College of American Pathologists
Printable Version





Pharmacogenetics in a Nutshell

Posted October 1, 2005

Zsolt Jobbagy, MD, PhD
Biochemical and Molecular Genetics Subcommittee

Pharmacogenetics refers to differences in drug metabolism and response associated with inherited DNA sequence variations. Pharmacogenomics addresses the general study of many different genes that affect drug behavior. The distinction between these two terms is now considered arbitrary and both are used interchangeably to indicate that genotype may affect an individual’s response to drugs.

Genes that code for receptors, protein targets or enzymes, which metabolize drugs, often contain genetic polymorphisms with functional significance. Cataloging these genomic variants is currently a major emphasis in biomedical science. These variants, often referred to as SNPs (single nucleotide polymorphisms, pronounced “snips”), can be used as a diagnostic adjunct to help predict a patient’s response to a drug.

For example, the enzyme thiopurine methyltransferase (TPMT) may contain sequence variants that inactivate TPMT’s ability to degrade 6-mercaptopurine (6-MP). Patients who inherit a defective TPMT gene from each parent (~1 in 1,300 individuals) develop aplastic anemia if given standard chemotherapeutic doses of 6-MP.1 Pharmocogenomics requires knowledge of a patient’s DNA sequence for relevant genes or SNPs. Traditional sequencing technology is relatively slow and expensive, impeding the widespread use of SNPs. Evolving technologies such as DNA microarrays (DNA “chips”;) provide the potential to examine patients for specific SNPs quickly and affordably.

A single microarray can be used to screen 100,000 SNPs found in the human genome in a matter of hours.2 Moreover, arrays can be used to screen for other genomic variations, that influence the metabolism and effectiveness of drugs, such as genetic duplications and deletions, mutations in regulatory genes and recently described large-scale copy variations.3

The cytochrome P450 (CYP) family of liver monooxygenases, one of the best-studied groups of polymorphic genes, affects the metabolism of over 100 currently used medicines in more than 30 different classes of drugs. At least 57 different human P450s (termed isoforms) are encoded by separate genes. Only 10 contribute to drug metabolism, with major contributions by 3 isoforms—CYP3A4, CYP2D6, and CYP2C9.4 Less active or inactive forms of CYP enzymes, which are unable to efficiently metabolize drugs, can cause drug overdoses or, in the case of pharmacologically active metabolites, drug ineffectiveness. Clinical trials are underway to evaluate the utility of genetic tests for variations in cytochrome P450 genes to screen and monitor patients.

The hope and potential of pharmacogenetics are that pharmaceuticals can be personalized for each patient’s genetic makeup, reducing the estimated 100,000 annual deaths and 2 million hospitalizations due to adverse drug response in the United States alone.5 Complementing the potential of individualized approaches, recent studies on inter-population instead of inter-individual differences for relevant polymorphisms may make it possible to more accurately predict drug response without testing each patient, thus potentially improving drug use in a more economical way.6


  1. Coulthard SA, Matheson EC, Hall AG, Hogarth LA. The clinical impact of thiopurine methyltransferase polymorphisms on thiopurine treatment. Nucleosides Nucleotides Nucleic Acids. 2004;23(8-9):1385-1391
  2. National Center for Biotechnology Information. Just the facts: a basic introduction to the science underlying NCBI resources. Accessed April 20, 2005.
  3. Iafrate AJ, Feuk L, Rivera MN, Listewnik ML, Donahoe PK, Qi Y, Scherer SW, Lee C. Detection of large-scale variation in the human genome. Nature Genetics. 2004;36: 949-951.
  4. Daly AK. Pharmacogenetics of the cytochromes P450. Curr Top Med Chem. 2004;4(16):1733-1744.
  5. Lazarou J, Pomeranz BH, Corey PN. Incidence of adverse drug reactions in hospitalized patients: a meta-analysis of prospective studies. JAMA. 1998; 279(15):1200-1205.
  6. Daar AS, Singer PA. Pharmacogenetics and geographical ancestry: implications for drug development and global health. Nat Rev Genet. 2005;6(3):241-246.

Download this article in Microsoft Word format.
Download this article in PDF format.

NewsPath® Editor: Megan J. DiFurio, MD, FCAP
This newsletter is produced in cooperation with the College of American Pathologists Public Affairs Committee and may be reproduced in whole or in part as a service to the medical community. Copyright © 2006 by the College of American Pathologists.
Please e-mail any comments to


Related Links