Abstract
Background
OATP1B1 is one of the key hepatocellular uptake transporters providing extraction of diverse compounds, including bile acids, xenobiotics, and a variety of drugs, from portal venous blood into the liver. Polymorphisms of the SLCO1B1 gene have been demonstrated to influence in vitro transport function and the pharmacokinetic profile of compounds.
Objective
The goal of our study was the comparison of SLCO1B1 gene sequence variability in three ethnic groups as a basis for future genetic association studies.
Methods
Eighteen exonic SLCO1B1 single nucleotide polymorphisms (SNPs) were genotyped by PCR and RFLP analysis in 300 German, 94 Turkish, and 115 African subjects. Calculation of pairwise linkage disequilibrium and estimation of population haplotype frequencies were carried out, and haplotype block structure was determined.
Results
Only eight genotyped SNPs (c.388A>G, c.411G>A, c.463C>A, c.521T>C, c.571C>T, c.597C>T, c.1463G>>C, c.1929A>C) were found in at least one of our German, Turkish, or African samples. A total of 12 haplotypes with a frequency ≥1% in at least one of the three populations could be inferred. Between the Caucasian and African samples, significant differences in sequence variability were observed leading to a different haplotype profile in these populations.
Conclusion
Our results demonstrate a high sequence variability of OATP1B1 within different popuations. In the future, distinct haplotypes should be taken into account when studying the effect of OATP1B1 on drugs in different populations.
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References
Kullak-Ublick GA, Stieger B, Meier PJ (2004) Enterohepatic bile salt transporters in normal physiology and liver disease. Gastroenterology 126(1):322–342
Konig J, Cui Y, Nies AT, Keppler D (2000) Localization and genomic organization of a new hepatocellular organic anion transporting polypeptide. J Biol Chem 275(30):23161–23168
Nishizato Y, Ieiri I, Suzuki H, Kimura M, Kawabata K, Hirota T, et al (2003) Polymorphisms of OATP-C (SLC21A6) and OAT3 (SLC22A8) genes: consequences for pravastatin pharmacokinetics. Clin Pharmacol Ther 73(6):554–565
Mwinyi J, Johne A, Bauer S, Roots I, Gerloff T (2004) Evidence for inverse effects of OATP-C (SLC21A6) 5 and 1b haplotypes on pravastatin kinetics. Clin Pharmacol Ther 75(5):415–421
Niemi M, Schaeffeler E, Lang T, Fromm MF, Neuvonen M, Kyrklund C (2004) High plasma pravastatin concentrations are associated with single nucleotide polymorphisms and haplotypes of organic anion transporting polypeptide-C (OATP-C, SLCO1B1). Pharmacogenetics 14(7):429–440
Chung JY, Cho JY, Yu KS, Kim JR, Oh DS, Jung HR, Lim KS, Moon KH, Shin SG, Jang IJ (2005) Effect of OATP1B1 (SLCO1B1) variant alleles on the pharmacokinetics of pitavastatin in healthy volunteers. Clin Pharmacol Ther 78(4):342–350
Pasanen MK, Neuvonen M, Neuvonen PJ, Niemi M (2006) SLCO1B1 polymorphism markedly affects the pharmacokinetics of simvastatin acid. Pharmacogenet Genomics 16(12):873–879
Pasanen MK, Fredrikson H, Neuvonen PJ, Niemi M (2007) Different effects of SLCO1B1 polymorphism on the pharmacokinetics of atorvastatin and rosuvastatin. Clin Pharmacol Ther [Epub ahead of print]
Cvetkovic M, Leake B, Fromm MF, Wilkinson GR, Kim RB (1999) OATP and P-glycoprotein transporters mediate the cellular uptake and excretion of fexofenadine. Drug Metab Dispos 27(8):866–871
Tamai I, Nezu J, Uchino H, Sai Y, Oku A, Shimane M, Tsuji A (2000) Molecular identification and characterization of novel members of the human organic anion transporter (OATP) family. Biochem Biophys Res Commun 273(1):251–260
Niemi M, Backman JT, Kajosaari LI, Leathart JB, Neuvonen M, Daly AK, Eichelbaum M, Kivisto KT, Neuvonen PJ (2005) Polymorphic organic anion transporting polypeptide 1B1 is a major determinant of repaglinide pharmacokinetics. Clin Pharmacol Ther 77(6):468–478
