Pharmacogenetics of OATP Transporters Reveals That SLCO1B1 c.388A>G Variant Is Determinant of Increased Atorvastatin Response

Faculty of Pharmaceutical Sciences, University of Sao Paulo, Sao Paulo 05508-900, Brazil
International Journal of Molecular Sciences (Impact Factor: 2.86). 12/2011; 12(9):5815-27. DOI: 10.3390/ijms12095815
Source: PubMed


The relationship between variants in SLCO1B1 and SLCO2B1 genes and lipid-lowering response to atorvastatin was investigated.
One-hundred-thirty-six unrelated individuals with hypercholesterolemia were selected and treated with atorvastatin (10 mg/day/4 weeks). They were genotyped with a panel of ancestry informative markers for individual African component of ancestry (ACA) estimation by SNaPshot(®) and SLCO1B1 (c.388A>G, c.463C>A and c.521T>C) and SLCO2B1 (-71T>C) gene polymorphisms were identified by TaqMan(®) Real-time PCR.
Subjects carrying SLCO1B1 c.388GG genotype exhibited significantly high low-density lipoprotein (LDL) cholesterol reduction relative to c.388AA+c.388AG carriers (41 vs. 37%, p = 0.034). Haplotype analysis revealed that homozygous of SLCO1B1*15 (c.521C and c.388G) variant had similar response to statin relative to heterozygous and non-carriers. A multivariate logistic regression analysis confirmed that c.388GG genotype was associated with higher LDL cholesterol reduction in the study population (OR: 3.2, CI95%:1.3-8.0, p < 0.05).
SLCO1B1 c.388A>G polymorphism causes significant increase in atorvastatin response and may be an important marker for predicting efficacy of lipid-lowering therapy.

