Dept of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden
Objectives of the Presentation
Describe the clinical characteristics of several immunological diseases including diabetes mellitus.
Explain how the careful clinical characterization will aim in genome-wide association to find genes for complex diseases.
Provide examples of the mapping of a complex trait and how the data can be used by breeders and clinicians.
Overview of the Issue
Many of the dog's chronic diseases are suspected to have a complex etiology with several genes and environmental factors involved. By identifying the gene variations responsible for these diseases, a better understanding of the disease mechanisms will be achieved and new treatments possible. Many of these complex diseases show a strong breed predilection. From various databases, these predisposed breeds may be identified. To map the genes associated with a complex disease, it may be enough with as little as one hundred affected and one hundred healthy control dogs from the same breed. It is however, of greatest importance, that the dogs in each group are correctly classified.
For some of these immunological diseases e.g. diabetes mellitus, Shar-Pei Fever, atopy and systemic lupus erythematosus (SLE)-related disease, we have primarily focused our research on classification of the different subtypes that are hidden under the mask of identical symptoms.
Diabetes mellitus is a major global public health problem in humans and also of concern in dogs. The disease results from the body's inability to maintain a normal glucose concentration. The major complaint at first veterinary consultation is usually an increased thirst and increased urination. The owner might also have noticed a loss of weight, in spite of a good appetite. The diagnosis is based on measurement of glucose in the blood and urine. Dogs with diabetes mellitus are most often dependent on daily injections of insulin for survival. Intact female dogs are usually spayed shortly after diagnosis, because of the insulin-antagonistic features of the sex hormone progesterone. One-year-survival is reported to 64% for dogs that survive initial stabilisation.
Breeds that are consistently reported to have a high frequency of diabetes mellitus are the Samoyed, Cairn terrier and Australian terrier. Breeds that are consistently reported to have a low frequency are golden retriever, boxer and the German shepherd. Most dogs are older than five years at onset of diabetes mellitus. Several studies have found female dogs to have an increased risk for diabetes mellitus.
In human medicine, four classes with more than 50 subtypes of diabetes is recognized.(1) Our research shows that different dog breeds are predisposed to different subtypes of diabetes. An example of this is that in some breeds such as the Norwegian elkhound, the Swedish Elkhound and the border collie, only female dogs are affected by the disease(2) indicating a predisposition to a subtype of diabetes that is related to progesterone. This was confirmed in another study of dogs with gestational diabetes.(3) A genome-wide association study is underway for a large cohort of female elkhounds. We are currently developing a new classification system for canine diabetes mellitus, which will provide a framework within which to identify and differentiate various forms and stages of diabetes mellitus.
Shar Pei Fever
Shar-pei fever is a hereditary periodic fever syndrome of an autoinflammatory nature seen in the Chinese Shar-pei. The immune system of these dogs creates a spontaneous fever and inflammation response that do not have an infectious or an autoimmune reaction as the cause.
The disease is characterized by random inflammatory events with fever, sometimes with an accompanying joint swelling, that usually last 24-36 hours. The part of the dog which is most affected of inflammation are the hocks, the condition is therefore also referred to as "swollen hock syndrome" (SHS). The first episode typically occurs in a very young age when the dog is less than six months old and the frequency of the episodes vary a lot between individuals. Recovery is rapid and there are no detectable symptoms between the episodes.
Dogs with Shar-pei fever have a dysregulation of the cytokine interleukin6 (IL-6) (Rivas et al 1993), which is a main mediator of fever. IL-6 is not only the most important stimulator of fever but also triggers the production of Acute Phase Proteins (APP:s). The chronic background of inflammation puts them at risk for developing reactive systemic amyloidosis, which is the accumulation of APP:s in the organs and can lead to death from kidney failure. Not every dog with Shar-pei fever will develop amyloidosis but the fevers are a big red flag that they have defects leading to aberrant auto-inflammation and are at high risk for kidney failure.
Shar-Pei fever has been reported to be inherited in an autosomal recessive manner based on pedigree studies, but symptoms are quite common within the breed and complex in nature so it is difficult to ascertain the inheritance pattern accurately. The prevalence of this episodic fever is high in the breed; around 20-50% of the individuals in U.S. are affected (Linda Tintle, personal communication). We have been characterizing the clinical symptoms for dogs used in a genome-wide screen to find the genes for Shar Pei Fever.
Systemic Lupus Erythematosus (SLE)-Related Disease Complex
We have characterized a systemic lupus erythematosus (SLE)-related disease complex comprising immune-mediated rheumatic disease (IMRD) and steroid-responsive meningitis-arteritis (SRMA) in the canine breed Nova Scotia duck tolling retriever (NSDTR). The IMRD disease involves chronic musculoskeletal signs with stiffness, mainly after resting, and pain from several joints. Also, the dogs often display antinuclear antibodies (ANA), showing that an auto-immune reaction to the body's own cells occurs. SRMA-affected dogs display pain from the neck, stiffness, fever, depression, anorexia and response to corticosteroid treatment.
A similar disease is seen, but is less frequent in several other breeds including German shepherd dog and cocker spaniels (IMRD) and boxers and petite basset griffon Vendeen (SRMA).
For all of these diseases and several other immunological diseases we are performing careful characterization f the disease followed by genome-wide screens to identify the disease genes.
Once disease genes are found, genetic tests can be developed and used for diagnosis, breeding advice or to guide treatment options. Since several genes are likely to influence each disease, and multiple diseases often are present within each breed, the information gathered from genetic tests will have to be used cautiously and in concert.
1. Report of the expert committee on the diagnosis and classification of diabetes mellitus. Diabetes Care, 2003. 26 Suppl 1: p. S5-20.
2. Fall, T, Hamlin, H H, Hedhammar, A, Kampe, O, and Egenvall, A, Diabetes mellitus in a population of 180,000 insured dogs: incidence, survival, and breed distribution. J Vet Intern Med, 2007. 21(6): p. 1209-16.
3. Fall, T, Johansson Kreuger, S, Juberget, A, Bergstrom, A, and Hedhammar, A, Gestational diabetes mellitus in 13 dogs. J Vet Intern Med, 2008. 22(6): p. 1296-300.