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21 November 2006 | Volume 145 Issue 10 | Pages 749-757
The outcome of drug therapy is often unpredictable, ranging from beneficial effects to lack of efficacy to serious adverse effects. Variations in single genes are 1 well-recognized cause of such unpredictability, defining the field of pharmacogenetics (see Glossary). Such variations may involve genes controlling drug metabolism, drug transport, disease susceptibility, or drug targets. The sequencing of the human genome and the cataloguing of variants across human genomes are the enabling resources for the nascent field of pharmacogenomics (see Glossary), which tests the idea that genomic variability underlies variability in drug responses. However, there are many challenges that must be overcome to apply rapidly accumulating genomic information to understand variable drug responses, including defining candidate genes and pathways; relating disease genes to drug response genes; precisely defining drug response phenotypes; and addressing analytic, ethical, and technological issues involved in generation and management of large drug response data sets. Overcoming these challenges holds the promise of improving new drug development and ultimately individualizing the selection of appropriate drugs and dosages for individual patients.
Author and Article Information
From Vanderbilt University, Nashville, Tennessee; Stanford University Medical Center, Stanford, California; University of California, San Francisco, San Francisco, California; Indiana University, Indianapolis, Indiana; University of Florida, Gainesville, Florida; Children's Hospital Oakland Research Institute, Oakland, California; University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; University of Chicago, Chicago, Illinois; St. Jude Children's Research Hospital, Memphis, Tennessee; SRI International, Menlo Park, California; University of Maryland, Baltimore, Maryland; Mayo Clinic, Rochester, Minnesota; and Channing Laboratory, Boston, Massachusetts.
Acknowledgments: The authors thank Rochelle Long, Dina Paltoo, and Eileen Dolan for their comments on earlier versions of the manuscript.
Grant Support: Sites in the Pharmacogenetics Research Network are supported by the following U01 awards: GM61373, GM61390, GM74492, HL69757, GM61393, GM63340, HL65962, GM74518, GM61388, DA20830, and HL65899. The Pharmacogenetics and Pharmacogenomics Knowledge Base created by the network is housed at http://www.pharmgkb.org and is supported by U01 GM61374.
Potential Financial Conflicts of Interest: Consultancies: D.M. Roden (GlaxoSmithKline, Pfizer Inc., AstraZeneca, Abbott Laboratories, Novartis, 1st Genetic Trust), R.M. Krauss (Abbott Laboratories, AstraZeneca, Bristol-Myers Squibb, Merck & Co. Inc., Pfizer Inc., International Dairy Foods Association), M.J. Ratain (Prometheus, Genzyme Corp., Genentech), R.M. Weinshilboum (National Institutes of Health); S.T. Weiss (Glaxo-Wellcome, Roche Pharmaceuticals, Millennium Pharmaceuticals, Genetech, Schering-Plough, Variagenics, Genome Therapeutics, Merck Frost); Honoraria: D.M. Roden (GlaxoSmithKline, Pfizer, Inc., AstraZeneca, Abbott Laboratories, Novartis, 1st Genetic Trust), Dr. Krauss (Kos Pharmaceuticals, Pfizer); Stock ownership or options (other than mutual funds): M.J. Ratain (Variagenics, Nuvelo, Applera); Grants received: D.M. Roden (1st Genetic Trust), R.M. Krauss (King, Merck & Co. Inc., Schering-Plough, Pfizer Inc.), H.L.M. Leod (National Institutes of Health), M.J. Ratain (National Institutes of Health), R.M. Weinshilboum (Eli Lilly Inc.); S.T. Weiss (Glaxo Wellcome, AstraZeneca, Pfizer Inc.); Grants pending: D.M. Roden (GlaxoSmithKline), M.J. Ratain (National Institutes of Health); Patents received: M.J. Ratain (National Institutes of Health), M.V. Relling (National Institutes of Health); Patents pending: M.J. Ratain (National Institutes of Health); Royalties: D.M. Roden (Genaissance), M.J. Ratain (National Institutes of Health).
Requests for Single Reprints: Dan M. Roden, MD, Vanderbilt University School of Medicine, 2215B Garland Avenue, Room 1285B, MRB4, Nashville, TN 37232; e-mail, dan.roden{at}vanderbilt.edu.
Current Author Addresses: Dr. Roden: Vanderbilt University School of Medicine, 2215B Garland Avenue, Room 1285B, MRB4, Nashville, TN 37232-0575.
Dr. Altman: Department of Genetics, Stanford University Medical Center, 300 Pasteur Drive, Lane L301, Mail Code 5120, Stanford, CA 94305-5120.
Dr. Benowitz: University of California, San Francisco, Box 1220, 1001 Potrero Avenue, San Francisco General Hospital, 30 3316, San Francisco, CA 94143-1220.
Dr. Flockhart: Indiana University, 1001 West 10th Street, W-7123, Indianapolis, IN 46202.
Dr. Giacomini: University of California, San Francisco, 1550 4th Street, Mission Bay GD 584, San Francisco, CA 94143-2911.
Dr. Johnson: University of Florida, 1600 Southwest Archer Road, Room PG-22, Gainesville, FL 32610-0486.
Dr. Krauss: Children's Hospital Oakland Research Institute, 5700 Martin Luther King Jr. Way, Oakland, CA 94609.
Dr. McLeod: University of North Carolina, Chapel Hill, Campus Box 7360, 3203 Kerr Hall, Chapel Hill, NC 27599-7360.
Dr. Ratain: University of Chicago, 5841 South Maryland Avenue, MC 2115, Chicago, IL 60637-1470.
Dr. Relling: St. Jude Children's Research Hospital, 332 North Lauderdale, Memphis, TN 38105.
Dr. Ring: SRI International, 333 Ravenswood Avenue, Menlo Park, CA 94025.
Dr. Shuldiner: Department of Medicine, Division of Endocrinology, Diabetes and Nutrition, University of Maryland School of Medicine, 660 West Redwood Street, HH-Room 494, Baltimore, MD 21201.
Dr. Weinshilboum: Mayo Clinic, 200 First Street SW, Rochester, MN 55905.
Dr. Weiss: Channing Laboratory, Brigham & Women's Hospital, 181 Longwood Avenue, Boston, MA 02115. REVIEW
Pharmacogenomics: Challenges and Opportunities
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