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Genome-wide approaches to identify pharmacogenetic contributions to adverse drug reactions

The Pharmacogenomics Journal volume 9, pages 23–33 (2009)Cite this article

Abstract

Adverse drug reactions (ADRs) have a major impact on patients, physicians, health care providers, regulatory agencies and pharmaceutical companies. Identifying the genetic contributions to ADR risk may lead to a better understanding of the underlying mechanisms, identification of patients at risk and a decrease in the number of events. Technological advances have made the routine monitoring and investigation of the genetic basis of ADRs during clinical trials possible. We demonstrate through simulation that genome-wide genotyping, coupled with the use of clinically matched or population controls, can yield sufficient statistical power to permit the identification of strong genetic predictors of ADR risk in a prospective manner with modest numbers of ADR cases. The results of a 500 000 single nucleotide polymorphism analysis of abacavir-associated hypersensitivity reaction suggest that the known HLA-B gene region could be identified with as few as 15 cases and 200 population controls in a sequential analysis.

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Abbreviations

ABC:

abacavir

ADR:

adverse drug reaction

GRR:

genotype relative risk

HSR:

hypersensitivity reaction

LD:

linkage disequilibrium

MHC:

major histocompatibility complex

SNP:

single nucleotide polymorphism

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Acknowledgements

We thank Jill Ratchford, Brendan Jones, David Yarnall and Stephanie Chissoe for support of the Affymetrix genotyping; Charles Cox and Kirstie Davies for support of Luminex-based genotyping; Karen King for genotype data management and support of the intensity QC process; Dan Burns for his support of the POPRES and pharmacogenetics projects; Patrick Ryan, June Almenoff and Michael Irizarry for helpful discussions about the study of adverse drug reactions; and Arlene Hughes and Bill Spreen for their work on abacavir-associated hypersensitivity reaction pharmacogenetics research.

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Authors and Affiliations

  1. Pharmacogenetics, GlaxoSmithKline, Research Triangle Park, NC, USA

    M R Nelson, S-A Bacanu, M Mosteller, L Li, C E Bowman, A D Roses, E H Lai & M G Ehm

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  1. M R Nelson
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  2. S-A Bacanu
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  3. M Mosteller
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  4. L Li
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  6. A D Roses
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  7. E H Lai
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  8. M G Ehm
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Correspondence to M R Nelson.

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None declared.

Supplementary Information accompanies the paper on the The Pharmacogenomics Journal website (http://www.nature.com/tpj)

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Nelson, M., Bacanu, SA., Mosteller, M. et al. Genome-wide approaches to identify pharmacogenetic contributions to adverse drug reactions. Pharmacogenomics J 9, 23–33 (2009). https://doi.org/10.1038/tpj.2008.4

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