Gene–Gene–Environment Interactions Between Drugs, Transporters, Receptors, and Metabolizing Enzymes: Statins, SLCO1B1, and CYP3A4 as an Example

ABSTRACTPharmacogenetic biomarker tests include mostly specific single gene-drug pairs, capable of accounting for a portion of interindividual variability in drug response and toxicity. However, multiple genes are likely to contribute, either acting independently or epistatically, with the CYP2C9–VKORC1–warfarin test panel, an example of a clinically used gene–gene–dug interaction. I discuss here further instances of gene–gene–drug interactions, including a proposed dynamic effect on statin therapy by genetic variants in both a transporter (SLCO1B1) and a metabolizing enzyme (CYP3A4) in liver cells, the main target site where statins block cholesterol synthesis. These examples set a conceptual framework for developing diagnostic panels involving multiple gene-drug combinations.