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It is a given that 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, drug interactions (see Chapter 4 and Appendix I), 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 component of variable drug responses. 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.



ABCB1: multidrug resistance transporter (P-glycoprotein)

ACE: angiotensin-converting enzyme

ADR: adverse drug reaction

AUC: area under the curve

CBS: cystathionine β-synthase

CF: cystic fibrosis

CNV: copy number variation

cSNP: coding SNP

CYP: cytochrome P450

EGFR: epidermal growth factor receptor

EMR: electronic medical record

FDA: U.S. Food and Drug Administration

FH: familial hypercholesterolemia

GI: gastrointestinal

G6PD: glucose-6-phosphate dehydrogenase

GST: glutathione-S-transferase

GSTM1: glutathione-S-transferase M1

GWAS: genome-wide association study

HIV: human immunodeficiency virus

HMG-CoA: 3-hydroxy-3-methylglutaryl coenzyme A

5HT: 5-hydroxytryptamine, serotonin

indels: insertions or deletions

INR: international normalized ratio

iPSC: induced pluripotent stem cell

LDL: low-density lipoprotein

MAF: minor allele frequency

MDR1: multidrug resistance protein 1

mRNA: messenger RNA

MTHFR: methylenetetrahydrofolate reductase

nsSNP: nonsynonymous SNP

PharmGKB: Pharmacogenomics Knowledgebase

PheWAS: phenome-wide association study

PM: poor metabolizer

RCT: randomized clinical trial

SNP: single-nucleotide polymorphism

SNV: single-nucleotide variant

sSNP: synonymous or sense SNP

TPMT: thiopurine methyltransferase

TYMS: thymidylate synthase

UDP: uridine diphosphate

UGT: UDP-glucuronosyltransferase

UTR: untranslated region

VKORC1: vitamin K epoxide reductase


An individual’s response to a drug depends on the complex interplay among environmental factors (e.g., diet, age, infections, other drugs, exercise level, occupation, exposure to toxins, and tobacco and alcohol use) and genetic factors. Genetic variation may result in altered protein sequence and function or in altered protein levels through regulatory variation. Key genes involved in driving variable drug actions include those encoding drug-metabolizing enzymes, drug transport molecules, the molecular targets with which drugs interact, 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 nongermline genomes (e.g., in cancers or in infectious agents) can be critical determinants of variable drug responses.

Drug metabolism is highly heritable, as assessed using drug exposures in monozygotic versus fraternal twins, drug exposures in cell lines from related subjects, or analysis of very large data sets ...

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