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 , FenótipoRESUMO
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/patologiaRESUMO
ATP-binding cassette (ABC) membrane transporters determine the disposition of many drugs, metabolites and endogenous compounds. Coding region variation in ABC transporters is the cause of many genetic disorders, but much less is known about the genetic basis and functional outcome of ABC transporter expression level variation. We used genotype and mRNA transcript level data from human lymphoblastoid cell lines to assess population and gender differences in ABC transporter expression, and to guide the discovery of genomic regions involved in transcriptional regulation. Nineteen of 49 ABC genes were differentially expressed between individuals of African, Asian and European descent, suggesting an important influence of race on expression level of ABC transporters. Twenty-four significant associations were found between transporter transcript levels and proximally located genetic variants. Several of the associations were experimentally validated in reporter assays. Through influencing ABC expression levels, these single-nucleotide polymorphisms may affect disease susceptibility and response to drugs.
Assuntos
Transportadores de Cassetes de Ligação de ATP/genética , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Elementos Reguladores de Transcrição , Transportadores de Cassetes de Ligação de ATP/metabolismo , Linhagem Celular Tumoral , Bases de Dados de Ácidos Nucleicos , Feminino , Regulação da Expressão Gênica , Genes Reporter , Genótipo , Humanos , Análise dos Mínimos Quadrados , Modelos Lineares , Masculino , Análise Multivariada , Grupos Raciais/genética , Fatores Sexuais , Transcrição Gênica , TransfecçãoRESUMO
The goal of pharmacogenomics research is to discover genetic polymorphisms that underlie variation in drug response. Increasingly, pharmacogenomics research involves large numbers of patients and the application of new technologies and methodologies to enable discovery. The Pharmacogenomics Research Network (PGRN) has become a community-driven network of investigators spanning scientific and clinical disciplines. Here, we highlight the activities and types of resources that enable PGRN members to enhance and drive basic and translational research in pharmacogenomics.
Assuntos
Pesquisa Biomédica/organização & administração , Farmacogenética/organização & administração , Medicina de Precisão/métodos , Pesquisa Translacional Biomédica/organização & administração , HumanosRESUMO
Therapeutic response to metformin, a first-line drug for type 2 diabetes (T2D), is highly variable, in part likely due to genetic factors. To date, metformin pharmacogenetic studies have mainly focused on the impact of variants in metformin transporter genes, with inconsistent results. To clarify the significance of these variants in glycemic response to metformin in T2D, we performed a large-scale meta-analysis across the cohorts of the Metformin Genetics Consortium (MetGen). Nine candidate polymorphisms in five transporter genes (organic cation transporter [OCT]1, OCT2, multidrug and toxin extrusion transporter [MATE]1, MATE2-K, and OCTN1) were analyzed in up to 7,968 individuals. None of the variants showed a significant effect on metformin response in the primary analysis, or in the exploratory secondary analyses, when patients were stratified according to possible confounding genotypes or prescribed a daily dose of metformin. Our results suggest that candidate transporter gene variants have little contribution to variability in glycemic response to metformin in T2D.
Assuntos
Glicemia/efeitos dos fármacos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Proteínas de Membrana Transportadoras/genética , Metformina/uso terapêutico , Variantes Farmacogenômicos , Polimorfismo de Nucleotídeo Único , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Glicemia/metabolismo , Bases de Dados Factuais , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/genética , Feminino , Genótipo , Hemoglobinas Glicadas/metabolismo , Humanos , Masculino , Proteínas de Membrana Transportadoras/metabolismo , Pessoa de Meia-Idade , Fator 1 de Transcrição de Octâmero/genética , Fator 1 de Transcrição de Octâmero/metabolismo , Proteínas de Transporte de Cátions Orgânicos/genética , Proteínas de Transporte de Cátions Orgânicos/metabolismo , Transportador 2 de Cátion Orgânico , Fenótipo , Simportadores , Resultado do TratamentoRESUMO
Genomewide association studies (GWAS) have resulted in the identification of many heritable genetic factors that underlie risk for human disease or variation in physiologic traits. In contrast, there are fewer GWAS of drug response phenotypes, despite extensive unexplained interindividual variability. To address this urgent need, the NIH Pharmacogenomics Research Network (PGRN) and the Center for Integrative Medical Sciences (IMS) at RIKEN support a collaboration, PGRN-RIKEN, with the goal of accelerating GWAS of drug response phenotypes.
