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Large-scale whole-exome sequencing association studies identify rare functional variants influencing serum urate levels.
Tin A, Li Y, Brody JA, Nutile T, Chu AY, Huffman JE, Yang Q, Chen MH, Robinson-Cohen C, Macé A, Liu J, Demirkan A, Sorice R, Sedaghat S, Swen M, Yu B, Ghasemi S, Teumer A, Vollenweider P, Ciullo M, Li M, Uitterlinden AG, Kraaij R, Amin N, van Rooij J, Kutalik Z, Dehghan A, McKnight B, van Duijn CM, Morrison A, Psaty BM, Boerwinkle E, Fox CS, Woodward OM, Köttgen A
(2018) Nat Commun 9: 4228
MeSH Terms: Exome, Genetic Predisposition to Disease, Glucose Transport Proteins, Facilitative, Humans, Kidney Function Tests, Meta-Analysis as Topic, Organic Anion Transporters, Organic Cation Transport Proteins, Protein Structure, Secondary, Uric Acid
Show Abstract · Added January 3, 2019
Elevated serum urate levels can cause gout, an excruciating disease with suboptimal treatment. Previous GWAS identified common variants with modest effects on serum urate. Here we report large-scale whole-exome sequencing association studies of serum urate and kidney function among ≤19,517 European ancestry and African-American individuals. We identify aggregate associations of low-frequency damaging variants in the urate transporters SLC22A12 (URAT1; p = 1.3 × 10) and SLC2A9 (p = 4.5 × 10). Gout risk in rare SLC22A12 variant carriers is halved (OR = 0.5, p = 4.9 × 10). Selected rare variants in SLC22A12 are validated in transport studies, confirming three as loss-of-function (R325W, R405C, and T467M) and illustrating the therapeutic potential of the new URAT1-blocker lesinurad. In SLC2A9, mapping of rare variants of large effects onto the predicted protein structure reveals new residues that may affect urate binding. These findings provide new insights into the genetic architecture of serum urate, and highlight molecular targets in SLC22A12 and SLC2A9 for lowering serum urate and preventing gout.
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MeSH Terms
Contribution of Organic Anion-Transporting Polypeptides 1A/1B to Doxorubicin Uptake and Clearance.
Lee HH, Leake BF, Kim RB, Ho RH
(2017) Mol Pharmacol 91: 14-24
MeSH Terms: ATP Binding Cassette Transporter, Subfamily B, Member 1, Animals, Biological Transport, Cell Membrane, Dogs, Doxorubicin, HeLa Cells, Humans, Kinetics, Liver, Liver-Specific Organic Anion Transporter 1, Madin Darby Canine Kidney Cells, Male, Mice, Models, Biological, Mutant Proteins, Organic Anion Transporters, Organic Anion Transporters, Sodium-Independent, Organic Cation Transport Proteins, Rats, Transfection
Show Abstract · Added November 10, 2016
The organic anion-transporting polypeptides represent an important family of drug uptake transporters that mediate the cellular uptake of a broad range of substrates including numerous drugs. Doxorubicin is a highly efficacious and well-established anthracycline chemotherapeutic agent commonly used in the treatment of a wide range of cancers. Although doxorubicin is a known substrate for efflux transporters such as P-glycoprotein (P-gp; MDR1, ABCB1), significantly less is known regarding its interactions with drug uptake transporters. Here, we investigated the role of organic anion transporting polypeptide (OATP) transporters to the disposition of doxorubicin. A recombinant vaccinia-based method for expressing uptake transporters in HeLa cells revealed that OATP1A2, but not OATP1B1 or OATP1B3, and the rat ortholog Oatp1a4 were capable of significant doxorubicin uptake. Interestingly, transwell assays using Madin-Darby canine kidney II cell line cells stably expressing specific uptake and/or efflux transporters revealed that OATP1B1, OATP1B3, and OATP1A2, either alone or in combination with MDR1, significantly transported doxorubicin. An assessment of polymorphisms in SLCO1A2 revealed that four variants were associated with significantly impaired doxorubicin transport in vitro. In vivo doxorubicin disposition studies revealed that doxorubicin plasma area under the curve was significantly higher (1.7-fold) in Slco1a/1b versus wild-type mice. The liver-to-plasma ratio of doxorubicin was significantly decreased (2.3-fold) in Slco1a/1b2 mice and clearance was reduced by 40% compared with wild-type mice, suggesting Oatp1b transporters are important for doxorubicin hepatic uptake. In conclusion, we demonstrate important roles for OATP1A/1B in transporter-mediated uptake and disposition of doxorubicin.
Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.
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21 MeSH Terms
Effects of Advancing Gestation and Non-Caucasian Race on Ductus Arteriosus Gene Expression.
Waleh N, Barrette AM, Dagle JM, Momany A, Jin C, Hills NK, Shelton EL, Reese J, Clyman RI
(2015) J Pediatr 167: 1033-41.e2
MeSH Terms: Aorta, Continental Population Groups, DNA, Ductus Arteriosus, Ductus Arteriosus, Patent, Female, Gene Expression Regulation, Developmental, Genotype, Gestational Age, Humans, Indomethacin, Nitric Oxide Synthase Type III, Organic Anion Transporters, Oxygen, Polymerase Chain Reaction, Polymorphism, Genetic, Pregnancy, Pregnancy Trimester, Second, Regression Analysis, Signal Transduction, Time Factors
Show Abstract · Added February 21, 2016
OBJECTIVE - To identify genes affected by advancing gestation and racial/ethnic origin in human ductus arteriosus (DA).
STUDY DESIGN - We collected 3 sets of DA tissue (n = 93, n = 89, n = 91; total = 273 fetuses) from second trimester pregnancies. We examined four genes, with DNA polymorphisms that distribute along racial lines, to identify "Caucasian" and "non-Caucasian" DA. We used real time polymerase chain reaction to measure RNA expression of 48 candidate genes involved in functional closure of the DA, and used multivariable regression analyses to examine the relationships between advancing gestation, "non-Caucasian" race, and gene expression.
RESULTS - Mature gestation and non-Caucasian race are significant predictors for identifying infants who will close their patent DA when treated with indomethacin. Advancing gestation consistently altered gene expression in pathways involved with oxygen-induced constriction (eg, calcium-channels, potassium-channels, and endothelin signaling), contractile protein maturation, tissue remodeling, and prostaglandin and nitric oxide signaling in all 3 tissue sets. None of the pathways involved with oxygen-induced constriction appeared to be altered in "non-Caucasian" DA. Two genes, SLCO2A1 and NOS3, (involved with prostaglandin reuptake/metabolism and nitric oxide production, respectively) were consistently decreased in "non-Caucasian" DA.
CONCLUSIONS - Prostaglandins and nitric oxide are the most important vasodilators opposing DA closure. Indomethacin inhibits prostaglandin production, but not nitric oxide production. Because decreased SLCO2A1 and NOS3 expression can lead to increased prostaglandin and decreased nitric oxide concentrations, we speculate that prostaglandin-mediated vasodilation may play a more dominant role in maintaining the "non-Caucasian" patent DA, making it more likely to close when inhibited by indomethacin.
Copyright © 2015 Elsevier Inc. All rights reserved.
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21 MeSH Terms
Contribution of hepatic organic anion-transporting polypeptides to docetaxel uptake and clearance.
