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1.
Pharmacogenomics J ; 17(2): 137-145, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-26856248

RESUMO

Variation in the expression level and activity of genes involved in drug disposition and action ('pharmacogenes') can affect drug response and toxicity, especially when in tissues of pharmacological importance. Previous studies have relied primarily on microarrays to understand gene expression differences, or have focused on a single tissue or small number of samples. The goal of this study was to use RNA-sequencing (RNA-seq) to determine the expression levels and alternative splicing of 389 Pharmacogenomics Research Network pharmacogenes across four tissues (liver, kidney, heart and adipose) and lymphoblastoid cell lines, which are used widely in pharmacogenomics studies. Analysis of RNA-seq data from 139 different individuals across the 5 tissues (20-45 individuals per tissue type) revealed substantial variation in both expression levels and splicing across samples and tissue types. Comparison with GTEx data yielded a consistent picture. This in-depth exploration also revealed 183 splicing events in pharmacogenes that were previously not annotated. Overall, this study serves as a rich resource for the research community to inform biomarker and drug discovery and use.


Assuntos
Processamento Alternativo , Biologia Computacional , Sequenciamento de Nucleotídeos em Larga Escala , Farmacogenética , Variantes Farmacogenômicos , Análise de Sequência de RNA , Transcriptoma , Tecido Adiposo/metabolismo , Linhagem Celular , Bases de Dados Genéticas , Genótipo , Humanos , Rim/metabolismo , Fígado/metabolismo , Miocárdio/metabolismo , Fenótipo
2.
Pharmacogenomics J ; 13(2): 110-20, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22231567

RESUMO

Human organic cation transporter 3 (OCT3 and SLC22A3) mediates the uptake of many important endogenous amines and basic drugs in a variety of tissues. OCT3 is identified as one of the important risk loci for prostate cancer, and is markedly underexpressed in aggressive prostate cancers. The goal of this study was to identify genetic and epigenetic factors in the promoter region that influence the expression level of OCT3. Haplotypes that contained the common variants, g.-81G>delGA (rs60515630) (minor allele frequency 11.5% in African American) and g.-2G>A (rs555754) (minor allele frequency>30% in all ethnic groups) showed significant increases in luciferase reporter activities and exhibited stronger transcription factor-binding affinity than the haplotypes that contained the major alleles. Consistent with the reporter assays, OCT3 messenger RNA expression levels were significantly higher in Asian (P<0.001) and Caucasian (P<0.05) liver samples from individuals who were homozygous for g.-2A/A in comparison with those homozygous for the g.-2G/G allele. Studies revealed that the methylation level in the basal promoter region of OCT3 was associated with OCT3 expression level and tumorigenesis capability in various prostate cancer cell lines. The methylation level of the OCT3 promoter was higher in 62% of prostate tumor samples compared with matched normal samples. Our studies demonstrate that genetic polymorphisms in the proximal promoter region of OCT3 alter the transcription rate of the gene and may be associated with altered expression levels of OCT3 in human liver. Aberrant methylation contributes to the reduced expression of OCT3 in prostate cancer.


Assuntos
Metilação de DNA/genética , Epigenômica , Proteínas de Transporte de Cátions Orgânicos/genética , Neoplasias da Próstata/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Farmacológicos/metabolismo , Linhagem Celular Tumoral , Transformação Celular Neoplásica , Etnicidade/genética , Feminino , Regulação da Expressão Gênica , Frequência do Gene , Haplótipos , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético , Regiões Promotoras Genéticas , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/patologia
3.
Clin Pharmacol Ther ; 90(5): 674-84, 2011 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-21956618

RESUMO

Multidrug and toxin extrusion 2 (MATE2-K (SLC47A2)), a polyspecific organic cation exporter, facilitates the renal elimination of the antidiabetes drug metformin. In this study, we characterized genetic variants of MATE2-K, determined their association with metformin response, and elucidated their impact by means of a comparative protein structure model. Four nonsynonymous variants and four variants in the MATE2-K basal promoter region were identified from ethnically diverse populations. Two nonsynonymous variants-c.485C>T and c.1177G>A-were shown to be associated with significantly lower metformin uptake and reduction in protein expression levels. MATE2-K basal promoter haplotypes containing the most common variant, g.-130G>A (>26% allele frequency), were associated with a significant increase in luciferase activities and reduced binding to the transcriptional repressor myeloid zinc finger 1 (MZF-1). Patients with diabetes who were homozygous for g.-130A had a significantly poorer response to metformin treatment, assessed as relative change in glycated hemoglobin (HbA1c) (-0.027 (-0.076, 0.033)), as compared with carriers of the reference allele, g.-130G (-0.15 (-0.17, -0.13)) (P=0.002). Our study showed that MATE2-K plays a role in the antidiabetes response to metformin.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/farmacocinética , Metformina/farmacocinética , Proteínas de Transporte de Cátions Orgânicos/genética , Adulto , Idoso , Alelos , Animais , Feminino , Variação Genética , Hemoglobinas Glicadas/metabolismo , Células HCT116 , Células HEK293 , Haplótipos , Humanos , Hipoglicemiantes/farmacologia , Células LLC-PK1 , Luciferases/metabolismo , Masculino , Metformina/farmacologia , Pessoa de Meia-Idade , Polimorfismo Genético , Regiões Promotoras Genéticas , Grupos Raciais/genética , Estudos Retrospectivos , Suínos , Resultado do Tratamento
4.
Clin Pharmacol Ther ; 89(4): 571-8, 2011 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21368754

