Pharmacogenetics

Pharmacogenomics in Drug Discovery and Clinical Application

• Current approach in drug discovery involves using genomic and phenomic data to identify target proteins and refine their regions to find genes, followed by further characterization of the genome and phenome relationship.
• Molecular mechanisms of variant are determined with a focus on inhibitory target proteins, making it easier to design inhibitory drugs, and loss of function mutations are sought to assess clinical adverse effects.
• Multiple omics and big data analysis are used to infer mechanisms, followed by experimental testing using in vitro and animal models.
• Genomics is leveraged in clinical trials for the selection of participants.
• A more recent approach in drug discovery involves using CRISPR to screen for protein function in cell models, focusing on non-housekeeping/essential genes and developing a panel of 3,000 – 5,000 target proteins.
• This approach was used in the recent discovery of a protein essential for HBV protein production in a liver cell model with HBV sequence inserted in the genome.
• Classical pharmacogenetics focuses on genes involved in pharmacokinetic and pharmacodynamic mechanisms, with initial studies focusing on DNA sequence analysis to find variants and develop assays.
• The slow incorporation of pharmacogenetics into routine clinical application is hindered by the complexity of assays, inconsistent/non-interpretable data presentation, and cost.
• Pharmacokinetic variants involve drug activation, inactivation, clearance, and excretion within the body/cells, with main genes of interest including Cytochrome P450 enzymes, Dihydropyridine dehydrogenase, Thiopurine S-methyltransferase, and Organic acid carriers.
• Pharmacodynamic variants include both loss of function and gain of function variants for target proteins, with examples such as VKOR for vitamin K activation in relation to warfarin treatment and RYR1 gene for malignant hyperthermia.
• Currently, there are over 280 prescription drugs with FDA genetic testing labeling, but a low level of testing is being conducted.
• PharmGKB is a knowledge resource that annotates genetic variants and gene-drug-disease relationships, summarizes important pharmacogenomic genes and associations, curates FDA drug labels containing pharmacogenomic information, and enables consortia examining important questions in pharmacogenomics.