WP3 Inflammatory disorders

WP3.1 Atopic dermatitis (AD) – Leader : University of Bern

Atopic dermatitis (AD), recently renamed atopic eczema (AE), in humans is a very common disease with current lifetime prevalence in children in developed countries of 10-20%. It can be estimated that around 15 million people are affected by atopic dermatitis in the European Union. Human twin studies point to a strong genetic component for AD: concordance rates for monozygotic twins have been estimated between 72 and 86%, compared to 21-23% for dizygotic twins. Mutations in fillagrin have been shown to contribute the AD susceptibility but only account for part of the inherited predisposition. Studies in dogs have shown remarkable similarities of clinical signs and pathophysiological mechanisms between dogs and humans. At present, it is the only characterized non-mouse spontaneous animal model for AD. Dog models thus offer a very good chance to learn more about the predisposing genetic factors involved in AD.

Canine atopic dermatitis (cAD) represents a chronic relapsing inflammatory skin disease with characteristic clinical features. Genetic background, exposure to aeroallergens and possibly food allergens, microbial antigens, and distinct immunologic features contribute to the development of recurrent pruritic skin lesions. By definition cAD is associated with IgE antibodies to environmental allergens. The diagnosis of cAD is based upon the fulfilment of a minimum number of strongly associated clinical criteria and elimination of other relevant differential diagnoses. A diagnosis of cAD can only be made after exclusion of other pruritic diseases such as food adverse reactions, flea bite hypersensitivity and sarcoptes infection. There is a strong breed predisposition: Labrador and Golden Retrievers, Boxers, Dalmatians, Poodles, and West Highland White Terriers, are known to be at increased risk. The heritability of cAD in Labrador and Golden Retrievers was recently estimated to be 0.47 (± 0.17). Our goal is the identification of genetic factors in the dog involved in the aetiology of AD.

WP3.2 Diabetes – Leader : University of Uppsala

Human diabetes mellitus (DM) is a heterogeneous group of metabolic disorders characterised by chronic hyperglycaemia resulting from a disruption of insulin secretion, insulin action or both. Long term complications of the disease, regardless of ætiology, are damage to the kidneys, nerves, eyes, blood vessels and heart, leading to renal failure, neuropathy, blindness, cardiovascular disease and increased mortality. As many as 1% of the population world wide may be affected. At present, diabetes is increasing rapidly at approximately 4% per year and it is estimated that in some countries by 2025, caring for such patients will consume 25% of national health budgets.

In humans there are two main sub-groups of DM, Type 1 (T1D) and Type 2 (T2D). Other forms, including gestational diabetes and monogenetically inherited diabetes, e.g. MODY (maturity onset diabetes of the young) and mitochondrial disorders exist, but are less common. Although T1D occurs predominantly in children or young adults, it has become increasingly recognised that a slowly progressive form of autoimmune T1D can occur, known as latent autoimmune diabetes of adults (LADA), where diabetes does not usually manifest until adulthood (i.e. >30 years of age). It is estimated that as many as 20% of patients initially diagnosed as T2D, actually have LADA. All forms of human DM are considered to have a genetic component to their aetiology. Some are caused by the effects of single gene mutations, whereas T1D and T2D are complex disorders where multiple risk genes and environmental factors contribute to disease pathogenesis. Twin and family studies have been useful in resolving their relative contributions. Extensive efforts have already been put into identifying the genetic factors in both T1D and T2D. Strong associations of the human Major Histocompatibility Complex (MHC) with T1D have been identified as well as with LADA. Areas of linkage have been identified in human studies and a number of disease genes for both T1D and T2D characterised, but results are still preliminary. Inbred rodent models of DM have been useful in both physiological and genetic studies, although these are not without their limitations. It is now increasingly realised that canine DM represents an important model of the human condition which offers unique advantages for identifying genes involved in the development of the disease.

Diabetes phenotypes in the dog

Canine DM is a heterogeneous disorder, in terms of disease pathogenesis. There are, however, striking similarities comparing some sub-types of canine diabetes with their human counterparts, particularly for neonatal diabetes, dioestrus/gestational diabetes and LADA. The aim is to focus on specific forms of canine diabetes with very strong evidence for genetic predisposition.

