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.
Kaarina Kowalec*, Galen EB Wright*, Britt I Drögemöller, Folefac Aminkeng, Amit P Bhavsar, Elaine Kingwell, Eric M Yoshida, Anthony Traboulsee, Ruth Ann Marrie, Marcelo Kremenchutzky, others, *Authors contributed equally to this work
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.
Galen EB Wright, Ursula Amstutz, Britt I Drögemöller, Joanne Shih, Shahrad R Rassekh, Michael R Hayden, Bruce C Carleton, Colin JD Ross, Canadian Pharmacogenomics Network for Drug Safety Consortium
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 12â084 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.
GEB Wright, B Carleton, MR Hayden, CJD Ross
The Pharmacogenomics Journal,
2016
