利用次世代定序技術建立藥物基因體學之基因檢測平台

Abstract

Medical drugs show different efficacy and/or adverse drug reactions (ADRs) on patients. This is mostly due to the variations of DNA sequence. Pharmacogenomics is the study and applications about how genetic variations in individuals influence the drug response, which is composed of both pharmacokinetics and pharmacodynamics. Pharmacogenomics plays an important role in optimal drug choice and drug dosing. There are numerous genes involved in pharmacogenomics, which imposes a big challenge because of the complexity and high cost using conventional techniques like Sanger sequencing. In the present study, we set up a genetic testing platform through capture-based target enrichment followed by next-generation sequencing (NGS). Our panel covered approximately 345 major pharmacogenomics genes, including pharmacokinetics genes (for example, ADME genes regarding to absorption, distribution, metabolism and excretion) and pharmacodynamics genes, such as ABCB1, CFTR, CYPs, DRYP, EGFR, HLAs, KRAS, NAT2, RYR1, TPMT, UGT1A1 and VKORC1. A great proportion of our genes overlapped with those listed on FDA labeled biomarkers, Pharmacogenomics Knowledgebase (PharmGKB) and PharmaADME. We applied this panel to 34 individuals, including 6 controls with whole genome sequencing data from Taiwan Biobank for technical validation and 28 patients recruited from NTUH, trying to find specific ADR gene biomarkers. Also, we used LOVD (Leiden Open Variation Database) system to build a pharmacogenomics database in a uniform table format contains information on gene, variant, and drug response according to the PharmGKB clinical annotation file of warfarin, dabigatran, rivaroxaban, oxaliplatin and paclitaxel. In conclusion, the NGS-based pharmacogenomics panel and the pharmacogenomics LOVD database could be beneficial for precision medicine in clinical applications and academic research.