  • A neonatal form of insulin deficiency diabetes observed in a pedigree of Labradors from the UK.
  • A Familial form of insulin deficiency diabetes in the Polish Lowland sheepdog or Polski Owczarek Nizinny (PON).
  • Dioestrus/gestational diabetes in Swedish Elkhounds, Beagles and Border Collies.
  • Autoimmune insulin deficiency diabetes in older dogs of several breeds, similar to LADA in humans. There are clear breed differences in susceptibility to DM with the Samoyed, Cairn and Tibetan terriers overrepresented, whereas DM is rarely seen in German shepherd dogs and Boxers. This strongly suggests that there are genetic factors associated with disease susceptibility and resistance. There is also evidence that autoantibodies directed against GAD65, can be detected in a proportion of diabetic dogs, which is similar to that seen in human T1D.

WP3.3 Hypothyroid disease – Leader : University of Manchester

Autoimmune thyroid diseases affect more than 1% of the human population and are the most common autoimmune diseases in human. Hashimoto’s thyroiditis and Graves’ disease are the two main clinical types of thyroid disease. Genetic mapping of thyroid disease genes in humans has met with limited success, although associations with the Major Histocompatibility Complex (MHC) have been demonstrated. Genetic linkage and association studies of human immune mediated thyroid conditions have provided evidence for the contribution of non-MHC susceptibility gene regions and loci. Perhaps the strongest susceptibility gene is the CTLA-4 gene. Recent studies have shown association between a regulatory mutation in the CTLA-4 promoter and increased anti-thyroperoxidase autoantibodies in Hashimoto’s thyroiditis. Other reported disease genes include the CD40, thyroglobulin and the immune mediated regulator gene on chromosome 21. The explanation for observing multiple associated loci suggests multiple different autoantigens besides thyroglobulin and thyroperoxidase. Another possibility may be the existence of other MHC-linked disease genes in linkage disequilibrium with the class II alleles and haplotypes associated with thyroiditis. As with other autoimmune diseases in mammals, autoimmune thyroid conditions are likely to have additional genetic components besides MHC in their aetiology and this is supported by the fact that these diseases display a broad range of clinical features and are difficult to diagnose.

Canine Hypothyroid disease

Primary hypothyroidism is a common endocrinopathy in dog, and it is often caused by lymphocytic thyroiditis. Canine lymphocytic thyroiditis is considered to be an immune mediated disease based on its clinical and histological similarities to Hashimoto’s thyroiditis in man, and because of the prevalence of autoantibodies to thyroglobulin. Antibodies to circulating T3 (tri-iodothyronine) and/or T4 (thyroxine) and thyroperoxidase may also be present.

Very significant differences in prevalence of cHD in different breeds support an inherited component to predisposition. As an example, cHD reaches incidences of 14% in both Giant Schnauzer and Hovawart, but is also over-represented in Rhodesian Ridgeback, Dobermann and Boxers. Association with MHC Class II haplotypes has been reported in some populations but can’t account for all inherited predispositions, thus justifying the search for additional susceptibility loci by means of GWA.

WP3.4 Resistance to Leishmaniosis – Leader : Universitat Autònoma de Barcelona

Visceral leishmaniasis is endemic in 88 countries on 4 continents and in terms of global disease burden it is the third most important vector-borne disease. The overall prevalence is 12 million people although the population at risk is 350 million. Leishmaniasis is regarded as the most important zoonotic disease within Europe. Zoonotic visceral leishmaniasis, caused by the protozoan Leishmania infantum and transmitted by sandfly vectors, is a fatal disease of domestic dogs, wild canids and humans which occurs mainly in the Mediterranean, Middle East and South America. The domestic dog is considered the major host for zoonotic leishmaniasis, and the prevalence of infection in dogs can be as high as 60% in endemic areas. Leishmaniasis is emerging within non endemic areas and is thus increasingly becoming an important concern both from human public health and animal welfare perspectives due to movement of infected dogs, ongoing climatic change and the consequent extension of the range of the sandfly vector towards more northern latitudes. Our goal is the identification of susceptibility genes for Leishmania infection in dogs.

Susceptibility to Leishmania infection is known to be under genetic control in mice, humans and also in dogs, and several genes and candidate regions (MHC, Slc11a1 formerly known as Nramp1, IL4, IFNGR) have been significantly associated with susceptibility to visceral leishmaniasis in different populations. Evidence for genetic control in dogs is provided by the variable outcome of infection in experimentally-infected dogs and the difference of prevalence of infection between dog breeds. Genetic epidemiology of Leishmania infection in dogs reveals higher prevalence of the disease (up to 25%) in Boxer, German Shepherd, Doberman and Cocker Spaniel and among Foxhounds in North America. Conversely, it has been suggested that certain breeds may be resistant to leishmaniasis, i.e. the Mediterranean Ibizan Hound, an autochthonous breed from the Balearic Island of Ibiza.