Lee HH, Leake BF, Teft W, Tirona RG, Kim RB, Ho RH
(2015) Mol Cancer Ther 14: 994-1003
MeSH Terms: ATP Binding Cassette Transporter, Subfamily B, Member 1, Animals, Antineoplastic Agents, Biological Transport, Cell Line, Tumor, Docetaxel, Humans, Liver, Liver-Specific Organic Anion Transporter 1, Male, Mice, Mice, Knockout, Organic Anion Transporters, Organic Anion Transporters, Sodium-Independent, Rats, Solute Carrier Organic Anion Transporter Family Member 1B3, Taxoids, Tubulin Modulators
Show Abstract · Added February 25, 2015
The antimicrotubular agent docetaxel is a widely used chemotherapeutic drug for the treatment of multiple solid tumors and is predominantly dependent on hepatic disposition. In this study, we evaluated drug uptake transporters capable of transporting radiolabeled docetaxel. By screening an array of drug uptake transporters in HeLa cells using a recombinant vaccinia-based method, five organic anion-transporting polypeptides (OATP) capable of docetaxel uptake were identified: OATP1A2, OATP1B1, OATP1B3, OATP1C1, and Oatp1b2. Kinetic analysis of docetaxel transport revealed similar kinetic parameters among hepatic OATP1B/1b transporters. An assessment of polymorphisms (SNPs) in SLCO1B1 and SLCO1B3 revealed that a number of OATP1B1 and OATP1B3 variants were associated with impaired docetaxel transport. A Transwell-based vectorial transport assay using MDCKII stable cells showed that docetaxel was transported significantly into the apical compartment of double-transfected (MDCKII-OATP1B1/MDR1 and MDCKII-OATP1B3/MDR1) cells compared with single-transfected (MDCKII-OATP1B1 and MDCKII-OATP1B3) cells (P < 0.05) or control (MDCKII-Co) cells (P < 0.001). In vivo docetaxel transport studies in Slco1b2(-/-) mice showed approximately >5.5-fold higher plasma concentrations (P < 0.01) and approximately 3-fold decreased liver-to-plasma ratio (P < 0.05) of docetaxel compared with wild-type (WT) mice. The plasma clearance of docetaxel in Slco1b2(-/-) mice was 83% lower than WT mice (P < 0.05). In conclusion, this study demonstrates the important roles of OATP1B transporters to the hepatic disposition and clearance of docetaxel, and supporting roles of these transporters for docetaxel pharmacokinetics.
©2015 American Association for Cancer Research.
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18 MeSH Terms
The clinical pharmacogenetics implementation consortium guideline for SLCO1B1 and simvastatin-induced myopathy: 2014 update.
Ramsey LB, Johnson SG, Caudle KE, Haidar CE, Voora D, Wilke RA, Maxwell WD, McLeod HL, Krauss RM, Roden DM, Feng Q, Cooper-DeHoff RM, Gong L, Klein TE, Wadelius M, Niemi M
(2014) Clin Pharmacol Ther 96: 423-8
MeSH Terms: Drug Interactions, Genotype, Humans, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Liver-Specific Organic Anion Transporter 1, Muscular Diseases, Organic Anion Transporters, Pharmacogenetics, Polymorphism, Genetic, Simvastatin
Show Abstract · Added June 26, 2014
Simvastatin is among the most commonly used prescription medications for cholesterol reduction. A single coding single-nucleotide polymorphism, rs4149056T>C, in SLCO1B1 increases systemic exposure to simvastatin and the risk of muscle toxicity. We summarize evidence from the literature supporting this association and provide therapeutic recommendations for simvastatin based on SLCO1B1 genotype. This article is an update to the 2012 Clinical Pharmacogenetics Implementation Consortium guideline for SLCO1B1 and simvastatin-induced myopathy.
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10 MeSH Terms
Applied pharmacogenomics in cardiovascular medicine.
Weeke P, Roden DM
(2014) Annu Rev Med 65: 81-94
MeSH Terms: Adrenergic beta-Antagonists, Antihypertensive Agents, Antithrombins, Aryl Hydrocarbon Hydroxylases, Cardiovascular Diseases, Clopidogrel, Cytochrome P-450 CYP2C19, Cytochrome P-450 CYP2C9, Humans, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Liver-Specific Organic Anion Transporter 1, Organic Anion Transporters, Pharmacogenetics, Polymorphism, Single Nucleotide, Precision Medicine, Ticlopidine, Vitamin K Epoxide Reductases, Warfarin
Show Abstract · Added March 7, 2014
Interindividual heterogeneity in drug response is a central feature of all drug therapies. Studies in individual patients, families, and populations over the past several decades have identified variants in genes encoding drug elimination or drug target pathways that in some cases contribute substantially to variable efficacy and toxicity. Important associations of pharmacogenomics in cardiovascular medicine include clopidogrel and risk for in-stent thrombosis, steady-state warfarin dose, myotoxicity with simvastatin, and certain drug-induced arrhythmias. This review describes methods used to accumulate and validate these findings and points to approaches--now being put in place at some centers--to implementing them in clinical care.
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Discordant associations between SLCO1B1 521T→C and plasma levels of ritonavir-boosted protease inhibitors in AIDS clinical trials group study A5146.
