Chapter 7: Pharmacogenetics and Pharmacogenomics

INTRODUCTION

Patients vary in their responses to drug therapy. Some patients derive striking and sustained benefits from drug administration, others may display no benefit, and still others display mild, severe, or even fatal adverse drug reactions (ADRs). Common sources of such variability include noncompliance, medication errors, clinical factors, drug interactions (see Chapter 4 and Appendices I and II), and genetic factors. Pharmacogenetics is the study of the genetic basis for variation in drug response and often implies large effects of a small number of DNA variants. Pharmacogenomics, on the other hand, studies larger numbers of variants, in an individual or across a population, to explain the genetic influences on drug response. Discovering which variants or combinations of variants have functional consequences for drug effects, validating those discoveries, and ultimately applying them to patient care and to drug discovery are the tasks of modern pharmacogenetics and pharmacogenomics.

ABBREVIATIONS

IMPORTANCE OF PHARMACOGENETICS TO VARIABILITY IN DRUG RESPONSE

An individual’s response to a drug depends on the complex interplay of drug factors (e.g., dose, route, formulation), environmental factors (e.g., diet, infections, other drugs, exercise level, exposure to toxins), clinical factors (e.g., age, indication for drug, organ function), and genetic factors. Key genes known to be involved in driving variable drug actions, called pharmacogenes, may influence drug response via variable drug concentrations (pharmacokinetics) or variable drug effects (pharmacodynamics). Pharmacogenes include those encoding drug-metabolizing enzymes, drug transport molecules, drug targets, and a host of other genes that modulate the molecular context within which drugs act, notably genes dysregulated in the disease for which the drug is administered. In some situations, variation in non-germline genomes (e.g., in cancer cells or in infectious agents) can be critical determinants of drug response.

Many well-established pharmacogenes encode drug-metabolizing enzymes. Drug metabolism is highly heritable, as assessed using drug exposures in monozygotic versus fraternal twins, drug exposures in cell lines from related subjects, and analysis of very large data sets using technologies such as genome-wide genotyping, discussed further in this chapter. Some drug metabolism traits behave in a conventional “monogenic” fashion, with clearly definable (and separable) groups of drug response phenotypes: poor metabolizers who inherit two alleles with no function, intermediate metabolizers who have one functional allele and one nonfunctional allele (heterozygotes), and normal metabolizers who have two functional alleles. The study of these traits has helped define key genetic variants that contribute to the individual variability in responses described ...