Assuntos
Estudo de Associação Genômica Ampla/métodos , Colaboração Intersetorial , Farmacogenética/métodos , Farmacogenética/organização & administração , HumanosRESUMO
One-third of type-2 diabetic patients respond poorly to metformin. Despite extensive research, the impact of genetic and nongenetic factors on long-term outcome is unknown. In this study we combine nonlinear mixed effect modeling with computational genetic methodologies to identify predictors of long-term response. In all, 1,056 patients contributed their genetic, demographic, and long-term HbA1c data. The top nine variants (of 12,000 variants in 267 candidate genes) accounted for approximately one-third of the variability in the disease progression parameter. Average serum creatinine level, age, and weight were determinants of symptomatic response; however, explaining negligible variability. Two single nucleotide polymorphisms (SNPs) in CSMD1 gene (rs2617102, rs2954625) and one SNP in a pharmacologically relevant SLC22A2 gene (rs316009) influenced disease progression, with minor alleles leading to less and more favorable outcomes, respectively. Overall, our study highlights the influence of genetic factors on long-term HbA1c response and provides a computational model, which when validated, may be used to individualize treatment.
Assuntos
Diabetes Mellitus Tipo 2/metabolismo , Progressão da Doença , Hemoglobinas Glicadas/metabolismo , Proteínas de Membrana/genética , Metformina/uso terapêutico , Proteínas de Transporte de Cátions Orgânicos/genética , Variantes Farmacogenômicos/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Diabetes Mellitus Tipo 2/tratamento farmacológico , Feminino , Humanos , Hipoglicemiantes/uso terapêutico , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Dinâmica não Linear , Transportador 2 de Cátion Orgânico , Polimorfismo de Nucleotídeo Único/genética , Proteínas Supressoras de Tumor , Adulto JovemRESUMO
Transporter-mediated drug-drug interactions (DDIs) are a major cause of drug toxicities. Using published genome-wide association studies (GWAS) of the human metabolome, we identified 20 metabolites associated with genetic variants in organic anion transporter, OATP1B1 (P < 5 × 10-8 ). Of these, 12 metabolites were significantly higher in plasma samples from volunteers dosed with the OATP1B1 inhibitor, cyclosporine (CSA) vs. placebo (q-value < 0.2). Conjugated bile acids and fatty acid dicarboxylates were among the metabolites discovered using both GWAS and CSA administration. In vitro studies confirmed tetradecanedioate (TDA) and hexadecanedioate (HDA) were novel substrates of OATP1B1 as well as OAT1 and OAT3. This study highlights the use of multiple datasets for the discovery of endogenous metabolites that represent potential in vivo biomarkers for transporter-mediated DDIs. Future studies are needed to determine whether these metabolites can serve as qualified biomarkers for organic anion transporters. Quantitative relationships between metabolite levels and modulation of transporters should be established.
Assuntos
Ácidos e Sais Biliares/sangue , Ácidos Dicarboxílicos/sangue , Ácidos Graxos/sangue , Estudo de Associação Genômica Ampla , Transportador 1 de Ânion Orgânico Específico do Fígado/genética , Transportador 1 de Ânion Orgânico Específico do Fígado/metabolismo , Metabolômica , Biomarcadores/metabolismo , Ciclosporina/farmacologia , Interações Medicamentosas/genética , Células HEK293 , Humanos , Transportador 1 de Ânion Orgânico Específico do Fígado/antagonistas & inibidores , Miristatos/metabolismo , Proteína 1 Transportadora de Ânions Orgânicos/metabolismo , Transportadores de Ânions Orgânicos Sódio-Independentes/metabolismo , Ácidos Palmíticos/metabolismo , Pravastatina/farmacologiaRESUMO
The first-line treatment of hyperuricemia, which causes gout, is allopurinol. The allopurinol response is highly variable, with many users failing to achieve target serum uric acid (SUA) levels. No genome-wide association study (GWAS) has examined the genetic factors affecting allopurinol effectiveness. Using 2,027 subjects in Kaiser Permanente's Genetic Epidemiology Research on Adult Health and Aging (GERA) Cohort, we conducted a GWAS of allopurinol-related SUA reduction, first in the largest ethnic group, non-Hispanic white (NHW) subjects, and then in a stratified transethnic meta-analysis. ABCG2, encoding the efflux pump BCRP, was associated with SUA reduction in NHW subjects (P = 2 × 10(-8) ), and a missense allele (rs2231142) was associated with a reduced response (P = 3 × 10(-7) ) in the meta-analysis. Isotopic uptake studies in cells demonstrated that BCRP transports allopurinol and genetic variants in ABCG2 affect this transport. Collectively, this first GWAS of allopurinol response demonstrates that ABCG2 is a key determinant of response to the drug.
