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Genome-based pharmacogenetics and the pharmaceutical industry

Nature Reviews Drug Discovery volume 1, pages 541–549 (2002)Cite this article

Key Points

  • Whole-genome single-nucleotide polymorphism (SNP) mapping to determine pharmacogenetic profiles for the response of patients to drugs is in progress.

  • Because of the scant amount of published data that describe high-density SNP mapping for the identification of complex susceptibility-gene variants, as well as responses to medicines, examples of SNP-mapping strategies for testing the hypothesis that whole-genome SNP profiling is practical are drawn from work carried out at GlaxoSmithKline.

  • Two examples of adverse-event pharmacogenetics, which highlight the potential speed and utility of these methods in drug development and surveillance, are described.

  • Use of SNP profiling of patients for efficacy pharmacogenetics — with the goal of decreasing the size, complexity, time and expense of clinical trials — is described and contrasted with post-marketing surveillance for adverse-event pharmacogenetic applications.

  • Proposed methodologies for applying SNP-mapping pharmacogenetics for prediction of efficacy and adverse events for individual subjects is summarized.

  • Detailed statistical methods for analysis will be derived empirically, using actual high-density SNP-association data in conjunction with other proposals for statistical evaluation in the literature. Determining a defined pharmacogenetic profile, which contains many variables for high statistical matching, and comparing it with each individual is analogous to current statistical 'forensic' applications of polymorphism screening, in which DNA from two sources can be determined with extraordinary statistical significance.

Abstract

Pharmacogenetic capabilities have changed markedly since The SNP Consortium made a dense single-nucleotide polymorphism (SNP) map freely available in 2001. For more than 40 years, pharmacokinetics and pharmacodynamics of drug-metabolizing molecules were the focus of practical applications. Today, it is possible to use SNP-mapping technologies to create a genetic profile of each individual that can be used to identify patterns of susceptibility genes for common diseases as well as genetic risk/efficacy factors that are related to the effects of drugs.

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Figure 1: Genetic markers in the HLA-B region that are associated with hypersensitivity to abacavir.
Figure 2: Bilirubin levels pre- and post-treatment in 1,400 individuals from a Phase III clinical trial of Tranilast.
Figure 3: Relationship between genotype and response to Tranilast or placebo.
Figure 4: Example of between-chip reproducibility of proteomic mass spectra.

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Acknowledgements

A.D.R. acknowledges the GlaxoSmithKline (GSK) department heads and project leaders whose teams contributed to the experiments and examples described in this review: D. Burns, D. Campbell, R. Dement, A. Hughes, E. Lai, P. Manasco, A. McCarthy, I. Purvis, J. Riley, A. Saunders, S. Sehgal, Y. Smithies and N. Spurr. Also, the many scientists involved in creating the SNP mapping strategy and capability within GSK; T. Isenhour and E. McPherson, who assisted in preparing and editing the manuscript; A. Holden and D. Wang, who accelerated The SNP Consortium to be on time, under budget and to exceed all expectations; and M. McPeak, E. Haner, M. Beadle and S. Groh, who contributed support for team coordination. J. Niedel, T. Yamada, A. Hennah, J. Palmer, J. Robinson, B. Koch and K. Spitz provided essential early and continued support for pharmacogenetics and pharmacogenomics in the Genetics Research Directorate in GSK.

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Authors and Affiliations

  1. Genetics Research, GlaxoSmithKline, Five Moore Drive, Research Triangle Park, North Carolina, 27709, USA

    Allen D. Roses

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Related links

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DATABASES

Cancer.gov

ovarian cancer

LocusLink

APOC1

APOE

HLA-A

HLA-B

HLA-DR

TNF-α

UGT1

Medscape DrugInfo

abacavir

OMIM

Alzheimer's disease

Crigler–Najjar syndrome type I

Crohn's disease

Gilbert's syndrome

psoriasis

sickle-cell disease

FURTHER INFORMATION

The Human Genome Project

The SNP Consortium

The Wellcome Trust

LINKS

Applied Biosystems

GlaxoSmithKline

Illumina

Orchid BioSciences

Roche Diagnostics

Sequenom

Glossary

SINGLE-NUCLEOTIDE POLYMORPHISM

(SNP). A specific location in a DNA sequence at which different people have different DNA bases. This can change the protein sequence, leading to disease (for example, sickle-cell disease), or have no known consequences.

SNP MAPPING

A linear map of SNPs across the genome allows genetic traits to be localized by statistical association to the specific region of the genome that is marked by the SNP or several SNPs nearby. In the cases of complex diseases or responses to medicine, multiple SNP markers in several specific regions of the genome act as markers that are associated with the phenotype (disease or drug response).

CANDIDATE-GENE ASSOCIATIONS

A candidate gene is frequently indicated by previous hypotheses or genetic-linkage studies. Gene variants can cause or enhance susceptibility to a disease or drug-response phenotype.

SNP-LINKAGE MAPPING PANEL

The collection of SNPs that defines the linear map of the genome that is being studied. To localize the APOE gene, these SNPs would be located on chromosome 19. For HLA-B57, the SNPs are located on chromosome 6. To find other unknown regions, a SNP mapping panel that covers the whole genome can be used.

LINKAGE DISEQUILIBRIUM

(LD). Defines a region of allele (or inherited-variation) sharing along a relatively small length of the genome. If there is an association with one marker, then the likelihood of association with another marker within that region is increased.

PENETRANT GENETIC DISEASES

Describes the expression of the phenotype that results from the inheritance of disease-associated or phenotype-associated alleles. Some diseases have relatively highly penetrant mutant alleles, such as Huntington's disease. Penetrance of other traits, such as eye colour or late-onset Alzheimer's disease, might be due to combinations of less-penetrant polymorphic alleles found at several locations along the genome.

AUTOSOMAL RECESSIVE

A mode of inheritance that requires that the mutation of a single gene is present on both paternally and maternally derived alleles for the clinical phenotype to be expressed.

AUTOSOMAL DOMINANT

A mode of inheritance that requires that the mutation of a single gene is present on either of the paternally and maternally derived alleles for the clinical phenotype to be expressed.

SNP PRINTsm

Describes the pattern of inheriting SNP variations from a panel of SNPs. In the case of SNP mapping along the whole genome, it is analogous to the detection of highly private sets of traits, such as those that determine fingerprints, which make individuals unique. In the case of pharmacogenetics, it is the specific set of measured SNPs that define a drug response, and which can therefore be abstracted from the whole map to develop a more simple medicine-response profile.

MEDICINE-RESPONSE PROFILE

(MRP). A test or set of tests that indicates the likely response of a patient to a medicine. In the context of developing a test from a SNP Printsm, the test might be the selection of SNPs from the genome scan that are associated with the phenotypic response; for example, adverse event.

HYPERBILIRUBINAEMIA

Bilirubin is a metabolite of cholesterol, and its elevation above normal serum levels is called hyperbilirubinaemia. This state can be caused by several liver- and gall-bladder-related problems.

CLUSTER ANALYSIS

A formal method of statistical analysis that can be used to determine the significance of clusters of data points. For example, the clustering of disease-associated SNP variants in a region of LD, or the identification of multiple regions of nearby SNP variants (∼LD) at particular locations along the genome that defines a high probability that a specific drug response will occur.

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Roses, A. Genome-based pharmacogenetics and the pharmaceutical industry. Nat Rev Drug Discov 1, 541–549 (2002). https://doi.org/10.1038/nrd840

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