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1.
High Blood Press Cardiovasc Prev ; 26(5): 413-420, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31617197

RESUMO

INTRODUCTION: Population ageing in developed countries will inevitably increase the need for knee and hip replacement surgery. Over the years, direct oral anticoagulants, such as rivaroxaban, have been widely used for thromboprophylaxis in patients undergoing knee and hip replacement surgery. The study of pharmacogenetic characteristics of rivaroxaban is important for enhancing the effectiveness and safety of rivaroxaban thromboprophylaxis. AIM: Evaluation of CYP3A4, CYP3A5 and ABCB1 gene polymorphisms influence on rivaroxaban pharmacokinetics and prothrombin time dynamics in patients undergoing total hip and knee replacement surgery. METHODS: The study included 78 patients undergoing total hip and knee replacement surgery. The patients received 10 mg of rivaroxaban once a day. Genotyping of polymorphisms ABCB1 rs1045642, ABCB1 rs4148738, CYP3A4 rs35599367 and CYP3A5 rs776746 was performed. Peak steady-state and trough steady-state rivaroxaban concentrations were determined. Prothrombin time was also evaluated. RESULTS: The study revealed the following haplotypes: (1) ABCB1 rs1045642-CYP3A4 rs35599367 and (2) ABCB1 rs4148738-CYP3A4 rs35599367. The analysis of the peak steady-state rivaroxaban concentration between mutant haplotypes and wild haplotypes revealed no significant differences. However, there was a statistically significant average correlation between peak steady-state rivaroxaban concentration and prothrombin time (r = 0.421; r2 = 0.178; p < 0.001). CONCLUSION: No significant difference was identified in peak steady-state rivaroxaban concentration between mutant haplotypes and wild haplotypes. The revealed statistically significant average correlation between the prothrombin time and peak steady-state rivaroxaban concentration is important in clinical practice for assessing the anticoagulant activity of rivaroxaban.


Assuntos
Artroplastia de Quadril , Artroplastia do Joelho , Citocromo P-450 CYP3A/genética , Inibidores do Fator Xa/farmacocinética , Variantes Farmacogenômicos/genética , Rivaroxabana/farmacocinética , Trombose/prevenção & controle , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Idoso , Artroplastia de Quadril/efeitos adversos , Artroplastia do Joelho/efeitos adversos , Citocromo P-450 CYP3A/metabolismo , Monitoramento de Medicamentos/métodos , Inibidores do Fator Xa/administração & dosagem , Feminino , Haplótipos , Humanos , Masculino , Pessoa de Meia-Idade , Tempo de Protrombina , Rivaroxabana/administração & dosagem , Trombose/etiologia , Resultado do Tratamento
3.
Eur J Paediatr Neurol ; 23(5): 674-684, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31280948

RESUMO

BACKGROUND: In recent years advances in the field of pharmacogenomics have expanded the concept for more individualized treatments. Our aim is to provide literature data about the relationship between genetic polymorphisms and efficacy of antiepileptic drugs in children. METHODS: Pubmed was used as the main medical database source. Only original research papers were considered. No year-of-publication restriction was placed. Quality of evidence was assessed according to American Academy of Neurology guidelines. RESULTS: A total of 12 cross-sectional and case-control studies fulfilled our selection criteria. ABCB1 gene was associated with drug responsiveness in 2 out of 6 studies and ABCC2 gene in 1 out of 1 studies. SCN1A gene was also associated with seizure control in 4 out of 5 studies. Cytochrome P450 genes were found to significantly affect drug responsiveness in 2 out of 4 studies, while polymorphisms of uridinediphosphateglucuronosyltransferaseUGT2B7 gene predisposed to drug-resistance in 1 out of 2 studies. CONCLUSION: Variability in genes coding for sodium channels, drug transporters and cytochrome P450 enzymes can have a significant impact on response to antiepileptic drugs. Larger prospective studies with better stratification of samples are needed to shed light on these associations.


Assuntos
Anticonvulsivantes/uso terapêutico , Resistência a Medicamentos/genética , Epilepsia/tratamento farmacológico , Farmacogenética , Variantes Farmacogenômicos/genética , Estudos de Casos e Controles , Criança , Estudos Transversais , Feminino , Humanos , Masculino , Estudos Prospectivos
4.
Transplant Proc ; 51(6): 1754-1757, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31255354

RESUMO

BACKGROUND: Although high tacrolimus (FK) intrapatient variability (IPV) was shown to be associated with poor graft outcome in kidney transplant recipients (KTRs), it is uncertain whether there is any association between the CYP3A5 genotype and IPV of FK concentrations. Instead of trough level, we use calculated abbreviated AUC0-12 to investigate the impact of CYP3A5 genetic polymorphism on IPV of FK pharmacokinetics. METHODS: We conducted a retrospective, single-center study of 86 adult Chinese KTRs with known CYP3A5 genotype. Coefficient of variation (CV) was used for the quantification of FK IPV. CV of dose-normalized FK AUC0-12 was calculated and was compared between the CYP3A5 expresser group and nonexpresser group. RESULTS: Forty-one patients (47.7%) were classified as CYP3A5 expressers while 45 were nonexpressers. No significant differences in the baseline characteristics were found between expressers and nonexpressers. CYP3A5 expressers required 1.8 times higher FK dose compared with the nonexpressers. There was no significant difference in the FK CV between CYP3A5 expressers (18.2 ± 7.5%) and nonexpressers (16.7 ± 5.7%) (P = .31). CONCLUSION: The IPV of FK exposure was not associated with CYP3A5 genotype in stable KTRs. Further studies should focus on other factors such as medication nonadherence, which may explain FK IPV.


