ABCB1 polymorphism is associated with atorvastatin-induced liver injury in Japanese population.

Koya Fukunaga,Toshihisa Ishikawa,Taisei Mushiroda,Hiroshi Nakagawa,Michiaki Kubo

doi:10.1186/s12863-016-0390-5

Koya Fukunaga, Toshihisa Ishikawa + Show 3 more

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https://doi.org/10.1186/s12863-016-0390-5

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Abstract

BackgroundTo investigate the associations between atorvastatin-induced liver injury (AILI) and polymorphisms in eight genes possibly involved in the hepatic metabolism (CYP2C9, CYP2C19, CYP3A4, CYP3A5 and UGT1A1) and membrane transport (ABCB1, ABCG2 and SLCO1B1) of atorvastatin, we genotyped 30 AILI and 414 non-AILI patients recruited at BioBank Japan for 15 single nucleotide polymorphisms (SNPs).ResultsAn SNP in ABCB1 (rs2032582: 2677G > T/A) was significantly associated with AILI (P = 0.00068, odds ratio (OR) = 2.59 with 95 % confidence interval (CI) of 1.49-4.50, G allele versus T and A alleles), indicating that the G allele might be a risk factor for AILI. The cytotoxicity test demonstrated that IC50 value of atorvastatin to inhibit the growth and/or viability of Flp-In-293/ABCB1 (2677G) cells was 5.44 ± 0.10 mM, which was significantly lower than those in Flp-In-293/ABCB1 (2677 T) (6.02 ± 0.07 mM) and Flp-In-293/ABCB1 (2677A) cells (5.95 ± 0.08 mM).ConclusionsThese results indicate that ABCB1 rs2032582 may predict the risk of AILI in Japanese population.Electronic supplementary materialThe online version of this article (doi:10.1186/s12863-016-0390-5) contains supplementary material, which is available to authorized users.

Highlights

To investigate the associations between atorvastatin-induced liver injury (AILI) and polymorphisms in eight genes possibly involved in the hepatic metabolism (CYP2C9, CYP2C19, CYP3A4, CYP3A5 and UGT1A1) and membrane transport (ABCB1, ABCG2 and SLCO1B1) of atorvastatin, we genotyped 30 AILI and 414 non-AILI patients recruited at BioBank Japan for 15 single nucleotide polymorphisms (SNPs)
We hypothesized that the genetic variability of eight candidate genes associated with the hepatic metabolism and membrane transport of atorvastatin may affect the risk of AILI because higher concentrations of atorvastatin can cause hepatocellular injury, even at appropriate atorvastatin dosages
We investigated whether 15 functional SNPs in eight candidate genes that are possibly involved in the pharmacokinetics of atorvastatin were associated with AILI in Japanese population

Summary

Introduction

To investigate the associations between atorvastatin-induced liver injury (AILI) and polymorphisms in eight genes possibly involved in the hepatic metabolism (CYP2C9, CYP2C19, CYP3A4, CYP3A5 and UGT1A1) and membrane transport (ABCB1, ABCG2 and SLCO1B1) of atorvastatin, we genotyped 30 AILI and 414 non-AILI patients recruited at BioBank Japan for 15 single nucleotide polymorphisms (SNPs). Atorvastatin-induced liver injury (AILI) can be caused after atorvastatin treatment [1, 2]. AILI falls within the hepatocellular injury category because ALT level of two patients treated with atorvastatin reportedly raised three-fold. We hypothesized that the genetic variability of eight candidate genes associated with the hepatic metabolism and membrane transport of atorvastatin may affect the risk of AILI because higher concentrations of atorvastatin can cause hepatocellular injury, even at appropriate atorvastatin dosages.

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