Key Points
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Until recently, pharmacogenetic studies focused attention on only a few candidate genes. Developments in genomic technologies now allow a drastic expansion in the scope of pharmacogenetic studies.
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The genetic bases of inter-individual variation in drug response are likely to be simpler in many cases than the genetic bases of common diseases, which indicates that progress in pharmacogenetics might move faster than disease genetics.
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Forty-two polymorphisms that have been significantly associated with drug response in at least two studies show that obvious candidate genes, such as drug-metabolizing enzymes and drug targets, often carry important pharmacogenetic polymorphisms, and that such polymorphisms are often owing to common alleles.
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Most pharmacogenetics studies so far have been limited, both in terms of sample sizes and the genetic data analysed, and provide insufficient information for assessing clinical usefulness. Progress in pharmacogenetics will require notable increases in study size and the quality of the genetic analyses, including the efficient use of haplotype mapping.
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The translation of pharmacogenetic results into improved therapies will usually require the identification of the causal variants that underlie associations between genotypes and phenotypes. Effective translation will also require prospective clinical evaluation of how to use the polymorphism.
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Realizing the benefits of pharmacogenetics will be facilitated by research environments that combine a clinical diagnostic activity with basic pharmacogenetic research.
Abstract
Most people in the developed world will sooner or later be given prescription drugs to treat common diseases or to reduce the risk of getting them. Almost everyone who takes medicines will, at some stage, encounter those that do not work as well as they do in other people or even that cause an adverse reaction. Pharmacogenetics seeks to reduce the variation in how people respond to medicines by tailoring therapy to individual genetic make-up. It seems increasingly likely that investment in this field might be the most effective strategy for rapidly delivering the public health benefits that are promised by the Human Genome Project and related endeavours.
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Acknowledgements
D.B.G. is a Royal Society/Wolfson Research Merit Award holder. The authors thank R. Shah for background information concerning the discovery of the debrisoquine poor-metabolizer phenotype and A. Need for help with the creation of Table 1.
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DATABASES
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FURTHER INFORMATION
Glossary
- DEBRISOQUINE
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A drug (now superseded) that was used to treat high blood pressure and is metabolized by the enzyme CYP2D6.
- PRO-DRUG
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A biologically inactive compound that is changed in the body into a biologically active form, for example, by the action of one or more drug-metabolizing enzymes.
- CANDIDATE GENES
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Genes that are thought to be more likely to have polymorphisms that influence response to a given drug compared with a random gene from the genome.
- XENOTOXINS
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Compounds from outside the body (for example, in the diet) that are harmful. These are often neutralized and/or processed for elimination by drug-metabolizing enzymes.
- PHARMACOKINETIC
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Classically defined as the absorption, distribution, metabolism and elimination of drugs; this is usually studied by measuring circulating plasma drug levels as a function of time.
- DISPOSITION
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The processes that influences the distribution of a drug throughout the body following its absorption.
- PHARMACODYNAMICS.
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The biological effects of a drug.
- QT INTERVAL
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The time between definable points on an electrocardiogram that reflect ventricular contraction. The QT-interval duration is considered to be a marker for life threatening arrhythmias, which result from idiosyncratic reactions to some drugs.
- LEUKOTRIENES
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Inflammatory factors that are derived from arachidonic acid by 5-lipoxygenase.
- VARIABLE NUMBER OF TANDEM REPEATS
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(VNTR). Loci that contain variable numbers of short tandemly repeated sequences that are highly polymorphic.
- STATINS
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A class of cholesterol-lowering drugs that inhibit a key enzyme in the synthesis of cholesterol.
- STRATIFICATION
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If a genetic-association study is done in a population that is genetically structured, associations might be observed between polymorphisms that reflect allele-frequency differences between the unknown subgroups in the test populations. There are methods available to both detect and correct for such spurious association.
- CANDIDATE-POLYMORPHISM STUDY
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A previously known polymorphism, usually thought to be functional, which is tested for its effect on a drug response. This should not be confused with a candidate-gene study, which would seek to exhaustively represent variation in the gene.
- HYPOMORPH
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Low activity of forms of a gene.
- MAP BASED
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An approach to genetic-association studies that is focused on putatively functional SNPs, for example, identified by re-sequencing exons and other functional regions in relatively large samples, or directly in patients. This approach is also sometimes called direct.
- SEQUENCE BASED
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An approach to genetic-association studies that is focused on a set of genetic markers, often now called tagging SNPs, which are statistically associated with whichever variants influence the phenotype.
- LINKAGE DISEQUILIBRIUM
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The non-random association of alleles at different polymorphic sites in the gene.
- MYELOSUPPRESSION
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Suppression of the normal activity of bone marrow in the production of mature effective blood cells.
- ASSOCIATED INTERVAL
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A stretch of sequence surrounding a polymorphism that has been associated with a phenotype, in which linkage disequilibrium levels between polymorphisms and the associated marker might be sufficiently high to drive the originally observed association. In general, the associated interval will need to be exhaustively re-sequenced to identify the causal variant.
- CONJUGATION
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The molecular linking of a specific substance, such as a drug or drug metabolite, with another moiety. The product is then able to be processed in a particular fashion (for example, excretion) by a general mechanism that is dependent on the added moiety. The conjugation usually reduces or eliminates the pharmacological activity of the compound. This step is also known as a phase II reaction.
- HERCEPTIN
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An anti-tumour agent that is used for breast cancer, which targets the HER2 tyrosine kinase receptor and is most effective in patients who over-express this protein.
- PHILADELPHIA CHROMOSOME
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A translocation, usually reciprocal between chromosomes 9 and 22, which causes a specific form of leukaemia.
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Goldstein, D., Tate, S. & Sisodiya, S. Pharmacogenetics goes genomic. Nat Rev Genet 4, 937–947 (2003). https://doi.org/10.1038/nrg1229
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DOI: https://doi.org/10.1038/nrg1229
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