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5 Pharmacogenomics
C H A P T E R

Jennifer E. Hibma, PharmD,
& Kathleen M. Giacomini, PhD

C ASE STUD Y

A 35-year-old male with newly diagnosed human immu- experienced visible yellow discoloration of the skin and eyes.
nodeficiency virus (HIV) infection was prescribed an anti- Blood samples were drawn, and grade 4 hyperbilirubinemia
retroviral regimen, which included the protease inhibitor was documented. When atazanavir was discontinued and
atazanavir 300 mg to be taken by mouth once daily, along the antiretroviral regimen was modified to include lopinavir,
with ritonavir, a pharmacokinetic enhancer, and two nucleo- the plasma levels of bilirubin returned to the normal range,
side analog antiretroviral agents. Liver function and renal and skin and eye color were cleared. Could a UGT1A1*28
function were normal. After 1 year of treatment, the patient polymorphism have led to the adverse effects?

Pharmacogenomics, the study of genetic factors that underlie the past decade has ushered in “precision medicine,” also known
variation in drug response, is a modern term for pharmacoge- as “stratified or personalized medicine,” in which genetic
netics. Pharmacogenomics implies a recognition that more than information is used to guide drug and dosing selection for sub-
one genetic variant may contribute to variation in drug response. groups of patients or individual patients in medical practice. The
Historically, the field began with observations of severe adverse Clinical Pharmacogenetics Implementation Consortium (CPIC)
drug reactions in certain individuals, who were found to harbor published a series of guidelines for using genetic information in
genetic variants in drug-metabolizing enzymes. As a scientific selecting medications and in dosing. These highly informative
field, pharmacogenomics has advanced rapidly since the sequenc- guidelines are being used by practitioners in prescribing drugs to
ing of the human genome. In the last decade, powerful genome- more effectively treat patients. In this chapter, we begin with a case
wide association (GWA) studies, in which hundreds of thousands study and then describe genetic variants that are determinants of
of genetic variants across the genome are tested for association drug response. Where appropriate, CPIC recommendations are
with drug response, led to the discovery of many other important included to provide information on how to use genetic variant
polymorphisms that underlie variation in both therapeutic and data appropriately in therapeutic medicine.
adverse drug response. In addition to polymorphisms in genes The description in this chapter of DNA sequence variations
that encode drug-metabolizing enzymes, it is now known that in germline DNA involves a number of terms that describe the
polymorphisms in genes that encode transporters, human leu- nature of the variations and their locations within the genome.
kocyte antigen (HLA) loci, cytokines, and various other proteins A glossary of commonly used terms is presented in the Glossary
are also predictive of variation in therapeutic and adverse drug Table. Some of the more common and important variations are
responses. In addition to the new discoveries that have been made, described in the text that follows.

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