sponsors: American Boxer Charitable Foundation, Golden Retriever Club of America, Golden Retriever Foundation, Great Dane Club of America, Health Trust Fund Scottish Terrier Club of America, Medallion Rottweiler Club, Rottweiler Health Foundation 
Abstract: The research conducted in this study will provide the basis for future research that may, ultimately, lead to scientists being able to provide a better assessment of individuals' risks for cancer (or for cancer in progeny), as well as determine whether a given dog is a good candidate for a given therapy. This project has helped to broaden the understanding of why tumors happen, so that the abnormalities can be targeted and better therapies devised. Researchers developed and tested gene therapy for melanoma. In a clinical trial involving five dogs with facial or oral melanoma, they found that the gene therapy, in which tumors were injected with modified genes, was both free of adverse effects and effective. 

Autoimmune Hemolytic Anemia

Active Grant No. 1849: Determinants of Risk in Dogs with Immune Mediated Hemolytic Anemia 
Philip H. Kass, DVM, PhD; University of California, Davis 
Sponsor: Anonymous in Memory of Pippin, Great Dane Club of America 
Abstract: Autoimmune or immune-mediated hemolytic anemia (IMHA) is a potentially fatal disorder affecting humans, dogs, mice and occasionally other species. This condition results when an animal's immune system destroys the animal's own red blood cells, resulting in anemia. There are several causes or "triggering events" known to induce this condition in people including drug administration, vaccinations, certain cancers, infections, and transplants. There is speculation that the incidence of the syndrome is increasing in dogs, and there may be identifiable triggering events that account for the increase in cases. However, we do not know how many dogs currently get IMHA, whether these cases differ from cases in the past, or whether we can identify common triggering events if we look. The goals of this study are to: 1) define the characteristics of dogs recently affected (breed, age, gender) and see if these differ from cases over the last twenty years, 2) determine if vaccinations can act as triggering events for the development of IMHA in dogs, 3) determine the incidence in dogs in the Sacramento Valley region, and 4) follow cases for a one year period to find characteristics that can be used to predict the outcome of cases (death, survival, relapses). 

Cardiomyopathy

Completed Grant No. 1428: Inheritance Patterns and Molecular Genetic Analysis of Doberman Pinschers and Boxer Dogs with Familial Dilated Cardiomyopathy 
Kathryn Meurs, DVM, PhD; The Ohio State University 
Sponsors: American Boxer Charitable Foundation, Great Dane Club of America 
Abstract: This study found that ventricular arrhythmias in Boxers are inherited as an autosomal dominant trait. Researchers found that asymptomatic Boxers have frequent ventricular premature complexes (VPCs), a specific type of irregular heartbeat that is a common form of ventricular arrhythmia. They determined that a two- to three-minute electrocardiogram (ECG) is a poorly sensitive indicator of VPCs, and instead recommend the use of a 24-hour ambulatory ECG (Holter monitor), even on asymptomatic Boxers. In studying Doberman Pinschers, they ruled out some potential candidate genes for study by demonstrating that two specific proteins and a specific gene that are abnormal in some humans with dilated cardiomyopathy (DCM)-a primary heart muscle disorder that can cause the heart to beat erratically-are normal in Dobermans with DCM. Linkage analyses for both Boxers and Dobermans continue. 

Completed Grant No. 2009: Determination of the Clinical Phenotype and Inherited Nature of Dilated Cardiomyopathy in the Great Dane. Kathryn M. Meurs, DVM, PhD; The Ohio State University. Sponsor: Great Dane Club of America, Great Dane Health Foundation. 

Abstract: Dilated cardiomyopathy is one of the most common heart diseases observed in the dog. Many breeds of dogs have a high risk of developing this disease including Boxers, Doberman pinschers, Great Danes and Cocker Spaniels. Although many breeds of dogs suffer from dilated cardiomyopathy, the disease is unique in each breed with regards to clinical signs, response to treatment and long term prognosis. Unfortunately, in most cases the disease is severe and the dogs die suddenly or die from a progressive congestive heart failure. In most cases, the cause of the disease is unknown, although there is significant evidence that the disease is inherited in Boxers and Doberman Pinschers. Although the disease is reported in the Great Dane, there is very little information regarding the clinical nature of the disease. Furthermore, although Great Dane enthusiasts have suggested a possible familial cause, there is no scientific evidence for this. The objective of this study is to determine the unique clinical attributes of DCM in the Great Dane as well as to begin to evaluate for a familial nature.

Completed Grant No. 1252: Prospective Study of Morphometric, Genetic and Dietary Risk Factors for Bloat. Lawrence Glickman, VMD, PhD; Purdue University 
Sponsors: Akita Club of America, American Bloodhound Club, American Rottweiler Club, Collie Club of America Foundation, Irish Setter Club of America, Irish Wolfhound Club of America, Morris Animal Foundation, New-Pen-Del Newfoundland Club, Weimaraner Club of America, Great Dane Club of America. 

Abstract: In the largest prospective health study ever done involving companion animals, this project identified 1900 healthy dogs of 11 giant and large breeds and collected information from owners. The dogs were followed for five years to measure the incidence of bloat, evaluate the effectiveness of commonly used bloat-prevention practices and determine the relationship between diet and bloat. The researchers found that the risk of bloat increased with increasing age, having a first-degree relative with bloat and increasing chest/width ratio. The breed at the highest risk was the Great Dane. None of the practices usually advised by experts to prevent bloat, such as raising the food bowl and limiting the amount of exercise and water before or after eating, appeared effective. In fact one of these, raising the food bowl, was associated with a higher incidence of bloat. 

 

Vaccinosis

GDCA Grant for Support of Research Colony of Beagles
Larry Glickman, DVM; Purdue University 

Abstract: Evaluation of Antithyroglobulin Antibodies After Routine Vaccination in Pet and
Research Dogs. Scott-Moncrieff JC, Azcona-Olivera J, Glickman NW, Glickman LT, HogenEsch Published in J Am Vet Med Assoc. 2002 Aug 15;221(4):515-21. 

Objective: To determine whether routine vaccination induces antibodies against bovine thyroglobulin and autoantibodies against canine thyroglobulin in dogs.

Subjects: 20 healthy research Beagles and 16 healthy pet dogs.

Procedure: For the research Beagles, five dogs were vaccinated with a multivalent vaccine and a rabies vaccine, five dogs received only the multivalent vaccine, five dogs received only the rabies vaccine, and five dogs were unvaccinated controls. The multivalent vaccine was administered at 8, 10, 12, 16, 20, 26, and 52 weeks of age and every six months thereafter. The rabies vaccine was
administered at 16 and 52 weeks of age and then once per year. Blood was collected from all dogs at 8, 16, and 26 weeks of age and then four times yearly. Assays for antibodies directed against bovine and canine thyroglobulin were performed prior to and two weeks after each yearly vaccination. For the pet dogs, blood was collected prior to and two weeks after one vaccination. 

Results: In the research Beagles, there was a significant increase in anti-bovine thyroglobulin
antibodies in all vaccinated dogs, compared with control dogs. There was a significant increase in anti-canine thyroglobulin antibodies in the two groups of dogs that received the rabies vaccine but not in the group that received the multivalent vaccine alone. In the pet dogs, there was a significant increase in anti-canine thyroglobulin antibodies after vaccination but no significant change in anti-bovine thyroglobulin antibodies. 

Conclusions and Clinical Relevance: Recent vaccination may result in increased anti-canine thyroglobulin antibodies. Whether these antibodies have a deleterious effect on canine thyroid function is unknown.

 

 

 

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