Genetics of breed susceptibility to canine diabetes mellitus and insulinoma: From one extreme to the other
Lead Research Organisation:
Royal Veterinary College
Department Name: Pathology and Pathogen Biology
Abstract
Pet dogs exhibit tremendous diversity across different breeds, not only in physical appearance but also in disease susceptibility. Diabetes mellitus (DM), affects 1 in 300 dogs and results from destruction of pancreatic beta-cells, leading to insulin deficiency. Samoyed dogs are highly susceptible to DM (OR = 21.7), whereas Boxer dogs are resistant (OR =0.06), suggesting that beta-cells in the former breed are more 'fragile'. However, Boxers are susceptible to developing insulinomas (INSA), implying that the price paid for improved beta-cell survival is the potential for malignant transformation and tumour formation. The genetic risk associated with these two disease syndromes is likely to be 'fixed' within each breed. We propose an approach whereby we compare whole genome sequences (WGS) in dogs at the extremes of the pancreatic beta cell phenotype.
HYPOTHESIS
We hypothesise that comparison of the Boxer genome to the Samoyed genome will reveal unique variations in genes critical for beta-cell health and survival. Such variants may protect from DM, but predispose to INSA and vice versa. Identification of genes and mechanisms involved in beta-cell health and resilience will reveal new pathways for intervention in prevention or treatment of DM and INSA.
AIMS
To undertake WGS (Illumina HiSeqX) of at least 10 Samoyeds and 10 Boxers (10x to 30x coverage, dependent on pilot work), with a focus on cases of DM and INSA. Labrador retrievers will be used as a reference breed, with a neutral risk of both diseases.
To identify breed-specific variants with relevance to pancreatic beta-cell biology and investigate these in a larger cohort of dogs (n=100) affected with DM and INSA across a range of breeds
METHODS
DNA samples for this project are already available. A bespoke bioinformatic pathway will be used for analysis, utilising the high-performance computer cluster at the Wellcome Trust Centre for Human Genetics, University of Oxford.
HYPOTHESIS
We hypothesise that comparison of the Boxer genome to the Samoyed genome will reveal unique variations in genes critical for beta-cell health and survival. Such variants may protect from DM, but predispose to INSA and vice versa. Identification of genes and mechanisms involved in beta-cell health and resilience will reveal new pathways for intervention in prevention or treatment of DM and INSA.
AIMS
To undertake WGS (Illumina HiSeqX) of at least 10 Samoyeds and 10 Boxers (10x to 30x coverage, dependent on pilot work), with a focus on cases of DM and INSA. Labrador retrievers will be used as a reference breed, with a neutral risk of both diseases.
To identify breed-specific variants with relevance to pancreatic beta-cell biology and investigate these in a larger cohort of dogs (n=100) affected with DM and INSA across a range of breeds
METHODS
DNA samples for this project are already available. A bespoke bioinformatic pathway will be used for analysis, utilising the high-performance computer cluster at the Wellcome Trust Centre for Human Genetics, University of Oxford.
Publications
Denyer AL
(2020)
Dog leucocyte antigen (DLA) class II haplotypes and risk of canine diabetes mellitus in specific dog breeds.
in Canine medicine and genetics
Denyer AL
(2021)
Genetics of canine diabetes mellitus part 1: Phenotypes of disease.
in Veterinary journal (London, England : 1997)
Denyer AL
(2021)
Genetics of canine diabetes mellitus part 2: Current understanding and future directions.
in Veterinary journal (London, England : 1997)
O'Kell AL
(2023)
Etiology and Pathophysiology of Diabetes Mellitus in Dogs.
in The Veterinary clinics of North America. Small animal practice
Studentship Projects
| Project Reference | Relationship | Related To | Start | End | Student Name |
|---|---|---|---|---|---|
| BB/M009513/1 | 01/10/2015 | 31/03/2024 | |||
| 1902557 | Studentship | BB/M009513/1 | 01/10/2017 | 30/11/2021 | Alice Denyer |
| Description | Diabetes mellitus (DM) affects approximately 1 in 300 dogs in the UK and is much more common among some breeds that others. It is thought that a number of disease processes may be involved and genetic factors may explain why some breeds are predisposed to, or protected from, developing the disease. Previous evidence has suggested that the immune system may contribute to destruction of the pancreas, similar to in human type I DM. A key group of immune system genes, called the dog leucocyte antigen (DLA) genes, have been previously investigated and certain forms of these genes found to be more common among diabetic dogs. However, no investigations have yet been carried out in individual dog breeds. This study compared the DLA genes among diabetic and non-diabetic dogs within 18 different breeds and found that in five breeds, the DLA genes were associated with increased risk or protection from DM. These associations support a role for the immune system in the development of DM in certain dog breeds. |
| Exploitation Route | The outcomes so far will further support our research, and the research of others, investigation the causes and possible treatments for canine diabetes. In the longer term it is hoped that this will lead to improved diagnosis and treatment of canine diabetes and improvement of the welfare of animals and owners. |
| Sectors | Other |
| URL | https://onlinelibrary.wiley.com/doi/full/10.1111/jvim.15658 |
| Description | Free registration offered by Royal Canin for the 29th ECVIM-CA Congress |
| Amount | € 300 (EUR) |
| Organisation | Royal Canin |
| Sector | Private |
| Country | France |
| Start | 09/2019 |
| End | 09/2019 |
| Description | International Canine Health Award - Postgraduate Inspiration Award |
| Amount | £10,000 (GBP) |
| Organisation | The Kennel Club Charitable Trust |
| Sector | Charity/Non Profit |
| Country | United Kingdom |
| Start | 05/2018 |
| Title | The UK Canine Diabetes Register |
| Description | Certain breeds of dog, including the Samoyed, Cairn and Tibetan terriers are predisposed to developing diabetes, whereas others, including the Boxer and German shepherd dog, are less susceptible. Such breed differences suggest that there is a genetic component to disease susceptibility. To this end, our group has established a national canine diabetes register. This includes a database of clinical information and an archive of residual samples. This diabetic register is part of ongoing research being carried out by the Canine Diabetes Genetics Partnership. |
| Type Of Material | Database/Collection of data |
| Provided To Others? | No |
| Impact | Several previous publications have used the database for research into canine diabetes (prior to commencement of the current project). The database is also key to the current project and use of the archive is ongoing. |
| URL | https://www.rvc.ac.uk/diabetesregister/ |
| Description | Canine Diabetes Genetics Partnership |
| Organisation | The Canine Diabetes Genetics Partnership |
| Sector | Academic/University |
| PI Contribution | The partnership was founded by my supervisors a the start of my PhD. We oversee and run the partnership meetings, website and social media. I am currently the sole PhD student in the partnership and my research contributes to the outcomes of the partnership |
| Collaborator Contribution | The CDGP is a multi-disciplinary group of expert clinicians and scientists, from a range of UK institutions, sharing a special interest in the genetics of diabetes mellitus in dogs. The Partnership was formed in 2017 with funding from the PetPlan Charitable Trust, with the aim of using Whole Genome Sequencing to explore the genetic risk of canine diabetes in breeds considered to be at low risk (e.g. Boxer) and high risk (e.g. Samoyed) of developing the disease. We meet together to share expertise and sometimes facilitate access to data. |
| Impact | Poster presentation at 10th International Conference on Canine and Feline Genetics and Genomics 2019 and oral abstract presentation at ECVIM 2019. Other manuscripts and abstracts are in preparation for submission in 2020. |
| Start Year | 2017 |