Assuntos
Transportadores de Cassetes de Ligação de ATP/genética , Alopurinol/uso terapêutico , Supressores da Gota/uso terapêutico , Hiperuricemia/tratamento farmacológico , Hiperuricemia/genética , Proteínas de Neoplasias/genética , Polimorfismo de Nucleotídeo Único , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Transportadores de Cassetes de Ligação de ATP/metabolismo , Idoso , Alopurinol/metabolismo , Biomarcadores/sangue , California/epidemiologia , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Feminino , Frequência do Gene , Estudo de Associação Genômica Ampla , Genótipo , Supressores da Gota/metabolismo , Células HEK293 , Humanos , Hiperuricemia/sangue , Hiperuricemia/etnologia , Masculino , Pessoa de Meia-Idade , Mitoxantrona/metabolismo , Mitoxantrona/farmacologia , Proteínas de Neoplasias/metabolismo , Farmacogenética , Fenótipo , Transfecção , Resultado do Tratamento , Ácido Úrico/sangueRESUMO
Congenital nasolacrimal duct mucocele is an uncommon condition in the newborn. Prolapse or expansion of the mucocele into the nose may lead to respiratory distress and difficulty in feeding, as newborns are preferential nose breathers. Infants with congenital lacrimal sac distension should be examined for signs of respiratory distress and nasal pathology. In the presence of respiratory distress, nasal examination and imaging studies should be done to ensure the diagnosis of nasolacrimal duct mucocele. If significant respiratory distress exists, endoscopic marsupialization of the nasolacrimal duct mucocele in conjunction with nasolacrimal duct probing by the ophthalmologist and possible insertion of lacrimal drainage tubes should be considered. At our institution the nasolacrimal duct mucocele was expectantly managed in two of three cases. Only one of the three patients manifested a significant degree of respiratory distress and required intervention. Endoscopic marsupialization of the nasolacrimal duct mucocele resulted in complete resolution of the mucocele and improvement in symptoms.
Assuntos
Mucocele/congênito , Ducto Nasolacrimal , Insuficiência Respiratória/etiologia , Feminino , Humanos , Recém-Nascido , Doenças do Aparelho Lacrimal/complicações , Doenças do Aparelho Lacrimal/congênito , Doenças do Aparelho Lacrimal/diagnóstico por imagem , Masculino , Mucocele/complicações , Mucocele/diagnóstico por imagem , Obstrução Nasal/etiologia , Ducto Nasolacrimal/diagnóstico por imagem , Tomografia Computadorizada por Raios XRESUMO
Cystic fibrosis (CF) is a life-shortening disease arising as a consequence of mutations within the CFTR gene. Novel therapeutics for CF are emerging that target CF transmembrane conductance regulator protein (CFTR) defects resulting from specific CFTR variants. Ivacaftor is a drug that potentiates CFTR gating function and is specifically indicated for CF patients with a particular CFTR variant, G551D-CFTR (rs75527207). Here, we provide therapeutic recommendations for ivacaftor based on preemptive CFTR genotype results.
Assuntos
Aminofenóis/uso terapêutico , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Fibrose Cística/tratamento farmacológico , Farmacogenética , Quinolonas/uso terapêutico , Testes Genéticos , Humanos , Medição de RiscoRESUMO
One-third of type 2 diabetes patients do not respond to metformin. Genetic variants in metformin transporters have been extensively studied as a likely contributor to this high failure rate. Here, we investigate, for the first time, the effect of genetic variants in transcription factors on metformin pharmacokinetics (PK) and response. Overall, 546 patients and healthy volunteers contributed their genome-wide, pharmacokinetic (235 subjects), and HbA1c data (440 patients) for this analysis. Five variants in specificity protein 1 (SP1), a transcription factor that modulates the expression of metformin transporters, were associated with changes in treatment HbA1c (P < 0.01) and metformin secretory clearance (P < 0.05). Population pharmacokinetic modeling further confirmed a 24% reduction in apparent clearance in homozygous carriers of one such variant, rs784888. Genetic variants in other transcription factors, peroxisome proliferator-activated receptor-α and hepatocyte nuclear factor 4-α, were significantly associated with HbA1c change only. Overall, our study highlights the importance of genetic variants in transcription factors as modulators of metformin PK and response.
Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/genética , Hipoglicemiantes/farmacocinética , Metformina/farmacocinética , Farmacogenética , Polimorfismo de Nucleotídeo Único , Fatores de Transcrição/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/metabolismo , Diabetes Mellitus Tipo 2/sangue , Feminino , Estudo de Associação Genômica Ampla , Hemoglobinas Glicadas/metabolismo , Fator 4 Nuclear de Hepatócito/genética , Homozigoto , Humanos , Hipoglicemiantes/administração & dosagem , Masculino , Metformina/administração & dosagem , Pessoa de Meia-Idade , Modelos Biológicos , Análise Multivariada , PPAR alfa/genética , Fenótipo , Estudos Retrospectivos , Fator de Transcrição Sp1/genética , Resultado do Tratamento , Estados Unidos , Adulto JovemRESUMO
The 386 human SLC superfamily members are diverse in sequence, structure, and function. Using sequence similarity, we previously classified the SLC superfamily members and identified relationships among families. With the recent determination of new SLC structures and identification of previously unknown human SLC families, an update of our previous classification is timely. Here, we comprehensively compare the SLC sequences and structures and discuss the applicability of structure-based ligand discovery to key SLC members.
Assuntos
Proteínas de Membrana Transportadoras/classificação , Sequência de Aminoácidos , Transporte Biológico , Evolução Molecular , Humanos , Ligantes , Proteínas de Membrana Transportadoras/química , Modelos Teóricos , Alinhamento de SequênciaRESUMO
INTRODUCTION: Labour and delivery are processes associated with inflammation within intrauterine and cervical tissues. The mechanisms that induce labour-associated changes and, in particular, the role of microRNAs (miRNAs) remain to be elucidated. MiRNAs are small non-coding RNAs that repress gene expression via mRNA degradation and translational repression. Let-7 miRNAs are negatively regulated by RNA-binding protein, Lin28, and both function downstream of NF-κB signalling. In non-gestational tissues, let-7 and Lin28 reportedy function as negative and positive regulators of IL-6 expression. We hypothesised that labour-associated inflammation involves the downregulation of let-7 miRNAs and upregulation of Lin28 expression. AIM: To determine the expression of Lin28 protein and let-7 miRNA in human gestational tissue obtained before and after labour. METHOD: Gestational tissues were collected from women at term by Caesarean section with and without labour and following normal vaginal delivery (n = 6 per group). Protein and RNA was extracted and Lin28 and let-7 miRNA expression was measured by Western blotting and real-time PCR. RESULTS: The data obtained established that let-7 miRNA and Lin28 display tissue-specific expression: Lin28 was strongly expressed in the placenta and choriodecidua, but not measurable in amnion; and let-7b and -7c expression were significantly lower in choriodecidua compare to placenta and amnion, whereas the amnion expressed less let-7d and -7f than other tissues. CONCLUSION: While the expression of Lin28 protein and let-7 miRNA did not vary significantly with labour onset and delivery, changes in their bioactivity and impact on nuclear signalling pathways in human gestational tissues remain to be established.
Assuntos
Âmnio/metabolismo , Córion/metabolismo , Expressão Gênica/genética , MicroRNAs/análise , Placenta/metabolismo , Proteínas de Ligação a RNA/análise , Adulto , Âmnio/química , Cesárea , Córion/química , Decídua/química , Decídua/metabolismo , Parto Obstétrico/métodos , Feminino , Humanos , Trabalho de Parto/metabolismo , MicroRNAs/genética , Placenta/química , Gravidez , Proteínas de Ligação a RNA/genética , Transdução de SinaisRESUMO
The neuroprotective function of the blood-brain barrier (BBB) presents a major challenge for drug delivery to the central nervous system (CNS). Critical to this function, BBB membrane transporters include the ATP-binding cassette (ABC) transporters, which limit drug penetration across the BBB, and the less-well-studied solute carrier (SLC) transporters. In this work, expression profiling of 359 SLC transporters, comparative expression analysis with kidney and liver, and immunoassays in brain microvessels (BMVs) identified previously unknown transporters at the human BBB.