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Available from: Marcelo C Bertolami
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    • "Several studies in this area point to single-nucleotide polymorphisms (SNPs) in the gene encoding multiple organic anion transporting polypeptide 1B1 (OATP1B1), SLCO1B1, as responsible for the variability of atorvastatin response (Rodrigues et al. 2011; Pasanen et al. 2007; Thompson et al. 2005; Lee et al. 2010; Lau et al. 2007). OATP1B1, expressed on the sinusoidal membrane of human hepatocytes, is responsible for the transport of atorvastatin and its uptake from the sinusoidal blood into hepatocytes where atorvastatin not only manifests its pharmacodynamic effect but is metabolized as well (Rodrigues et al. 2011; Hubacek et al. 2012; Kim et al. 2004). SNPs 388A > G (*1b, rs2306283) and 521T > C (*5, rs4149056) that encode amino acid change at position 130 (Asn130Asp) and alanine substitution of valine at amino acid 174 (Val174Ala), respectively, are considered as the most prevalent SLCO1B1 variants relevant for the variability of drug response. "
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    ABSTRACT: OATP1B1 is an influx transporter known to mediate the uptake of various endogenous compounds and xenobiotics. Several sequence variations have been discovered in the SLCO1B1 gene encoding OATP1B1. The aim of this study was to investigate the effects of SLCO1B1 polymorphisms on the pharmacokinetics of atorvastatin in healthy volunteers of Macedonian origin. Twenty three participants, genotyped for SLCO1B1 c.388A > G, c.521T > C, c.571T > C, c.597C > T, c.1086C > T, c.1463G > C and c.*439T > G polymorphisms using TaqMan allelic discrimination assay, ingested a single 80 mg dose of atorvastatin. The plasma concentrations of atorvastatin were measured for 48 h using Tandem Liquid Chromatography-Mass Spectrometry, LC-MS-MS, and the peak plasma concentration (Cmax), time to peak plasma concentration (Tmax), elimination half-life (t1/2), constant rate of elimination (kel), mean residence time (MRT, expo), volume of distribution (Vd/kg), clearance (CL/kg), area under curve AUC0-48h and AUC0-∞ were determined. Our data confirmed that the SLCO1B1 gene is highly polymorphic, with a frequency of the c.521T > C single-nucleotide polymorphism (SNP) being the lowest (app. 15%) and of all other SNPs alleles above 40%. Exceptions were c.1463G > C and c.1086C > T SNPs for which variant alleles were not identified. The strongest correlation was observed between the c.521T > C and c.571T > C SNPs pair. The haplotype analysis revealed 10 different haplotypes, with *1J/*1K/*1L being the dominant, with a frequency of app. 40%. The haplotype *15/*16/*17, containing both variant alleles of the functionally most distinguished SNPs, c.388A > G and c.521T > C, occurred with a frequency of 13%. However, *15/*16/*17 homozygotes were not identified in the study group. In this study, no significant differences in the kel, t1/2, Cmax, Tmax, AUC0-48h, AUC0-∞, MRT expo, Vd and CL between the carriers of different c.388A > G, c.597C > T and c.*439T > G genotypes were observed. Subject with a variant allele C in the c.521T > C SNP, c.521CC genotype, had markedly higher values for Cmax and AUC0-48h, 140% and 67%, respectively, in comparison with the carriers of the c.521TT genotype. Also, the carriers of the variant allele C at c.571T > C SNP, c.571 CC genotype, had 55% and 43% lower mean Cmax and AUC0-48h in comparison with the carrier of c.571TT. These differences lacked statistical significance due to the size of the sample. In addition, no significant differences in the pharmacokinetic parameters of atorvastatin between the *15/*16/*17 heterozygotes and *15/*16/*17 non-carriers were observed. In conclusion, this extensive analysis of the effect of SLCO1B1 polymorphisms on the pharmacokinetic profile of atorvastatin showed that c.521T > C and c.571T > C SNPs may affect the inter-individual response to atorvastatin. Additional studies, with a large sample size, are needed to confirm this finding.
    Full-text · Article · Jul 2015 · Pharmazie
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    • "Alternatively, ancestry can be estimated using a selected number of SNPs ranging rom a few dozens to several hundreds; this option has been favored in different areas of biomedical research, including case-control association studies of complex disease (e.g. admixture mapping) [5–8], human population studies [9–11], and forensic genetics and police investigation [12–14]. The selected SNPs are commonly known as Ancestry Informative Markers (AIMs) and received this name because they exhibit large differences in allele frequencies between populations from different geographical or ethnic groups. "
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    ABSTRACT: Background There is a growing interest among geneticists in developing panels of Ancestry Informative Markers (AIMs) aimed at measuring the biogeographical ancestry of individual genomes. The efficiency of these panels is commonly tested empirically by contrasting self-reported ancestry with the ancestry estimated from these panels. Results Using SNP data from HapMap we carried out a simulation-based study aimed at measuring the effect of SNP coverage on the estimation of genome ancestry. For three of the main continental groups (Africans, East Asians, Europeans) ancestry was first estimated using the whole HapMap SNP database as a proxy for global genome ancestry; these estimates were subsequently compared to those obtained from pre-designed AIM panels. Panels that consider >400 AIMs capture genome ancestry reasonably well, while those containing a few dozen AIMs show a large variability in ancestry estimates. Curiously, 500-1,000 SNPs selected at random from the genome provide an unbiased estimate of genome ancestry and perform as well as any AIM panel of similar size. In simulated scenarios of population admixture, panels containing few AIMs also show important deficiencies to measure genome ancestry. Conclusions The results indicate that the ability to estimate genome ancestry is strongly dependent on the number of AIMs used, and not primarily on their individual informativeness. Caution should be taken when making individual (medical, forensic, or anthropological) inferences based on AIMs. Electronic supplementary material The online version of this article (doi:10.1186/1471-2164-15-543) contains supplementary material, which is available to authorized users.
    Full-text · Article · Jun 2014 · BMC Genomics
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    • "The increased hepatic atorvastatin uptake in c.388A > G carriers is also supported by haplotype data from previous studies indicating that only c.388A > G was associated with significant lower AUCs for the OATP1B1 substrates pravastatin and repaglinide [39-41]. Moreover, variant c.388A > G carriers showed a significantly improved response to statins measured by low-density lipoprotein cholesterol levels [42,43] and were even protected from statin-induced side effects [42]. Of note, however, the effect of the c.388A > G variant seems to be substrate-specific since the AUC was not altered, for example, for rosuvastatin [44], underscoring the requirement to perform pharmacokinetic studies for each OATP1B1 drug separately. "
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    ABSTRACT: Background Organic anion transporting polypeptide (OATP) 1B1, OATP1B3, and OATP2B1 (encoded by SLCO1B1, SLCO1B3, SLCO2B1) mediate the hepatic uptake of endogenous compounds like bile acids and of drugs, for example, the lipid-lowering atorvastatin, thereby influencing hepatobiliary elimination. Here we systematically elucidated the contribution of SLCO variants on expression of the three hepatic OATPs under consideration of additional important covariates. Methods Expression was quantified by RT-PCR and immunoblotting in 143 Caucasian liver samples. A total of 109 rare and common variants in the SLCO1B3-SLCO1B1 genomic region and the SLCO2B1 gene were genotyped by MALDI-TOF mass spectrometry and genome-wide SNP microarray technology. SLCO1B1 haplotypes affecting hepatic OATP1B1 expression were associated with pharmacokinetic data of the OATP1B1 substrate atorvastatin (n = 82). Results Expression of OATP1B1, OATP1B3, and OATP2B1 at the mRNA and protein levels showed marked interindividual variability. All three OATPs were expressed in a coordinated fashion. By a multivariate regression analysis adjusted for non-genetic and transcription covariates, increased OATP1B1 expression was associated with the coding SLCO1B1 variant c.388A > G (rs2306283) even after correction for multiple testing (P = 0.00034). This held true for haplotypes harboring c.388A > G but not the functional variant c.521T > C (rs4149056) associated with statin-related myopathy. c.388A > G also significantly affected atorvastatin pharmacokinetics. SLCO variants and non-genetic and regulatory covariates together accounted for 59% of variability of OATP1B1 expression. Conclusions Our results show that expression of OATP1B1, but not of OATP1B3 and OATP2B1, is significantly affected by genetic variants. The SLCO1B1 variant c.388A > G is the major determinant with additional consequences on atorvastatin plasma levels.
    Full-text · Article · Jan 2013 · Genome Medicine
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