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Yamada, S., Richardson, K. 
ORCID: https://orcid.org/0000-0002-0741-8413, Tang, M., Halaschek-Wiener, J., Cook, V. J., Fitzgerald, J. M., Elwood, K., Marra, F. and Brooks-Wilson, A.
(2010)
Genetic variation in carboxylesterase genes and susceptibility to isoniazid-induced hepatotoxicity.
The Pharmacogenomics Journal, 10 (6).
pp. 524-536.
ISSN 1470-269X
Abstract
Treatment of latent tuberculosis infection (LTBI) generally includes isoniazid (INH), a drug that can cause serious hepatotoxicity. Carboxylesterases (CES) are important in the metabolism of a variety of substrates, including xenobiotics. We hypothesized that genetic variation in CES genes expressed in the liver could affect INH-induced hepatotoxicity. Three CES genes are known to be expressed in human liver: CES1, CES2 and CES4. Our aim was to systematically characterize genetic variation in these novel candidate genes and test whether it is associated with this adverse drug reaction. As part of a pilot study, 170 subjects with LTBI who received only INH were recruited, including 23 cases with hepatotoxicity and 147 controls. All exons and the promoters of CES1, CES2 and CES4 were bidirectionally sequenced. A large polymorphic deletion was found to encompass exons 2 to 6 of CES4. No significant association was found. Eleven single-nucleotide polymorphisms (SNPs) in CES1 were in high linkage disequilibrium with each other. One of these SNPs, C(−2)G, alters the translation initiation sequence of CES1 and represents a candidate functional polymorphism. Replication of this possible association in a larger sample set and functional studies will be necessary to determine if this CES1 variant has a role in INH-induced hepatotoxicity.
| Item Type: | Article |
|---|---|
| Additional Information: | Acknowledgements: This study was funded by a grant from the BC Lung Association to FM and AB-W. AB-W is a senior scholar of the Michael Smith Foundation for Health Research. JH-W was supported in part by an Erwin Schroedinger Fellowship from the Austrian Science Foundation (FWF). VC was supported in part by ‘in it for life’, Vancouver Coastal Health Research Institute. JMFG is a recipient of a Michel Smith Distinguished Scholar Award and a CIHR/BC Lung Scientist Award. SY was supported in part by a Ritsumeikan University International Research Fellowship. |
| Faculty \ School: | Faculty of Medicine and Health Sciences > School of Health Sciences |
| UEA Research Groups: | Faculty of Science > Research Groups > Norwich Epidemiology Centre Faculty of Medicine and Health Sciences > Research Groups > Norwich Epidemiology Centre Faculty of Medicine and Health Sciences > Research Groups > Health Promotion |
| Depositing User: | Pure Connector |
| Date Deposited: | 05 Jan 2015 15:04 |
| Last Modified: | 21 May 2024 12:30 |
| URI: | https://ueaeprints.uea.ac.uk/id/eprint/51642 |
| DOI: | 10.1038/tpj.2010.5 |
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