Project Leaders:   
Bruce Carleton, Michael Hayden

Involved Institutions:   
Pharmaceutical Outcomes Children’s/Women’s Health Centre, Centre for Molecular Medicine and Therapeutics

Technology Applications:   
Personalized medicine, diagnostic techniques

Research Funding Program:   
Translational Program for Applied Health

Adverse drug reactions (ADR) cause 10,000-22,000 deaths and cost the Canadian healthcare system over 13 billion dollars per year.

The goal of this study is to develop a routine tool for clinicians to tailor medications to individual patients based on genetic data.

An estimated 50% of ADRs are caused by the normal genetic variation that exists within any population of patients. The study of pharmacogenomics attempts to understand the influence of an individual genetic profile on the response to drug treatment.

Over half of all newly approved therapeutic health products have serious adverse drug reactions that are often discovered after the product is widely available. This subset of patients that exhibit severe ADRs for each drug may be determined by an individual’s sequence of DNA. Every individual has over 10 million nucleotides in their entire genome that can differ compared to other individuals, called single nucleotide polymorphisms (SNPs). Pharmacogenomics aims to identify DNA variations that cause different drug responses between individuals.

The collaboration of Drs. Michael Hayden and Bruce Carleton is working towards identifying relationships between specific genetic variants and severe ADRs in pediatric patients. The first phase of the study used high throughput comparison of DNA sequence between patients with or without severe ADRs. From the first phase of research, the team has identified three specific ADRs in pediatric patients that have discrete genetic factors. Cisplatin is a chemotherapeutic drug that is used to treat a wide variety of cancers, but cisplatin causes deafness in some pediatric oncology patients. Similarly, anthracyclines are also used to treat many pediatric cancers; however, a subset of patients suffer long-term damage to the heart, which may be as a result of a genetically determined predisposition. Finally, the team has also identified potential genetic factors contributing to codeine-induced infant deaths.

This project will refine which SNPs are most accurate in predicting ADRs in a clinical setting. As well, the researchers will identify why these changes result in ADRs by determining the biochemical processes affected by the genetic changes between individuals.

In the first phase of Genome BC funding the research team identified three priority pediatric ADRs for further development: cisplatin-induced deafness in oncology, anthracycline-induced cardiotoxicity in oncology and codeine-induced infant mortality. This second phase of funding will involve refining the identity of genetic factors that contribute to ADRs in these three cases as well as revealing the biochemical mechanisms that explain the genetic variation. Once genetic factors are identified, a prospective clinical study will be conducted to evaluate the diagnostic tools for predicting ADR risk.