A 35-year-old man with newly diagnosed human immunodeficiency virus (HIV) infection was prescribed an antiretroviral regimen that included the protease inhibitor atazanavir 300 mg to be taken by mouth once daily, along with ritonavir, a pharmacokinetic enhancer, and two nucleoside analog antiretroviral agents. Liver function and renal function were normal. After 1 year of treatment, the patient experienced visible yellow discoloration of the skin and eyes. Blood samples were drawn, and grade 4 hyperbilirubinemia was documented. When atazanavir was discontinued and the antiretroviral regimen was modified to include lopinavir, the plasma levels of bilirubin returned to the normal range, and skin and eye color were cleared. Could a UGT1A1*28 polymorphism have led to the adverse effects?
Pharmacogenomics, the study of genetic factors that underlie variation in drug response, is a modern term for pharmacogenetics. Pharmacogenomics implies a recognition that more than one genetic variant may contribute to variation in drug response. Historically, the field began with observations of severe adverse drug reactions in certain individuals, who were found to harbor genetic variants in drug-metabolizing enzymes. As a scientific field, pharmacogenomics has advanced rapidly since the sequencing of the human genome. In the last decade, powerful genome-wide association (GWA) studies, in which hundreds of thousands of genetic variants across the genome are tested for association with drug response, led to the discovery of many other important polymorphisms that underlie variation in both therapeutic and adverse drug responses. In addition to polymorphisms in genes that encode drug-metabolizing enzymes, it is now known that polymorphisms in genes that encode transporters, human leukocyte antigen (HLA) loci, cytokines, and various other proteins also are predictive of variation in therapeutic and adverse drug responses. In addition to the new discoveries that have been made, the past decade has ushered in precision medicine, also known as stratified or personalized medicine, in which genetic information is used to guide drug and dosing selection for subgroups of patients or individual patients in medical practice. The Clinical Pharmacogenetics Implementation Consortium (CPIC) published a series of guidelines for using genetic information in selecting medications and in dosing (https://www.pharmgkb.org/). These highly informative guidelines are being used by practitioners in prescribing drugs to more effectively treat patients. In this chapter, we begin with a case study and then describe genetic variants that are determinants of drug response. Where appropriate, CPIC recommendations are included to provide information on how to use genetic variant data appropriately in therapeutic medicine. Other expert recommendations such as those from the Dutch Pharmacogenetics Working Group (DPWG) also are available (see https://www.knmp.nl/dossiers/farmacogenetica).
The description in this chapter of DNA sequence variations in germline DNA involves a number of terms that describe the nature of the variations and their locations within the genome. A glossary of commonly used terms is presented in the Glossary Table. Some of the more common and important variations are described in the text ...