Assuntos
Barreira Hematoencefálica/metabolismo , Encéfalo/irrigação sanguínea , Proteínas de Membrana Transportadoras/metabolismo , Microvasos/metabolismo , Córtex Cerebral/metabolismo , Perfilação da Expressão Gênica , Humanos , Bombas de Íon/metabolismo , Rim/metabolismo , Fígado/metabolismo , Reação em Cadeia da Polimerase em Tempo RealRESUMO
Interindividual variation in response to metformin, first-line therapy for type 2 diabetes, is substantial. Given that transporters are determinants of metformin pharmacokinetics, we examined the effects of promoter variants in both multidrug and toxin extrusion protein 1 (MATE1) (g.-66T â C, rs2252281) and MATE2 (g.-130G â A, rs12943590) on variation in metformin disposition and response. The pharmacokinetics and glucose-lowering effects of metformin were assessed in healthy volunteers (n = 57) receiving metformin. The renal and secretory clearances of metformin were higher (22% and 26%, respectively) in carriers of variant MATE2 who were also MATE1 reference (P < 0.05). Both MATE genotypes were associated with altered post-metformin glucose tolerance, with variant carriers of MATE1 and MATE2 having an enhanced (P < 0.01) and reduced (P < 0.05) response, respectively. Consistent with these results, patients with diabetes (n = 145) carrying the MATE1 variant showed enhanced metformin response. These findings suggest that promoter variants of MATE1 and MATE2 are important determinants of metformin disposition and response in healthy volunteers and diabetic patients.
Assuntos
Diabetes Mellitus Tipo 2/metabolismo , Hipoglicemiantes/farmacocinética , Metformina/farmacocinética , Proteínas de Transporte de Cátions Orgânicos/genética , Diabetes Mellitus Tipo 2/genética , Feminino , Genótipo , Humanos , Hipoglicemiantes/farmacologia , Rim/efeitos dos fármacos , Rim/metabolismo , Masculino , Metformina/farmacologia , Proteínas de Transporte de Cátions Orgânicos/metabolismoRESUMO
This Commentary focuses on genetic polymorphisms in membrane transporters. We present two polymorphisms for which there is a compelling body of literature supporting their clinical relevance: OATP1B1 (c.521T>C, p.V174A, rs4149056) and BCRP (c.421C>A, p.Q141K, rs2231142). The clinical evidence demonstrating their role in variation in pharmacokinetics and pharmacodynamics is described along with their allele frequencies in ethnic populations. Recommendations for incorporating studies of transporter polymorphisms in drug development are provided, along with the regulatory implications.
Assuntos
Transportadores de Cassetes de Ligação de ATP/genética , Proteínas de Membrana Transportadoras/genética , Proteínas de Neoplasias/genética , Transportadores de Ânions Orgânicos/genética , Polimorfismo Genético/genética , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Ensaios Clínicos como Assunto , Descoberta de Drogas , Frequência do Gene/genética , Humanos , Transportador 1 de Ânion Orgânico Específico do Fígado , FarmacogenéticaRESUMO
Thiopurine methyltransferase (TPMT) activity exhibits monogenic co-dominant inheritance, with ethnic differences in the frequency of occurrence of variant alleles. With conventional thiopurine doses, homozygous TPMT-deficient patients (~1 in 178 to 1 in 3,736 individuals with two nonfunctional TPMT alleles) experience severe myelosuppression, 30-60% of individuals who are heterozygotes (~3-14% of the population) show moderate toxicity, and homozygous wild-type individuals (~86-97% of the population) show lower active thioguanine nucleolides and less myelosuppression. We provide dosing recommendations (updates at http://www.pharmgkb.org) for azathioprine, mercaptopurine (MP), and thioguanine based on TPMT genotype.
Assuntos
Azatioprina/administração & dosagem , Mercaptopurina/administração & dosagem , Metiltransferases/genética , Tioguanina/administração & dosagem , Antimetabólitos Antineoplásicos/administração & dosagem , Antimetabólitos Antineoplásicos/efeitos adversos , Antimetabólitos Antineoplásicos/metabolismo , Azatioprina/efeitos adversos , Azatioprina/metabolismo , Relação Dose-Resposta a Droga , Genótipo , Humanos , Imunossupressores/administração & dosagem , Imunossupressores/efeitos adversos , Imunossupressores/metabolismo , Mercaptopurina/efeitos adversos , Mercaptopurina/metabolismo , Metiltransferases/metabolismo , Tioguanina/efeitos adversos , Tioguanina/metabolismoRESUMO
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 TranscriçãoRESUMO
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.