SickKids study shows how genome sequencing may help prevent adverse drug events

How your genes impact your response to medications

TORONTO – Today, in the era of precision medicine, genome sequencing has not only significantly improved doctors’ ability to diagnose inheritable diseases, but it has also enabled scientists and clinicians alike to create new treatments and tailor clinical care to the specific child’s genetic information.

New research from The Hospital for Sick Children (SickKids) demonstrates yet another way genetic information can benefit clinical care and may even enhance patient safety and preventative medicine. The study, published in the May 26, 2017 online edition of npj Genomic Medicine, focused on pharmacogenetics which looks at how individual differences in our genes impact how we may react to certain medications.

The study compared pharmacogenetics results from traditional testing with that of results generated by using genome sequencing.  The researchers looked at 67 DNA variants in 19 genes with known effects on drug response and compared the results with patients’ genome sequencing data.

“As whole genome sequencing is being done more regularly to help find a diagnosis for patients with rare diseases, this information could also be used to identify DNA variants in children that affect medication safety and effectiveness: pharmacogenes. In order to use this information confidently, we need to ensure that these technologies reliably and accurately identify pharmacogenes,” says Iris Cohn, lead author of the study and clinical research pharmacogenetics advisor at SickKids.

The research team found that sequencing was more than 99 per cent accurate for almost all of the pharmacologically important genes, except for one gene. Importantly, they also identified at least one medically actionable pharmacogenetic variant in 95 out of 98 paediatric patients who participated in the study.

“To find medically actionable variants in the vast majority of cases is astonishing,” says Cohn. She explains that the identification of genetic differences in our genes can be used to predict whether a medication will be effective for a particular person and can inform safe medication decisions, such as dosage as well as prevent adverse drug reactions.

Of those 95 patient participants, approximately 30 children had significant information which would influence how medication would be prescribed over the child’s lifetime, and could protect them from severe side effects if they had to be given this medication in the future. Some of the key findings include:

• Ten participants had a higher risk of developing a sensitivity to an anti-epileptic drug, which means they are at higher risk for adverse drug events. This is especially important information because many patients with rare diseases who undergo genome sequencing may also have seizures. This information could impact whether or not this drug was prescribed in the first place.
• Eight participants had a variant which impacts how an enzyme breaks down an immunosuppressant drug. If these children were given a normal dose they could have potentially fatal side effects.
• Three participants found to have lower capacity to make use of a blood thinning drug. If these children required this medication in the future, it would have no effect, so dosage would need to be carefully adjusted to the specific patient’s needs.
• Six participants had a variant which would put them at high risk of developing a multi-organ hypersensitivity reaction to a drug taken by individuals who are HIV-positive.

The term pharmacogenetics was coined by a University of Toronto pharmacology professor Dr. Werner Kalow half a century ago, and now we are entering an era of pharmacogenOMICS, broadening the search from gene to genome. The application into clinical practice is still in its early development, says Cohn. Not all labs can perform the tests, and in most cases, pharmacogenetic testing panels are done retrospectively to determine why an adverse event occurred, or why a patient did not respond to a drug.

“Our study shows how pharmacogenetics can play a critical role in the shift toward predictive and preventative medicine. There are only so many drug-gene interactions that we are aware of, so it will not prevent all adverse reactions, but it adds another important medication safety layer. Even if it would help prevent three out of 100 adverse events, I would say this is very successful!”

SickKids currently offers pharmacogenetic tests in a pilot project to approximately 200 children and 100 adults to see how we might be able to incorporate pharmacogenetic testing into clinical practice. In the future, the researchers hope that pharmacogenetic information will help health-care providers make effective and safe treatment decisions in children and adults throughout their lifetime.

This study was funded by the Centre for Genetic Medicine and the Centre for Applied Genomics at SickKids, Genome Canada, the University of Toronto McLaughlin Centre and Complete Genomics.

It is an example of how SickKids is contributing to making Ontario Healthier, Wealthier and Smarter.