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Pharmacogenomics: bench to bedside

Nature Reviews Drug Discovery volume 3, pages 739–748 (2004)Cite this article

Key Points

  • The latter portion of the twentieth century witnessed the emergence of the concept that inheritance is a major factor responsible for variation in drug response.

  • Once that principle had been established, the question immediately arose of the best way by which to translate this information to the bedside.

  • Here, after reviewing the process by which the disciplines of pharmacogenetics and pharmacogenomics have developed, we turn to challenges associated with the 'translation' of these disciplines from the research laboratory to the bedside, with the eventual goal of truly individualized drug therapy. These can be split into four major categories:

  • Pharmacogenomic science: Pharmacogenomics is moving beyond single-gene effects to study the effects of inheritance on pharmacokinetic and pharmacodynamic pathways involving multiple gene products. This type of study will require a large number of subjects and multi-disciplinary teams of investigators with complementary expertise, as well as the ability to genotype a very large number of polymorphisms or haplotypes.

  • Translational incentives: Successful translation of pharmacogenomics into the clinic will require the creation of positive incentives that will stimulate research funding agencies, academic centres, the pharmaceutical industry and drug regulatory agencies to work together to achieve translation.

  • Healthcare professional education: The translation of pharmacogenomics to the bedside will require the education of physicians and other healthcare professionals in clinical genomic science generally, and in its application to therapeutics in particular.

  • Patience acceptance: Patients will also have to become informed with regard to the application of genomics to drug selection and dosage. In addition, an effort will have to be made to keep patient expectations of pharmacogenomics realistic. Finally, patients must be assured that the confidentiality of their genomic information will be protected.

Abstract

Pharmacogenetics is the study of the role of inheritance in inter-individual variation in drug response. Since its origins in the mid-twentieth century, a major driving force in pharmacogenetics research has been the promise of individualized drug therapy to maximize drug efficacy and minimize drug toxicity. In recent years, the convergence of advances in pharmacogenetics with rapid developments in human genomics has resulted in the evolution of pharmacogenetics into pharmacogenomics, and led to increasing enthusiasm for the 'translation' of this evolving discipline into clinical practice. Here, we briefly summarize the development of pharmacogenetics and pharmacogenomics, and then discuss the key factors that have had an influence on — and will continue to affect — the translation of pharmacogenomics from the research bench to the bedside, highlighting the challenges that need to be addressed to achieve this goal.

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Figure 1: Classic pharmacogenetic traits: inherited variation in N-acetylation.
Figure 2: Classic pharmacogenetic traits: the thiopurine S-methyltransferase polymorphism.
Figure 3: Classic pharmacogenetic traits: polymorphisms in cytochrome P450 2D6.
Figure 4: Schematic representation of pharmacogenomic 'players' and their relationships.
Figure 5: An example initiative to facilitate the translation of pharmacogenetics: the Pharmacogenetics Research Network.

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Acknowledgements

We thank L. Wussow for her assistance with the preparation of this manuscript.

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Authors and Affiliations

  1. Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Medical School-Mayo Graduate School, Mayo Clinic College of Medicine, Rochester, 55905, Minnesota, USA

    Richard Weinshilboum & Liewei Wang

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Correspondence to Richard Weinshilboum.

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Competing interests

R.W. has either provided consulting services or presented seminars at Abbott Laboratories, Bristol-Myers Squibb, Eli Lilly, Johnson & Johnson, Roche and Merck, Inc. All fees and honoraria for these services and/or seminars were paid to Mayo Foundation. In addition, R.W. currently holds a peer-reviewed grant from Eli Lilly.

Related links

Related links

DATABASES

Entrez Gene

ALOX5

CYP2D6

EGFR

ERBB2

NAT2

TPMT

UGT1A1

Online Mendelian Inheritance in Man

Gilbert's syndrome

inflammatory bowel disease

National Cancer Institute Cancer List

Acute lymphoblastic leukaemia of childhood

FURTHER INFORMATION

Pharmacogenetics Research Network

Pharmacogenetics and Pharmacogenomics KnowledgeBase

Glossary

DEBRISOQUINE

An antihypertensive drug that is metabolized by cytochrome P450 2D6.

ALLELES

Different versions of the same gene.

VARIABLE NUMBER OF TANDEM REPEATS

A tandemly repeated DNA sequence with a variable number of repeats.

PRO-DRUG

A pharmacologically inactive compound that is converted to the active form of the drug by endogenous enzymes or metabolism.

HAPLOTYPE

A combination of alleles or sequence variations on the same chromosome.

POWER CALCULATIONS

A statistical calculation of the ability of an experiment to avoid false positive and/or negative results.

TATA BOX

DNA sequence motif of importance for transcription initiation.

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Weinshilboum, R., Wang, L. Pharmacogenomics: bench to bedside. Nat Rev Drug Discov 3, 739–748 (2004). https://doi.org/10.1038/nrd1497

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