title: Ticlopidine-induced hepatotoxicity is associated with specific human leukocyte antigen genomic subtypes in Japanese patients: a preliminary case-control study.
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 x 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 x 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.
authors.affiliation: Product Lifecycle Management Department, Daiichi Pharmaceutical Co. Ltd., 1-8 Nihonbashi-Koamicho, Chuo-ku, Tokyo, Japan. hiratyl9@daiichipharm.co.jp
authors.forename: K
authors.initials: K
authors.lastname: Hirata
authors.forename: H
authors.initials: H
authors.lastname: Takagi
authors.forename: M
authors.initials: M
authors.lastname: Yamamoto
authors.forename: T
authors.initials: T
authors.lastname: Matsumoto
authors.forename: T
authors.initials: T
authors.lastname: Nishiya
authors.forename: K
authors.initials: K
authors.lastname: Mori
authors.forename: S
authors.initials: S
authors.lastname: Shimizu
authors.forename: H
authors.initials: H
authors.lastname: Masumoto
authors.forename: Y
authors.initials: Y
authors.lastname: Okutani
mesh_terms: D001711:Biotransformation / Q000235:genetics; D016022:Case-Control Studies; D056486:Chemical and Drug Induced Liver Injury / Q000453:epidemiology / Q000235:genetics*; D002780:Cholestasis, Intrahepatic / Q000235:genetics; D003580:Cytochromes / Q000235:genetics / Q000378:metabolism; D030541:Databases, Genetic; D016678:Genome; D005838:Genotype; D006680:HLA Antigens / Q000235:genetics*; D006801:Humans; D007564:Japan / Q000453:epidemiology; D010975:Platelet Aggregation Inhibitors / Q000009:adverse effects* / Q000627:therapeutic use; D013988:Ticlopidine / Q000009:adverse effects* / Q000627:therapeutic use
chemical_list: D003580:Cytochromes; D006680:HLA Antigens; D010975:Platelet Aggregation Inhibitors; D013988:Ticlopidine