Abstract
Genetic risk factors for ticlopidine-induced hepatotoxicity were determined in 22 Japanese patients with ticlopidine-induced hepatotoxicity and 85 Japanese patients who tolerated ticlopidine therapy without experiencing adverse reactions. There was a significant correlation between ticlopidine-induced hepatotoxicity and five human leukocyte antigen (HLA) alleles: HLA-A*3303, HLA-B*4403, HLA-Cw*1403, HLA-DRB1*1302 and HLA-DQB1*0604 (corrected probability (P)-value (Pc)<0.01). In particular HLA-A*3303 was present in 15 (68%) of the 22 patients with ticlopidine-induced hepatotoxicity and in 12 (14%) of the 85 ticlopidine-tolerant patients (odds ratio, 13.04; 95% confidence interval (CI), 4.40–38.59; the corrected P-value (Pc)=1.24 × 10–5). HLA-A*3303 was present in 12 (86%) of the 14 patients with ticlopidine-induced cholestatic hepatotoxicity (odds ratio, 36.50; 95% CI, 7.25–183.82, Pc=7.32 × 10–7). Ticlopidine-induced severe cholestatic hepatotoxicity occurred more frequently in subjects with HLA-A*3303 and its haplotype in Japanese patients. These findings may explain the high incidence of ticlopidine-induced hepatotoxicity in Japanese patients mediated via an immune-mediated mechanism.
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Acknowledgements
We thank all of the patients who agreed to take part in this study. We also thank Dr Kingo Fujimura (Professor, Hiroshima University, Faculty of Medicine), Dr Takaaki Isshiki (Professor, Teikyo University, Department of Medicine), Dr Tsutomu Imaizumi (Professor, Kurume University School of Medicine), Dr Hideo Kusuoka (Vice Director, Osaka National Hospital), Dr Takahito Sone (Director, Ogaki Municipal Hospital), Dr Genki Mizukoshi (Nippon Medical School), Dr Masayuki Taniguchi (Associate Professor, Jikei University School of Medicine Daisan Hospital), Dr Satoshi Hirose (Assistant Professor, University of Fukui Hospital) and Dr Hiroyuki Takashima (Teaching Assistant, Shiga University of Medical Science) for patient recruitment and data collection, as well as Dr Masayuki Yamamoto (Professor, Center for Tsukuba Advanced Research Alliance), Dr Noritaka Ariyoshi (Associate Professor, Chiba University School of Medicine), ADME/TOX Research Institute of Daiichi Pure Chemicals Co., Ltd, and Mitsubishi Kagaku Bio-Clinical Laboratory Inc. for genotyping analyses.
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This study was supported by Daiichi Pharmaceutical Co., Ltd.
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Hirata, K., Takagi, H., Yamamoto, M. et al. Ticlopidine-induced hepatotoxicity is associated with specific human leukocyte antigen genomic subtypes in Japanese patients: a preliminary case–control study. Pharmacogenomics J 8, 29–33 (2008). https://doi.org/10.1038/sj.tpj.6500442
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DOI: https://doi.org/10.1038/sj.tpj.6500442
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