RESUMO

Little is known about how genetic variations in enhancers influence drug response. In this study, we investigated whether nucleotide variations in enhancers that regulate drug transporters can alter their expression levels. Using comparative genomics and liver-specific transcription factor binding site (TFBS) analyses, we identified evolutionary conserved regions (ECRs) surrounding nine liver membrane transporters that interact with commonly used pharmaceuticals. The top 50 ECRs were screened for enhancer activity in vivo, of which five--located around ABCB11, SLC10A1, SLCO1B1, SLCO1A2, and SLC47A1--exhibited significant enhancer activity. Common variants identified in a large ethnically diverse cohort (n = 272) were assayed for differential enhancer activity, and three variants were found to have significant effects on reporter activity as compared with the reference allele. In addition, one variant was associated with reduced SLCO1A2 mRNA expression levels in human liver tissues, and another was associated with increased methotrexate (MTX) clearance in patients. This work provides a general model for the rapid characterization of liver enhancers and identifies associations between enhancer variants and drug response.


Assuntos
Transportadores de Cassetes de Ligação de ATP/metabolismo , Metotrexato/farmacocinética , Transportadores de Ânions Orgânicos/metabolismo , Proteínas de Transporte de Cátions Orgânicos/metabolismo , Preparações Farmacêuticas/metabolismo , Membro 11 da Subfamília B de Transportadores de Cassetes de Ligação de ATP , Transportadores de Cassetes de Ligação de ATP/genética , Alelos , Animais , Sítios de Ligação , Transporte Biológico , Sequência Conservada , Feminino , Regulação da Expressão Gênica , Variação Genética , Genômica/métodos , Humanos , Fígado/metabolismo , Masculino , Camundongos , Transportadores de Ânions Orgânicos/genética , Proteínas de Transporte de Cátions Orgânicos/genética , Polimorfismo de Nucleotídeo Único , RNA Mensageiro/metabolismo , Grupos Raciais/genética , Fatores de Transcrição
5.
Pharmacogenomics J ; 5(3): 157-65, 2005.
Artigo em Inglês | MEDLINE | ID: mdl-15738947

RESUMO

The human concentrative nucleoside transporter, CNT3 (SLC28A3), plays an important role in mediating the cellular entry of a broad array of physiological nucleosides and synthetic anticancer nucleoside analog drugs. As a first step toward understanding the genetic basis for interindividual differences in the disposition and response to antileukemic nucleoside analogs, we examined the genetic and functional diversity of CNT3. In all, 56 variable sites in the exons and flanking intronic region of SLC28A3 were identified in a collection of 270 DNA samples from US populations (80 African-Americans, 80 European-Americans, 60 Asian-Americans, and 50 Mexican-Americans). Of the 16 coding region variants, 12 had not been previously reported. Also, 10 resulted in amino-acid changes and three of these had total allele frequencies of >/=1%. Nucleotide diversity (pi) at nonsynonymous and synonymous sites was estimated to be 1.81 x 10(4) and 18.13 x 10(4), respectively, suggesting that SLC28A3 is under negative selection. All nonsynonymous variants, constructed by site-directed mutagenesis and expressed in Xenopus laevis oocytes, transported purine and pyrimidine model substrates, except for c. 1099G>A (p. Gly367Arg). This rare variant alters an evolutionarily conserved site in the putative substrate recognition domain of CNT3. The presence of three additional evolutionarily conserved glycine residues in the vicinity of p. Gly367Arg that are also conserved in human paralogs suggest that these glycine residues are critical in the function of the concentrative nucleoside transporter family. The genetic analysis and functional characterization of CNT3 variants suggest that this transporter does not tolerate nonsynonymous changes and is important for human fitness.


Assuntos
Proteínas de Membrana Transportadoras/genética , Vidarabina/análogos & derivados , Adenosina/metabolismo , Animais , Antineoplásicos/metabolismo , Antineoplásicos/farmacocinética , Proteínas de Transporte de Cátions , Cladribina/metabolismo , Sequência Conservada , DNA/genética , Etnicidade , Variação Genética , Haplótipos , Humanos , Modelos Moleculares , Dados de Sequência Molecular , Mutagênese Sítio-Dirigida , Oócitos/metabolismo , Vidarabina/metabolismo , Xenopus laevis
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