Zhang X, Tierney C, Albrecht M, Demeter LM, Morse G, DiFrancesco R, Dykes C, Jiang H, Haas DW
(2013) Ther Drug Monit 35: 209-16
MeSH Terms: Acquired Immunodeficiency Syndrome, Adult, Female, Genetic Association Studies, HIV Protease Inhibitors, Humans, Linkage Disequilibrium, Liver-Specific Organic Anion Transporter 1, Male, Middle Aged, Organic Anion Transporters, Ritonavir
Show Abstract · Added March 13, 2015
OBJECTIVE - Among HIV-positive patients prescribed ritonavir-boosted lopinavir, SLCO1B1 521T→C (rs4149056) is associated with increased plasma lopinavir exposure. Protease inhibitors (PIs) are also substrates for cytochrome P450 (CYP) 3A and ABCB1, which are induced by NR1I2. We characterized relationships between ABCB1, CYP3A4, CYP3A5, NR1I2, and SLCO1B1 polymorphisms and trough PI concentrations among AIDS Clinical Trials Group study A5146 participants.
METHODS - At study entry, subjects with virologic failure on PI-containing regimens initiated new ritonavir-boosted PI regimens. We studied associations between week 2 PI plasma trough concentrations and 143 polymorphisms in these genes, including 4 targeted polymorphisms.
RESULTS - Among 275 subjects with both drug concentrations and genetic data, allelic frequencies of SLCO1B1 521T→C were 15%, 1%, and 8% in whites, blacks, and Hispanics, respectively. Further analyses were limited to 268 white, black, or Hispanic subjects who initiated ritonavir-boosted lopinavir (n = 98), fosamprenavir (n = 69), or saquinavir (n = 99). Of targeted polymorphisms, SLCO1B1 521T→C tended to be associated with higher lopinavir concentrations, with a 1.38-fold increase in the mean per C allele (95% confidence interval, 0.97-1.96; n = 98; P = 0.07). With fosamprenavir, SLCO1B1 521T→C was associated with lower amprenavir concentrations, with a 35% decrease in the mean per C allele (geometric mean ratio 0.65; 95% confidence interval, 0.44-0.94; n = 69; adjusted P = 0.02). There was no significant association with saquinavir concentrations, and none of the remaining 139 exploratory polymorphisms were statistically significant after correcting for multiple comparisons.
CONCLUSIONS - With ritonavir-boosted PIs, a SLCO1B1 polymorphism that predicts higher lopinavir trough concentrations seems to predict lower amprenavir trough concentrations. The mechanism underlying this discordant association is uncertain.
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12 MeSH Terms
A cancer-specific variant of the SLCO1B3 gene encodes a novel human organic anion transporting polypeptide 1B3 (OATP1B3) localized mainly in the cytoplasm of colon and pancreatic cancer cells.
Thakkar N, Kim K, Jang ER, Han S, Kim K, Kim D, Merchant N, Lockhart AC, Lee W
(2013) Mol Pharm 10: 406-16
MeSH Terms: Biological Transport, Cell Line, Tumor, Colonic Neoplasms, Cytoplasm, Exons, Genetic Variation, HCT116 Cells, Humans, Liver, Organic Anion Transporters, Sodium-Independent, Pancreatic Neoplasms, Protein Processing, Post-Translational, Sincalide, Solute Carrier Organic Anion Transporter Family Member 1B3
Show Abstract · Added March 26, 2014
OATP1B3 is a member of the OATP (organic anion transporting polypeptides) superfamily, responsible for mediating the transport of numerous endogenous and xenobiotic substances. Although initially reported to be exclusively expressed in the liver, several studies reported that OATP1B3 is frequently expressed in multiple types of cancers and may be associated with differing clinical outcomes. However, a detailed investigation on the expression and function of OATP1B3 protein in cancer has been lacking. In this study, we confirmed that colon and pancreatic cancer cells express variant forms of OATP1B3, different from OATP1B3 wild-type (WT) expressed in the normal liver. OATP1B3 variant 1 (V1), the most prevalent form among the variants, contains alternative exonic sequences (exon 2a) instead of exons 1 and 2 present in OATP1B3 WT. The translated product of OATP1B3 V1 is almost identical to OATP1B3 WT, with exception to the first 28 amino acids at the N-terminus. Exogenous expression of OATP1B3 V1 revealed that OATP1B3 V1 undergoes post-translational modifications and proteasomal degradation to a differing extent compared to OATP1B3 WT. OATP1B3 V1 showed only modest transport activity toward cholecystokin-8 (CCK-8, a prototype OATP1B3 substrate) in contrast to OATP1B3 WT showing a markedly efficient uptake of CCK-8. Consistent with these results, OATP1B3 V1 was localized mainly in the cytoplasm with a much lower extent of trafficking to the surface membrane compared to OATP1B3 WT. In summary, our results demonstrate that colon and pancreatic cancer cells express variant forms of OATP1B3 with only limited transport activity and different subcellular localization compared to OATP1B3 WT. These observed differences at the molecular and functional levels will be important considerations for further investigations of the biological and clinical significance of OATP1B3 expression in cancer.
