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Creating and evaluating genetic tests predictive of drug response

Abstract

A key goal of pharmacogenetics — the use of genetic variation to elucidate inter-individual variation in drug treatment response — is to aid the development of predictive genetic tests that could maximize drug efficacy and minimize drug toxicity. The completion of the Human Genome Project and the associated HapMap Project, together with advances in technologies for investigating genetic variation, have greatly advanced the potential to develop such tests; however, many challenges remain. With the aim of helping to address some of these challenges, this article discusses the steps that are involved in the development of predictive tests for drug treatment response based on genetic variation, and factors that influence the development and performance of these tests.

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Figure 1: Common genetic variation and rare genetic variation with allele frequencies.
Figure 2: Response to inhaled corticosteroids, as measured by FEV1.
Figure 3: Proposed methodology for developing pharmacogenetic predictive tests.

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Acknowledgements

We would like to thank Richard M. Weinshilboum, MD and the White Paper subcommittee of the PGRN network for valuable suggestions. Financial support is also acknowledged: U01 HL065899 (S.T.W.); U01 GM63340 (H.L.M.); UO1 GM061373 (D.A.F.); DA 20830 (N.L.B.); U01 GM074492 (J.A.J.); GM61393 (M.J.R. and M.E.D.); and GM61390 (K.M.G.).

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Correspondence to Scott T. Weiss.

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DATABASES

OMIM

ADRB2

CYP2C19

CYP2C9

CYP2D6

TPMT

UGT1A1

VKORC1

FURTHER INFORMATION

CYP2C9 allele nomenclature

HapMap Project

Human Genome Project

Pharmacogenetics Research Network

Glossary

Environmental phenocopy

A clinical case of a complex trait due solely to environmental factors.

Epistasis

The interaction or interdependence of two or more genes.

Incomplete penetrance

Occurs when less than 100% of a population with an identical mutant genotype display the associated phenotype.

Linkage disequilibrium

The nonrandom association of alleles in the genome.

Mode of inheritance

Dominant mode of inheritance occurs when only one copy of the allele is necessary to produce the phenotype. Recessive mode of inheritance occurs when both copies of the allele are necessary to produce the phenotype.

Pleiotropy

A single mutation that has more than one biological effect or phenotype.

Receiver operating characteristic (ROC) curve

A curve that plots I-sensitivity on the y axis and specificity on the x axis. The area under this curve is a measure of test performance.

Severe adverse event

An event that occurs less than 1 in 10,000 administrations of the medication and is life threatening.

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Weiss, S., McLeod, H., Flockhart, D. et al. Creating and evaluating genetic tests predictive of drug response. Nat Rev Drug Discov 7, 568–574 (2008). https://doi.org/10.1038/nrd2520

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