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Pharmacogenetic analysis of adverse drug effect reveals genetic variant for susceptibility to liver toxicity

The Pharmacogenomics Journal volume 2, pages 327–334 (2002)Cite this article

Abstract

A retrospective pharmacogenetic study was conducted to identify possible genetic susceptibility factors in patients in whom the administration of the anti-Parkinson drug, tolcapone (TASMAR®), was associated with hepatic toxicity. We studied 135 cases of patients with elevated liver transaminase levels (ELT) of ≥1.5 times above the upper limit of normal, in comparison with matched controls that had also received the drug but had not experienced ELT. DNA samples were genotyped for 30 previously described or newly characterized bi-allelic single nucleotide polymorphisms (SNPs), representing 12 candidate genes selected based on the known metabolic pathways involved in the tolcapone elimination. SNPs located within the UDP-glucuronosyl transferase 1A gene complex, which codes for the enzymes involved in the main elimination pathway of the drug, were found to be significantly associated with the occurrence of tolcapone-associated ELTs.

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Acknowledgements

We would like to thank all the patients that participated in this study and acknowledge the contributions of the study investigators who contacted the patients and collected the blood samples. These data were submitted to the European drug regulatory authorities (CPMP) on 15 July 2000. We would also like to thank the technical staff (T Burchill, J Mangaccat, R Olmos and Y Kidane) who ran the genotyping assays. Partial support through grant HG00008 (to JO) from the National Human Genome Research Institute is gratefully acknowledged.

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Author notes

  1. Gonzalo Acuña, Dorothee Foernzler and Diane Leong: The first three authors contributed equally to this work.

Authors and Affiliations

  1. F Hoffmann-La Roche Ltd, Basel, Switzerland

    Gonzalo Acuña, Dorothee Foernzler, Michael Rabbia, Ralf Smit, Ernest Dorflinger, Rodolfo Gasser, Edilio Borroni, Zung To, Annick Thompson, Lara Hashimoto & Klaus Lindpaintner

  2. Roche Molecular Systems Inc., Alameda, CA, USA

    Diane Leong & Jia Li

  3. Laboratory of Statistical Genetics, The Rockefeller University, NY, USA

    Josephine Hoh & Jürg Ott

Authors
  1. Gonzalo Acuña
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  2. Dorothee Foernzler
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  3. Diane Leong
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  4. Michael Rabbia
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  5. Ralf Smit
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  6. Ernest Dorflinger
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  7. Rodolfo Gasser
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  8. Josephine Hoh
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  9. Jürg Ott
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  10. Edilio Borroni
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  11. Zung To
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  12. Annick Thompson
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  13. Jia Li
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  14. Lara Hashimoto
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  15. Klaus Lindpaintner
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Corresponding author

Correspondence to Gonzalo Acuña.

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Acuña, G., Foernzler, D., Leong, D. et al. Pharmacogenetic analysis of adverse drug effect reveals genetic variant for susceptibility to liver toxicity. Pharmacogenomics J 2, 327–334 (2002). https://doi.org/10.1038/sj.tpj.6500123

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  • DOI: https://doi.org/10.1038/sj.tpj.6500123

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