Genetics of cardiomyopathy and association with other conditions
Despite known pre-dispositions to diseases in the majority of UK kennel club registered breeds, there are currently only 93 disease associated variants identified and only 61 genetic tests commercially available across all breeds [73-75].
In human genetic testing there are tests available for 10485 conditions [76, 77]. This is a large difference despite close similarity between many diseases affecting dogs and humans [78-80]. Many tools have been utilised when identifying genetic variants associated with human diseases, these include genome wide association studies, candidate gene studies, whole exome sequencing, and whole genome sequencing [81-84]. These tools have also been utilised to some extent in some canine studies, but these approaches are often restrictively expensive for companion animal studies with limited funding available [85, 86]. The cost of these methods is delaying their clinical and research application in evaluating the genetic basis of canine diseases. Identification of susceptibility loci for these diseases has the potential to bring improvements in diagnosis and may lead to improved treatments in line with diseases which already have genetic loci associated with them [87-92].The development and progression of common non-communicable diseases such as heart disease are influenced by a combination of risk factors. It has been shown in several diseases that interactions between environmental and genetic risk factors are important in the development and progression of disease [13, 15]. Environmental risk factors for people with DCM are often modifiable as individuals can make informed choices with regards to lifestyle changes to reduce their risk of developing disease [7, 10, 93], likewise dog owners may be able to modify environmental risk factors for their animals. Currently genetic risk factors are not modifiable, although genome editing technologies may allow this in the future [94].
Despite this, individuals identified as having a high genetic risk of developing a disease are currently able to reduce their risk of developing disease. Options available include making lifestyle changes to reduce other risk factors, increased disease surveillance, and prophylactic medicine and surgery [4, 7, 10, 92, 93, 95, 96]. Increased disease surveillance can allow for early disease detection and therefore early treatment, which is associated with improved prognosis [87, 92]. An additional benefit of knowledge of the underlying genetic cause of disease is that it could lead to targeted treatments such as rectifying the defective gene or drugs targeting affected pathways [88, 89].There are over 50 genes associated with DCM in people, some with multiple mutations, whereas there have only been 10 loci associated with canine DCM [85, 86, 97-100]. We have recently reviewed the genetics of canine and human DCM [27]. There has also been a RNAseq study examining the difference in expression of genes between canine DCM hearts and non-DCM hearts [101]. In the RNAseq study, genes involved in cellular energy metabolism were expressed less in the DCM hearts than the non-DCM hearts [101]. In several breeds canine DCM has been shown to be heritable [29, 31, 34]. To date mutations in only two genes (PDK4 and STRN) and a single nucleotide polymorphism (SNP) on chromosome 5 have been associated with canine DCM [85, 97, 98, 102], and these are limited to a few breeds, suggesting additional genetic causes remain unknown. Of note are also cardiac troponin T and dystrophin which have both been highlighted in people, dogs and other species in relation to dilated cardiomyopathy [103-105], as mentioned in relation to gene therapy trials.
Genetic models and studies have also shown sex-linked genetic influences in relation to pathogenesis and a multigenic contribution to canine DCM [102]. The work showed that by combining three factors (PDK4, Chr5 TIGRP2P73097 SNP and an X-linked locus) DCM incidence could be more accurately predicted in a canine population.
Overall this data showed that models incorporating multiple factors were more effective than those incorporating a single factor [102]. This has implications for future studies of the genetics and management of DCM, including monitoring which could enable earlier clinical intervention of individuals who are high risk.In addition to commonly being diagnosed with DCM, IWHs are frequently diagnosed with atrial fibrillation (AF) [16, 19]. Despite the presence of AF in a large percentage of dogs with DCM, the mechanistic and clinical relationship between DCM and AF has not been clarified [16-19]. IWHs can develop DCM without AF, though it seems that along with the use of animal models of disease, cell lines, and computer simulations [113-119]. Natural models of disease allow researchers access to additional cases of disease without inducing disease and causing additional suffering, because the animals involved develop disease irrespective of involvement in a study. Therefore, a relevant resource for investigating health and disease is the companion animal population, within which dogs in particular are useful as natural models of the equivalent human disease [1, 120-123].
The canine population overall is genetically heterogeneous, yet breeds are comparatively homogeneous which enhances their value as genetic models of disease [124]. Each breed of dog is a closed population and ancestry can typically be traced for many generations, often to the founding members of the breed [124-126]. This facilitates understanding the mode of inheritance of traits and diseases, and also restricts the amount of genetic diversity within a breed [34, 121, 125, 127]. Founder effects and subsequent inbreeding within pedigree dog breeds have led to differing allele frequencies between breeds, and some breeds are more prone to developing particular conditions than others [124, 128, 129]. This makes breeds with homologs of human conditions ideal for identifying potential genetic loci associated with disease for both canine and human benefit [123, 130].
Many canine disease phenotypes can be closely matched to human disease phenotypes with similar disease progression, pathology, treatment options, and prognosis [78-80]. Indeed there are currently 383 potential canine models for human disease listed in OMIA (Online Mendelian Inheritance in Animals), greater than any other species [78, 79]. Dogs are typically treated as family members and so inhabit the same environment as their owners with the associated exposure to the same potential environmental toxins, including, for example, air pollution [131]. Pet dogs also frequently benefit from high quality medical care, such that illnesses are detected and treated promptly, similar to the human population [132]. These characteristics of the canine population make it a valuable resource as a model of human disease. Examples of diseases with homologies in humans and dogs include diabetes, cardiomyopathies, cancers, and eye diseases [79, 120, 123, 133, 134].
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