This week we profile a recent publication in Nature Genetics from
Dr. Bruce Carleton (pictured) at BC Children’s Hospital Research Institute.
Can you provide a brief overview of your lab’s current research focus?
I’m a professor in the Department of Pediatrics, University of British Columbia, as well as the Director of the Pharmaceutical Outcomes Programme at BC Children’s Hospital. In this capacity, I lead the Canadian Pharmacogenomics Network for Drug Safety (CPNDS) and my research is focused on pharmacogenomic research, with the ultimate aim of improving drug safety and effectiveness. This is particularly important since adverse drug reactions are the fifth leading cause of death in North America. By performing active surveillance for various adverse drug reactions at healthcare centers throughout Canada, we are able to assemble one of the largest clinical and genetic databases for pharmacogenomic drug safety research. By looking at the DNA of patients, the CPNDS uses genetics to help explain why some individuals receiving the same drug, at the same dose, experience adverse drug reactions, while others do not. We strive to be involved in all aspects of translating pharmacogenomic findings into clinical practice from biomarker discovery, replication and functional validation to implementation.
What is the significance of the findings in this publication?
Multiple sclerosis (MS) is a neurodegenerative disease with an autoimmune component that affects the central nervous system. Canada has one of the highest prevalence rates of MS in the world and interferon-β is a first line therapy for the treatment of MS in the country. When this biologic was first introduced, it represented a major change in MS disease management, but unfortunately around one in 50 patients develop severe liver injury as a result of this treatment. Identifying a biomarker that can predict which patients are at an increased risk for liver damage before selecting an appropriate treatment would therefore be extremely useful. We therefore aimed to address this need by using a multidisciplinary team science approach, which involved two trainees from the University of British Columbia, Drs. Galen Wright (supervised by Dr. Bruce Carleton and Dr. Colin Ross) and Kaarina Kowalec (supervised by Dr. Bruce Carleton and Dr. Helen Tremlett) and collaborators from around the world. After performing an unbiased scan of over seven million genetic variants throughout the genome, we found a highly significant biomarker that conferred an eight times increased risk for causing drug induced liver injury in Canadian MS patients. Importantly, upon closer inspection, we noted that this interferon-β-related variant influences the expression of an interferon regulatory factor gene, IRF6. We then went on to validate the biomarker in two independent cohorts of MS patients, further strengthening the evidence surrounding this risk variant which puts patients at eight times the risk of drug-induced liver injury.
What are the next steps for this research?
Currently there are approximately 15 medications that are approved for the treatment of MS by the FDA and Health Canada, making the disease an ideal candidate for precision medicine approaches. We hope that the current study can act as a framework for our collaborators and other researchers to identify biomarkers for adverse drug reactions caused by some of these other treatments. The more pharmacogenomic information that we have available, the more informed clinicians can be when making drug therapy choices for the effective treatment of MS. As for the CPNDS, we are also partnering with medical laboratory service companies to make pharmacogenomic tests more readily accessible in Canada.
This research was funded by:
Our work was supported by the British Columbia Clinical Genomics Network. The CPNDS is also receives funding form the Canadian Institutes of Health Research, Genome Canada, Genome British Columbia, and British Columbia Children’s Hospital Research Institute.
