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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.
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Abbreviations
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
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IMPORTANCE OF PHARMACOGENETICS TO VARIABILITY IN DRUG RESPONSE
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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.
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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 ...