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Identification of a pharmacogenetic effect by linkage disequilibrium mapping

The Pharmacogenomics Journal volume 4, pages 374–378 (2004)Cite this article

ABSTRACT

A practical limitation to the identification of genetic profiles predictive of drug-induced adverse events is the number of patients with the adverse event that can be tolerated before the drug is withdrawn. Whole genome screening for regions of linkage disequilibrium (LD) associated with a particular phenotype may provide the mechanism to rapidly discover specific and sensitive profiles. We have used data from a large phase III clinical trial of tranilast and typed 76 SNPs over a 2.7 megabase region flanking the uridine diphosphate glucuronosyltranserferase 1A1 gene. Three SNPs within one LD block showed strong association with tranilast-induced hyperbilirubinemia (P<10−13). Our data illustrated that a genome-wide LD scan of 100 000–200 000 SNPs is sufficient to identify a pharmacogenetic association with a drug-induced adverse event.

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Abbreviations

AE:

adverse event

LD:

linkage disequilibrium

SNP:

single-nucleotide polymorphism

UGT1A1:

uridine diphosphate glucuronosyltranserferase 1A1

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Acknowledgements

We thank all the scientists within Discovery Genetics, GlaxoSmithKline for their scientific contributions. In addition, we would like to thank Pete Boyd and Aruna Basal for statistical advice and critical reading of the manuscript, and Mike Barnes for SNP mapping assistance. This study is wholly funded by GSK Research and Development.

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Authors and Affiliations

  1. Discovery and Pipeline Genetics, GlaxoSmithKline Medicines Research Centre, Stevenage, Hertfordshire, UK

    C-F Xu, K F Lewis, A J Yeo, L C McCarthy, M F Maguire, Z Anwar & I J Purvis

  2. Clinical Pharmacology and Discovery Medicine, GlaxoSmithKline, Philadelphia, PA, USA

    T M Danoff

  3. Genetics Research, GlaxoSmithKline, Research Triangle Park, NC, USA

    A D Roses

Authors
  1. C-F Xu
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  2. K F Lewis
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  7. T M Danoff
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Correspondence to C-F Xu.

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None declared.

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

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Xu, CF., Lewis, K., Yeo, A. et al. Identification of a pharmacogenetic effect by linkage disequilibrium mapping. Pharmacogenomics J 4, 374–378 (2004). https://doi.org/10.1038/sj.tpj.6500268

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