Research

Cardiac Arrhythmias

Irregular heart rhythms, or cardiac arrhythmias are thought to be an important cause of sudden death in horses during exercise. Most horses that develop arrhythmias have no underlying structural heart disease, making it challenging to detect animals that may succumb to the condition. We are working to develop cost effective and non-invasive methods to identify horses who will develop arrhythmias at exercise by:

Establishing the role that genetic variants play in causing arrhythmias. Studies in human athletes with arrhythmias but no underlying heart disease show the condition is almost exclusively caused by genetic variants. We have identified variants in horses with arrhythmias that were predicted to have a damaging effect of the gene they are in by computer software. We are in the process of determining if these variants are associated with arrhythmias in horses.
Using at-rest electrocardiograms (ECGs). Currently, exercising ECGs are required to identify horses that develop arrhythmias at exercise. Exercising ECGs are difficult to perform, unreliable, and frequently contain artifacts that make interpretation difficult. Our collaborators in the UK (Drs. Jeevaratanam and Marr) have already shown that it is possible to use at-rest ECGs to identify horses that have previously had atrial fibrillation (the most common arrhythmia known to cause problems in horses). We are now working with them to determine if other arrhythmias can be identified this way.

Overall, this work will allow us to develop screening protocols for early identification of horses at high risk of cardiac arrhythmias. This will allow for increased monitoring of these horses both to reduce their risk of sudden cardiac death and also to understand why certain horses do die during exercise. Long-term, this will reduce the rate of sudden cardiac death in exercising horses.

Translational potential. Racehorses are one of the few naturally occurring highly athletic domestic animal species. Therefore, they make an interesting animal model of arrhythmias and sudden cardiac death in human athletes. We hope that by improving understanding of arrhythmias and reducing the rate of sudden cardiac death in horses, we can also benefit humans.

Suspected Mendelian diseases that are analogous to human disease

Breeding practices in the horse have led to decreased genetic diversity and increased inbreeding, resulting in an increased incidence of genetic disease. Until recently, identification of disease in small numbers of affected cases was difficult or impossible. However, work in humans and cattle has shown that a catalog of genetic variation can be used to identify disease-causing mutations in patients with genetic disease resulting from a defect in a single gene (Mendelian genetic diseases). During my PhD we created the largest database of genetic variation using whole genome sequencing (WGS) of 534 horses. In the second aim of my PhD I prioritized variants for 11 diseases in the horse that are similar to a Mendelian genetic disease in humans. Our long term goal is to follow-up with these variants and identify the disease-causing variant(s) for each disease. Many of these equine diseases are challenging to diagnose and understanding the genetic basis of these diseases can improve our ability to diagnose them. In addition, the development of DNA based genetic tests will allow for owners and breeders to identify breeding stock that can pass disease genes on to their offspring to prevent the birth of affected foals or avoid costly therapy in the case of fatal conditions. Finally, understanding the cause of these diseases can enable the development of novel and specific treatments.

Idiopathic Renal Hematuria. Idiopathic renal hematuria manifests as severe and potentially fatal hemorrhage from one or both kidneys into the urine. No known cause has been identified, but over 50% of affected horses are Arabians. Similar syndromes are seen in humans and dogs, and genetic variants in the COL4A4 and COL4A3 genes have been identified as the cause of familial benign hematuria. We have prioritized 1,300 putative arrhythmia-causing variants from 9 cases of idiopathic renal hematuria in Arabian horses. We will refine these variants using additional variant prioritization software tools to identify the disease-causing variant for idiopathic renal hematuria.
Other diseases and traits: Alopecia areata, congenital bilateral absence of the vas deferens, eosinophilic myositis, hemochromatosis, marked muscle hypertrophy, HYPP and malignant hyperthermia without the known equine genetic variants, microphthalmia, and myotonia

Loss of function variants and the genetic burden

While developing the catalog of genetic variation for the horse we noticed that like humans, horses have a surprisingly high number of variants that are computational predicted to have a damaging effect on the gene that contains them. Some of these variants are likely to be false positives but others are likely to be real. The reason that these variants are tolerated and don’t seem to be having a damaging effect on the individual with these damaging variants is not known. We are interested in investigating these variants further to determine which variants are real and how they are tolerated despite being damaging.

Developing guidelines for the interpretation of possible phenotype-causing variants

Disease-causing genetic variants have been identified for <20% of currently recognized equine genetic diseases. Many groups are working to identify as many disease-causing variants as possible. This is great news because well developed genetic tests can be used to diagnose horses with a particular disease and to guide breeding decisions to decrease the risk of a foal being severely affected by the disease. For example, Polysaccharide Storage Myopathy type 1 and Hyperkalemic Periodic Paralysis. However, there are currently no guidelines for how to decide if a disease-causing variant is truly disease-causing.

During my PhD, we demonstrated that some variants that have been reported as being associated with a disease are more common in the horse population than we would expect given the prevalence of the disease. The implications of a false-positive disease-causing variant are huge, this is equivalent to a misdiagnosis which could lead to an incorrect management and/or treatment regime or even euthanasia due to the wrong diagnosis. Therefore, working with Dr. Molly McCue, we are developing recommendations for what is required to determine that a possible disease-causing variant is truly causing a disease. These will then be shared with groups that are identifying disease-causing variants, as well as veterinarians and owners to help them decide which genetic tests they can trust.

Publications

Full list of publications on PubMed
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