Åke A. Hedhammar, DVM, PhD, DECVIM-CA
The role of dogs in comparative studies has expanded to include natural models of comparative value for dysfunctions/diseases in humans. Accordingly, the role of small animal veterinarians has evolved from being simply caretakers of experimental animals to highly regarded collaborators in translational studies. The canine genome1 and follow up studies revealing its power in genome-wide (GW) analyses2 have resulted in a dramatic increase in published studies on segregation and molecular genetics in canine diseases of almost all organ systems. Several groups worldwide have focused on canine diseases of comparative value. Whether or not these groups have evolved out of primary focus on genomics, human or veterinary medicine, they all rely on the quality of the canine phenotypes, i.e., the diagnosis and definition of disease entities.
The veterinary profession has a role to indicate disease phenotypes of relevance and to guarantee inclusion and exclusion criteria of individuals chosen for cases as well as controls. The dual value of these studies for both canine and human health underlines the importance of the profession in translational medicine. The current focus is on the rapidly expanding genomic area; however, it is likely that animal models will also contribute to studies on proteomics and metabolomics. Studies using canine models for complex diseases have the potential to also reveal interactions with environmental factors. The objective of this paper is to give examples of current research on the value of breed related diseases for comparative studies and to discuss the role of the veterinary profession in this work.
Canine Models of Complex Diseases
Among collaborative efforts to take advantage of the features of the canine genome, structure of the canine populations and well-defined phenotypes, the European multicenter project LUPA, is a good example. LUPA, http://www.eurolupa.org/, named after the female wolf that nourished the human twin founders of Rome, is a large scale collaborative project supported by funding under the 7th Research Framework Programme of the European Commission in the Health domain. With the aim of "Unravelling the molecular basis of common complex human disorders using the dog as a model system" twenty-two institutions in 12 European countries are currently working on 25 disease phenotypes organized in work packages which include cancers (e.g., mammary tumour and melanoma), cardiovascular diseases (e.g., mitral valve disease and dilated cardiomyopathies), inflammatory conditions (e.g., atopic dermatitis and lymphocytic thyroiditis), and neurological abnormalities (e.g., epilepsy and aggressiveness).
Involvement of the veterinary profession within academic institutions and clinical practice is greatly appreciated, but could, for the benefit of the project and the profession, be further enhanced. Identifying adequate sample sizes of well-phenotyped cases as well as controls is of utmost importance for success. Revealing the genotype of canine diseases of comparative interest not only leads to the possibility to screen for affected genotypes in canine breeding programs but also, and probably even more importantly, gives both the veterinary and human medical professions further insights into aetiology, as basis for new therapies and prevention.
Breed, Sex and Age as Indicators of Suitable Populations for Comparative Studies
In search for canine models of complex diseases, the importance of population-based epidemiological data and strict inclusion criteria for cases as well as controls is essential. With access to insurance databases in Europe (Sweden, Norway and UK), we are able to indicate e.g., breed populations at high (and low) risk for various diseases to be utilised in a case control design for epidemiological as well as molecular genetic studies. From England3-4 and Sweden5-8 several epidemiological studies have been published including breed-, sex- and age-specific morbidity and mortality data for various diseases of comparative interest, including mammary tumour,4,5 atopy,6 diabetes3,7 and heart diseases such as cardiomyopathy and myxomatous mitral valve diseases.8 These data have been used to identify high risk breeds for cohort studies and to calculate the total number of cases to be expected over a certain time period.
In Sweden we have full access to the databases at Agria Insurance Company, as well as the Swedish Kennel Club (SKC). Within the scope of the collaboration between SLU and Agria/SKC, opportunities have been created to access individual dog data with specific diagnoses in the insurance database and link them with ancestral background at SKC. Specific information can be retrieved which enables us to contact owners of both dogs with specific phenotypes and related dogs and to access extensive genealogies and informative pedigrees. These features have already been used not only to identify birth cohorts but also individual dogs to be recruited as cases as well as controls and for identification of family material in studies of atopy, diabetes and mammary tumours. The same frame is also used for sampling of related and unrelated "controls" in molecular and epidemiological case-control studies.
