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| Original Article |
| Pharmacogenetic analysis of adverse drug effect reveals genetic variant for susceptibility to liver toxicity |
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| Gonzalo Acuña1,a, Dorothee Foernzler1,a, Diane Leong2,a, Michael Rabbia1, Ralf Smit1, Ernest Dorflinger1, Rodolfo Gasser1, Josephine Hoh3, Jürg Ott3, Edilio Borroni1, Zung To1, Annick Thompson1, Jia Li2, Lara Hashimoto1 and Klaus Lindpaintner1 |
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1F Hoffmann-La Roche Ltd, Basel, Switzerland
2Roche Molecular Systems Inc., Alameda, CA, USA
3Laboratory of Statistical Genetics, The Rockefeller University, NY, USA
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Correspondence to: Gonzalo Acuña, F Hoffmann-LaRoche Ltd, Ch-4070 Basel, Switzerland, E-mail: gonzalo.acuna@roche.com | |
aThe first three authors contributed equally to this work. |
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| 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 (TASMARÒ), 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. The Pharmacogenomics Journal (2002) 2, 327-334. doi:10.1038/sj.tpj.6500123 |
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| Keywords |
| pharmacogenetics; tolcapone; hepatotoxicity; UDP-glucuronosyl transferase 1; UGT1A |
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| Received 7 February 2002; revised 25 April 2002; accepted 6 May 2002 |
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| 2002, Volume 2, Number 5, Pages 327-334 |
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