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14 MeSH Terms
The clinical pharmacogenomics implementation consortium: CPIC guideline for SLCO1B1 and simvastatin-induced myopathy.
Wilke RA, Ramsey LB, Johnson SG, Maxwell WD, McLeod HL, Voora D, Krauss RM, Roden DM, Feng Q, Cooper-Dehoff RM, Gong L, Klein TE, Wadelius M, Niemi M, Clinical Pharmacogenomics Implementation Consortium (CPIC)
(2012) Clin Pharmacol Ther 92: 112-7
MeSH Terms: Drug Prescriptions, Humans, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Liver-Specific Organic Anion Transporter 1, Muscular Diseases, Organic Anion Transporters, Pharmacogenetics, Polymorphism, Single Nucleotide, Precision Medicine, Risk Assessment, Risk Factors, Simvastatin
Show Abstract · Added June 26, 2014
Cholesterol reduction from statin therapy has been one of the greatest public health successes in modern medicine. Simvastatin is among the most commonly used prescription medications. A non-synonymous coding single-nucleotide polymorphism (SNP), rs4149056, in SLCO1B1 markedly increases systemic exposure to simvastatin and the risk of muscle toxicity. This guideline explores the relationship between rs4149056 (c.521T>C, p.V174A) and clinical outcome for all statins. The strength of the evidence is high for myopathy with simvastatin. We limit our recommendations accordingly.
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12 MeSH Terms
Interaction of three regiospecific amino acid residues is required for OATP1B1 gain of OATP1B3 substrate specificity.
DeGorter MK, Ho RH, Leake BF, Tirona RG, Kim RB
(2012) Mol Pharm 9: 986-95
MeSH Terms: Amino Acids, Cholecystokinin, Liver-Specific Organic Anion Transporter 1, Mutagenesis, Site-Directed, Organic Anion Transporters, Organic Anion Transporters, Sodium-Independent, Peptide Fragments, Solute Carrier Organic Anion Transporter Family Member 1B3, Substrate Specificity
Show Abstract · Added March 5, 2014
The human organic anion-transporting polypeptides OATP1B1 (SLCO1B1) and OATP1B3 (SLCO1B3) are liver-enriched membrane transporters of major importance to hepatic uptake of numerous endogenous compounds, including bile acids, steroid conjugates, hormones, and drugs, including the 3-hydroxy-3-methylglutaryl Co-A reductase inhibitor (statin) family of cholesterol-lowering compounds. Despite their remarkable substrate overlap, there are notable exceptions: in particular, the gastrointestinal peptide hormone cholecystokinin-8 (CCK-8) is a high affinity substrate for OATP1B3 but not OATP1B1. We utilized homologous recombination of linear DNA by E. coli to generate a library of cDNA containing monomer size chimeric OATP1B1-1B3 and OATP1B3-1B1 transporters with randomly distributed chimeric junctions to identify three discrete regions of the transporter involved in conferring CCK-8 transport activity. Site-directed mutagenesis of three key residues in OATP1B1 transmembrane helices 1 and 10, and extracellular loop 6, to the corresponding residues in OATP1B3, resulted in a gain of CCK-8 transport by OATP1B1. The residues appear specific to CCK-8, as the mutations did not affect transport of the shared OATP1B substrate atorvastatin or the OATP1B1-specific substrate estrone sulfate. Regions involved in gain of CCK-8 transport by OATP1B1, when mapped to the crystal structures of bacterial transporters from the major facilitator superfamily, are positioned to suggest these regions could readily interact with drug substrates. Accordingly, our data provide new insight into the molecular determinants of the substrate specificity of these hepatic uptake transporters with relevance to targeted drug design and prediction of drug-drug interactions.
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9 MeSH Terms