Maeda K, Ieiri I, Yasuda K, Fujino A, Fujiwara H, Otsubo K, Hirano M, Watanabe T, Kitamura Y, Kusuhara H, Sugiyama Y (2006) Effects of organic anion transporting polypeptide 1B1 haplotype on pharmacokinetics of pravastatin, valsartan, and temocapril. Clin Pharmacol Ther 79(5):427–439
Tirona RG, Leake BF, Merino G, Kim RB (2001) Polymorphisms in OATP-C: identification of multiple allelic variants associated with altered transport activity among European- and African-Americans. J Biol Chem 276(38):35669–35675
Kim RB (2003) Organic anion-transporting polypeptide (OATP) transporter family and drug disposition. Eur J Clin Invest 33(Suppl 2):1–5
Ito K, Suzuki H, Horie T, Sugiyama Y (2005) Apical/basolateral surface expression of drug transporters and its role in vectorial drug transport. Pharm Res 22(10):1559–1577
Morimoto K, Oishi T, Ueda S, Ueda M, Hosokawa M, Chiba K (2004) A novel variant allele of OATP-C (SLCO1B1) found in a Japanese patient with pravastatin-induced myopathy. Drug Metab Pharmacokinet 19(6):453–455
Nozawa T, Nakajima M, Tamai I, Noda K, Nezu J, Sai Y et al (2002) Genetic polymorphisms of human organic anion transporters OATP-C (SLC21A6) and OATP-B (SLC21A9): allele frequencies in the Japanese population and functional analysis. J Pharmacol Exp Ther 302(2):804–813
Pasanen MK, Backman JT, Neuvonen PJ, Niemi M (2006) Frequencies of single nucleotide polymorphisms and haplotypes of organic anion transporting polypeptide 1B1 SLCO1B1 gene in a Finnish population. Eur J Clin Pharmacol 62(6):409–415, Epub 2006 Apr 21
Jada SR, Xiaochen S, Yan LY, Xiaoqiang X, Lal S, Zhou SF, Ooi LL, Chowbay B (2007) Pharmacogenetics of SLCO1B1: haplotypes, htSNPs and hepatic expression in three distinct Asian populations. Eur J Clin Pharmacol 63(6):555–563, Epub 2007 Apr 6
Barrett JC, Fry B, Maller J, Daly MJ (2005) Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21(2):263–265
Garnier-Gere P, Dillmann C (1992) A computer program for testing pairwise linkage disequilibria in subdivided populations. J Hered 83(3):239
Stephens M, Smith NJ, Donnelly P (2001) A new statistical method for haplotype reconstruction from population data. Am J Hum Genet 68(4):978–989
Stephens M, Donnelly P (2003) A comparison of Bayesian methods for haplotype reconstruction from population genotype data. Am J Hum Genet 73(5):1162–1169
Igel M, Sudhop T, von Bergmann K (2002) Pharmacology of 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins), including rosuvastatin and pitavastatin. J Clin Pharmacol 42(8):835–845
Hsiang B, Zhu Y, Wang Z, Wu Y, Sasseville V, Yang WP et al (1999) A novel human hepatic organic anion transporting polypeptide (OATP2). Identification of a liver-specific human organic anion transporting polypeptide and identification of rat and human hydroxymethylglutaryl-CoA reductase inhibitor transporters. J Biol Chem 274(52):37161–37168
Vavricka SR, Van Montfoort J, Ha HR, Meier PJ, Fattinger K (2002) Interactions of rifamycin SV and rifampicin with organic anion uptake systems of human liver. Hepatology 36(1):164–172
Acknowledgements
We thank Mrs. Ulrike Ehlert and Mrs. Kristin Krostitz for skillful technical assistance. Supported by the German Federal Ministry of Education and Research (BMBF), grant no. 03/4507 (InnoRegio Health Region Berlin-Buch - Pharmacogenomic optimization of drug therapy and drug development) given to Cenimed GmbH, Center for Individualized Medicine, Berlin, and by grant no. 031U209B (Berlin Centre for Genome Based Bioinformatics) given to Charité - Universitätsmedizin Berlin.
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Mwinyi, J., Köpke, K., Schaefer, M. et al. Comparison of SLCO1B1 sequence variability among German, Turkish, and African populations. Eur J Clin Pharmacol 64, 257–266 (2008). https://doi.org/10.1007/s00228-007-0409-y
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DOI: https://doi.org/10.1007/s00228-007-0409-y