By using survey information on cases and controls of various phenotypes, we are able to include environmental factors in the analyses of genotypes at risk. Early dietary exposure, daily energy intake, amount and intensity of exercise,9 body condition scoring and intake of iodine are examples of nutrition-related epidemiological data of interest in the aetiology of atopic dermatitis, diabetes, mammary tumours and lymphocytic thyroiditis.
One Specific Example
In the Swedish dog population--in which most males and females are not neutered--the overall incidence of diabetes mellitus (CDM) is 16.2 per 10,000 dog-years at risk with a high variation by breed. Australian Terriers, Samoyeds, Swedish Elkhounds and Swedish Lapphunds were found to have the highest incidence. There was no overall gender difference, but the proportion of affected females varies significantly between breeds. Swedish Elkhounds, Beagles, Norwegian Elkhounds and Border Collies which develop CDM are almost exclusively "intact" females. By these features and further elucidation on clinical manifestations of CDM in these breeds, a canine model has evolved for gestational and progesterone-related diabetes in humans.10 In addition, we have shown that, in these breeds, feeding habits, exercise and weight are significant risk factors for this type of CDM, known features also of most diabetes (type 2) in humans.9
Therapeutic Studies and Clinical Trials
There are already canine models available for gene therapy against i.e., various retinal diseases, Leucocyte Adhesion Deficiency and muscular dystrophies. And even if that is not the only and the ultimate goal for comparative studies more will probably emerge out of the current interest in canine models in the era of genomics. A natural next step after revealing similarities in pathophysiology for canine and human disorders would be clinical trials that can serve as proofs of concept rather than just experimental studies on toxicology. That calls for an improvement in reporting of clinical trials.11 Canine models of atopic dermatitis have recently been praised not only to help answer questions relative to pathogenesis, but also as a tool for rapid screening of drugs with potential clinical application.12
The Role of the Veterinary Profession
In small animal medicine we are now in the position to prove our value as important contributors to the field of translational medicine by not only conducting research and clinical practice for the benefit of companion animals, but also as an extra dimension to share these findings with the medical community. The term one medicine rests on the translation between human and veterinary medicine in both directions.
1. Lindblad-Toh, et al (2005) Genome sequence, comparative analysis and haplotype structure of the domestic dog. Nature 438(7069):803-19.
2. Karlsson, et al (2007) Efficient mapping of Mendelian traits in dogs through genome-wide association. Nat Genet 2007 39(11):1321-8.
3. Catchpole, et al (2005) Canine diabetes mellitus: can old dogs teach us new tricks? Diabetologia. 48(10):1948-56.
4. Dobson, et al. (2002) Canine neoplasia in the UK: estimates of incidence rates from a population of insured dogs. J Small Anim Pract 43(6):240-6.
5. Egenvall, et al (2005) Incidence of and survival after mammary tumours in a population of over 80,000 insured female dogs in Sweden from 1995-2002. Prev Vet Med 69, 109-127.
6. Nødtvedt, et al. (2006) Incidence of and risk factors for atopic dermatitis in a Swedish population of insured dogs. Veterinary Record 159, 241-246.
7. Fall, et al (2007) Diabetes mellitus in a population of 182,087 insured dogs: Incidence, survival and breed pattern. J Vet Intern Med 21(6):1209-16.
8. Egenvall, et al. (2006) Heart disease as a cause of death in insured Swedish dogs younger than 10 years of age. J Vet Intern Med 20(4):894-903.
9. Klinkenberg, et al. (2006) Feeding, exercise, and weight identified as risk factors in canine diabetes mellitus. J Nutr 136:1985S-1987S.
10. Fall, et al. (2008) Gestational diabetes mellitus in 13 dogs. J Vet Intern Med 22(6):1296-300.
11. Sargeant, et al. (2009) Quality of reporting of clinical trials of dogs and cats and associations with treatment effects.J Vet Intern Med.
12. Marsella, Girolomoni (2009) Canine models of atopic dermatitis: a useful tool with untapped potential. J Invest Dermatol 129(10):2351-7.