title: SLCO1B1 *15 haplotype is associated with rifampin-induced liver injury.
abstract: The organic anion transporting polypeptide 1B1 (OATP1B1, encoded by SLCO1B1) plays an important role in the transport of endogenous and xenobiotic compounds, such as bile acids and rifampin. In this study, the association between OATP1B1 polymorphisms and rifampin hepatotoxicity was investigated using integrated population genetic analysis and functional studies. A total of 273 unrelated patients treated with rifampin were recruited. The allele frequencies were examined in patients with drug (rifampin)-induced liver injury (DILI) (n = 118) and without (non-DILI) (n = 155). Functional analyses were conducted to determine whether the inhibition of bile acids by rifampin was associated with OATP1B1 variants. In the present study, 24 single nucleotide polymorphisms (SNPs) in OATP1B1 were detected in a Chinese population, with two of them causing an amino acid change (rs2306283 and rs4149056). The haplotypes constructed by these two SNPs were OATP1B1 *1a, *1b, *5 and *15, with their respective frequencies being 23.44, 66.30, 0.73 and 9.52% in a total of 273 individuals. The logistic regression analysis indicated that the *15 haplotype was associated with susceptibility to DILI (p = 0.03, OR = 2.04, 95% CI 1.05-3.96). The frequency of the *15 haplotype in DILI patients was significantly higher than that in non-DILI patients (p = 0.03). In the subgroup analysis, the *15 haplotype was associated with susceptibility to cholestatic/mixed injury (p = 0.03, OR = 2.31, 95% CI 1.06-5.02). Functional assessment of the OATP1B1 *15 haplotype revealed that the activity of bile acid uptake was markedly reduced compared to the three other haplotypes. In the inhibition study, the inhibition by rifampin in the *15 haplotype was greater compared to that in the other haplotypes. These results suggest that the OATP1B1 *15 haplotype is an important predisposing factor for rifampin-induced liver injury.
authors.affiliation: Institute of Digestive Disease, Southwest Hospital, The Third Military Medical University, Chongqing 400038, PR China.
authors.forename: Ling-Min
authors.initials: LM
authors.lastname: Li
authors.forename: Lei
authors.initials: L
authors.lastname: Chen
authors.forename: Guo-Hong
authors.initials: GH
authors.lastname: Deng
authors.forename: Wen-Ting
authors.initials: WT
authors.lastname: Tan
authors.forename: Yun-Jie
authors.initials: YJ
authors.lastname: Dan
authors.forename: Rong-Quan
authors.initials: RQ
authors.lastname: Wang
authors.forename: Wen-Sheng
authors.initials: WS
authors.lastname: Chen
mesh_terms: D000328:Adult; D000904:Antibiotics, Antitubercular / Q000009:adverse effects*; D016022:Case-Control Studies; D056486:Chemical and Drug Induced Liver Injury / Q000235:genetics* / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D057809:HEK293 Cells; D006239:Haplotypes; D006801:Humans; D027381:Liver-Specific Organic Anion Transporter 1; D008297:Male; D008875:Middle Aged; D027361:Organic Anion Transporters / Q000235:genetics* / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D012293:Rifampin / Q000009:adverse effects*; D055815:Young Adult
chemical_list: D000904:Antibiotics, Antitubercular; D027381:Liver-Specific Organic Anion Transporter 1; D027361:Organic Anion Transporters; C503999:SLCO1B1 protein, human; D012293:Rifampin