Categories of Pharmacogenetic Knowledge
There are many types of data relevant to pharmacogenetics. In order to facilitate their indexing and retrieval, PharmGKB data sets are (1) annotated with their associated genes and/or drugs, and (2) classified into five general categories of pharmacogenetic knowledge. These categories range from observations of genetic variation to assessment of variation in clinical outcomes in response to drugs. The five categories are1:
CO: Clinical Outcome
Genetic variations in the response to drugs can cause measurable differences in clinical endpoints such as rates of cure, morbidity, side effects, and death. Data in this category demonstrate that genetic variability in the context of a drug effect significantly changes medical outcomes. These data sets are different from pharmacodynamics data sets, which may show a difference that is not sufficiently significant to alter practice or policy.
| Example: | Variation in the outcome of acute lymphoblastic leukemia patients treated with methotrexate. |
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| Reference: | Krajinovic M, Costea I, Chiasson S. Polymorphism of the thymidylate synthase gene and outcome of acute lymphoblastic leukemia. Lancet (2002) 359(9311) 1033-4. [PMID:11937185] |
PD: Pharmacodynamics and Drug Response
Genetic variation in drug targets can cause measurable differences in the response of an organism to a drug. Data in this category document that the biological or physiological response to a drug varies, and that this variation can be associated with the variation of one or more genes. This variation is often measured at the whole-organism level. The measured variables may be surrogates for clinical responses, but do not constitute outcomes themselves.
| Example: | Variation in vascular response to phenylephrine associated with variations in the NOS3 gene. |
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| Reference: | Philip I, Plantefeve G, Vuillaumier-Barrot S, Vicaut E, LeMarie C, Henrion D, Poirier O, Levy BI, Desmonts JM, Durand G, Benessiano J. G894T polymorphism in the endothelial nitric oxide synthase gene is associated with an enhanced vascular responsiveness to phenylephrine. Circulation (1999 ) 99(24):3096-8. [PMID:10377070] |
PK: Pharmacokinetics
Genetic variation in processes involved in the absorption, distribution, metabolism, or elimination of a drug can result in changes in drug availability. Data in this category are primarily concerned with demonstrating that genetic polymorphisms lead to variations in the levels or concentrations of drugs or their metabolites at the site of action.
| Example: | Variation in the CYP2C9 gene effects blood warfarin levels. |
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| Reference: | Aithal GP, Day CP, Kesteven PJ, Daly AK. Association of polymorphisms in the cytochrome P450 CYP2C9 with warfarin dose requirement and risk of bleeding complications. Lancet (1999 ) 353(9154):717-9. [PMID:10073515] |
FA: Molecular and Cellular Functional Assays
Genetic variation can alter results of molecular and cellular functional assays, and this may correlate with variations in the organism's drug response. Data in this category demonstrate associations between genetic variation and laboratory assays of function at the molecular or cellular level. These assays may test the molecular properties of drug targets or drug metabolizing enzymes, or may test the cellular properties of cells involved in the response to a drug (such as whole-cell gene expression).
| Example: | Transfected cells expressing variants of ADRB2 respond differently in vitro. |
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| Reference: | Drysdale CM, McGraw DW, Stack CB, Stephens JC, Judson RS, Nandabalan K, Arnold K, Ruano G, Liggett SB. Complex promoter and coding region beta 2-adrenergic receptor haplotypes alter receptor expression and predict in vivo responsiveness.Proc Natl Acad Sci U S A. (2000) 97(19):10483-8. [PMID:10984540] (this paper is a good example of combining FA and PD data) |
GN: Genotype
Genotype is the internally coded, heritable information carried by the organism. Variation in genotype is fundamental to pharmacogenetics and is measured as sequence variation in individual genes--the type and location of the variation, and the frequency of the variation in the populations of interest. This genetic variation is independent of individual drugs, but forms the basis for variation in response to drugs.
| Example: | Sequence variation in the ABC transporter genes. |
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| Reference: | Ito S, Ieiri I, Tanabe M, Suzuki A, Higuchi S, Otsubo K. Polymorphism of the ABC transporter genes, MDR1, MRP1 and MRP2/cMOAT, in healthy Japanese subjects. Pharmacogenetics. (2001) 11(2):175-84. [PMID:11266082] |
Glossary of Terms
- Pharmacodynamics2 - Pharmacodynamics is the study of the relationships between the concentration of a drug at its site(s) of action and the magnitude of the biological or physiological effect that is achieved.
- Pharmacokinetics - Pharmacokinetics is the study of the bodily absorption, distribution, metabolism and excretion of drugs.
- Drug - A chemical or biological substance used in the diagnosis, treatment, or prevention of a disease or phenotype, or as a component of a medication.
- Molecular Assay - A molecular assay is an experiment in which the characteristics of a molecule (or ensemble of molecules) are measured.
- Cellular Assay - A cellular assay is an experiment in which the response or characteristics of a cell (or population of cells) is measured.
- Genotype - Genotype is the internally coded, heritable information carried by the organism. Variation in genotype represents differences in sequence within a species, such as SNPs, the location or the number of repeats, deletions, or critical splice sites.
- Phenotype - Phenotypes are the observable properties of an organism produced by the interaction of the genotype with the environment. For pharmacogenetics, the "environment" is often defined as exposure to a drug, although it may include other variables as well.
1 R.B. Altman, D.A. Flockhart, S.T. Sherry, D.E. Oliver, D.L. Rubin and T.E. Klein, "Indexing Pharmacogenetic Knowledge on the Web", Pharmacogenetics 2003 13:3-5.
2 Goodman & Gilman's The Pharmacological Basis of Therapeutics, J.G. Hardman and L.E. Limbird, Eds, A. Goodman Gilman, consulting ed., Tenth Edition, McGraw Hill, 2001, pages 1-2.