The identification of genomic variants associated with severe adverse drug reactions

Precision medicine and genomic modifiers in neurology

Assessing the role of population genetics and rare genetic variation in pharmacogenomics

Moving genomic findings towards implementation







Fly fishing

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Purpose: Tamoxifen is one of the principal treatments for estrogen receptor (ER)-positive breast cancer. Unfortunately, between 30 and …

Multiple sclerosis (MS) is a disease of the central nervous system treated with disease-modifying therapies, including the biologic, …

Objective To characterize, among European and Han Chinese populations, the genetic predictors of maculopapular exanthema (MPE), a …

Selected Publications

Multiple sclerosis (MS) is a disease of the central nervous system treated with disease-modifying therapies, including the biologic, interferon-beta (IFN-beta). Up to 60% of IFN-beta-exposed MS patients develop abnormal biochemical liver test results, and 1 in 50 experiences drug-induced liver injury. Since genomic variation contributes to other forms of drug-induced liver injury, we aimed to identify biomarkers of IFN-beta-induced liver injury using a two-stage genome-wide association study. The rs2205986 variant, previously linked to differential expression of IRF6, surpassed genome-wide significance in the combined two-stage analysis (P = 2.3 x 10-8, odds ratio = 8.3, 95% confidence interval = 3.6-19.2). Analysis of an independent cohort of IFN-beta-treated MS patients identified via electronic medical records showed that rs2205986 was also associated with increased peak levels of aspartate aminotransferase (P = 7.6 x 10-5) and alkaline phosphatase (P = 4.9 x 10-4). We show that these findings may be applicable to predicting IFN-beta-induced liver injury, offering insight into its safer use.
Nature Genetics, 2018

Vincristine is an effective chemotherapeutic drug for various cancers, including acute lymphoblastic leukemia (ALL). Unfortunately, clinical utility is restricted by dose-limiting vincristine-induced peripheral neuropathies (VIPN). We sought to determine the association of VIPN with a recently identified risk variant, CEP72 rs924607, and drug absorption, distribution, metabolism, and excretion (ADME) gene variants in pediatric ALL. This was followed by a meta-analysis of pharmacogenomic data from over 500 patients. CEP72 rs924607 was significantly associated with VIPN (P = 0.02; odds ratio (OR) = 3.4). ADME analyses identified associations between VIPN and ABCC1 rs3784867 (P = 5.34 x 10-5; OR = 4.9), and SLC5A7 rs1013940 (P = 9.00 x 10-4; OR= 8.6); genes involved in vincristine transport and inherited neuropathies, respectively. Meta-analysis identified an association with a variant related to TTPA (rs10504361: P = 6.85 x 10-4; OR = 2.0), a heritable neuropathy-related gene. This study provides essential corroboratory evidence for CEP72 rs924607 and highlights the importance of drug transporter and inherited neuropathy genes in VIPN.
Clinical Pharmacology & Therapeutics, 2018

Differences in response to medications have a strong genetic component. By leveraging publically available data, the spectrum of such genomic variation can be investigated extensively. Pharmacogenomic variation was extracted from the 1000 Genomes Project Phase 3 data (2504 individuals, 26 global populations). A total of 12â‰084 genetic variants were found in 120 pharmacogenes, with the majority (90.0%) classified as rare variants (global minor allele frequency <0.5%), with 52.9% being singletons. Common variation clustered individuals into continental super-populations and 23 pharmacogenes contained highly differentiated variants (FST>0.5) for one or more super-population comparison. A median of three clinical variants (PharmGKB level 1A/B) was found per individual, and 55.4% of individuals carried loss-of-function variants, varying by super-population (East Asian 60.9%>African 60.1%>South Asian 60.3%>European 49.3%>Admixed 39.2%). Genome sequencing can therefore identify clinical pharmacogenomic variation, and future studies need to consider rare variation to understand the spectrum of genetic diversity contributing to drug response.
The Pharmacogenomics Journal, 2016

Funding & Awards

I am currently a Co-Investigator and Research Leader for a Canadian Institutes of Health Research (CIHR) Drug Safety and Effectiveness Network Grant. During my postdoctoral research, I was supported by numerous funding organizations, including the CIHR Fellowship as well as the Drug Safety and Effectiveness Cross-Disciplinary Training Program. A detailed list can be found here.