Assuntos
Citocromo P-450 CYP3A/genética , Imunossupressores/farmacocinética , Transplante de Rim , Variantes Farmacogenômicos/genética , Tacrolimo/farmacocinética , Adulto , Grupo com Ancestrais do Continente Asiático , Feminino , Genótipo , Humanos , Imunossupressores/uso terapêutico , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Estudos Retrospectivos , Tacrolimo/uso terapêutico , Transplantados
5.
JAMA Netw Open ; 2(6): e195345, 2019 06 05.
Artigo em Inglês | MEDLINE | ID: mdl-31173123

RESUMO

Importance: Implementation of pharmacogenetic testing to guide drug prescribing has potential to improve drug response and prevent adverse events. Robust data exist for more than 30 gene-drug pairs linking genotype to drug response phenotypes; however, it is unclear which pharmacogenetic tests, if implemented, would provide the greatest utility for a given patient population. Objectives: To project the proportion of veterans in the US Veterans Health Administration (VHA) with actionable pharmacogenetic variants and evaluate how testing might be associated with prescribing decisions. Design, Setting, and Participants: This cross-sectional study included veterans who used national VHA pharmacy services from October 1, 2011, to September 30, 2017. Data analyses began April 26, 2018, and were completed February 6, 2019. Exposures: Receipt of level A drugs based on VHA pharmacy dispensing records. Main Outcomes and Measures: Projected prevalence of actionable pharmacogenetic variants among VHA pharmacy users based on variant frequencies from the 1000 Genomes Project and veteran demographic characteristics; incident number of level A prescriptions, and proportion of new level A drug recipients projected to carry an actionable pharmacogenetic variant. Results: During the study, 7 769 359 veterans (mean [SD] age, 58.1 [17.8] years; 7 021 504 [90.4%] men) used VHA pharmacy services. It was projected that 99% of VHA pharmacy users would carry at least 1 actionable pharmacogenetic variant. Among VHA pharmacy users, 4 259 153 (54.8%) received at least 1 level A drug with 1 188 124 (15.3%) receiving 2 drugs, and 912 189 (11.7%) receiving 3 or more drugs. The most common incident prescriptions during the study were tramadol (923 671 new recipients), simvastatin (533 928 new recipients), citalopram (266 952 new recipients), and warfarin (205 177 new recipients). Gene-drug interactions projected to have substantial clinical impacts in the VHA population include the interaction of SLCO1B1 with simvastatin (1 988 956 veterans [25.6%]), CYP2D6 with tramadol (318 544 veterans [4.1%]), and CYP2C9 or VKORC1 with warfarin (7 163 349 veterans [92.2%]). Conclusions and Relevance: Clinically important pharmacogenetic variants are highly prevalent in the VHA population. Almost all veterans would carry an actionable variant, and more than half of the population had been exposed to a drug affected by these variants. These results suggest that pharmacogenetic testing has the potential to affect pharmacotherapy decisions for commonly prescribed outpatient medications for many veterans.


Assuntos
Frequência do Gene/genética , Variantes Farmacogenômicos/genética , Medicamentos sob Prescrição/uso terapêutico , Saúde dos Veteranos , Estudos Transversais , Citocromo P-450 CYP2C9/genética , Citocromo P-450 CYP2D6/genética , Interações de Medicamentos/genética , Utilização de Instalações e Serviços , Feminino , Genótipo , Humanos , Transportador 1 de Ânion Orgânico Específico do Fígado/genética , Masculino , Pessoa de Meia-Idade , Assistência Farmacêutica/estatística & dados numéricos , Polimorfismo Genético/genética , Prevalência , Sinvastatina/farmacologia , Tramadol/farmacologia , Estados Unidos , United States Department of Veterans Affairs/estatística & dados numéricos , Vitamina K Epóxido Redutases/genética , Varfarina/farmacologia
6.
Pharmacogenet Genomics ; 29(4): 76-83, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30724853

RESUMO

OBJECTIVE: To evaluate perceptions toward pharmacogenetic testing of patients undergoing percutaneous coronary intervention (PCI) who are prescribed dual antiplatelet therapy (DAPT) and whether geographical differences in these perceptions exist. PARTICIPANTS AND METHODS: TAILOR-PCI is the largest genotype-based cardiovascular clinical trial randomizing participants to conventional DAPT or prospective genotyping-guided DAPT. Enrolled patients completed surveys before and 6 months after randomization. RESULTS: A total of 1327 patients completed baseline surveys of whom 28, 29, and 43% were from Korea, Canada and the USA, respectively. Most patients (77%) valued identifying pharmacogenetic variants; however, fewer Koreans (44%) as compared with Canadians (91%) and USA (89%) patients identified pharmacogenetics as being important (P<0.001). After adjusting for age, sex, and country, those who were confident in their ability to understand genetic information were significantly more likely to value identifying pharmacogenetic variants (odds ratio: 30.0; 95% confidence interval: 20.5-43.8). Only 21% of Koreans, as opposed to 86 and 77% of patients in Canada and USA, respectively, were confident in their ability to understand genetic information (P<0.001). CONCLUSION: Although genetically mediated clopidogrel resistance is more prevalent amongst Asians, Koreans undergoing PCI identified pharmacogenetic variants as less important to their healthcare, likely related to their lack of confidence in their ability to understand genetic information. To enable successful implementation of pharmacogenetic testing on a global scale, the possibility of international population differences in perceptions should be considered.


Assuntos
/efeitos adversos , Intervenção Coronária Percutânea/efeitos adversos , Testes Farmacogenômicos , Inibidores da Agregação de Plaquetas/uso terapêutico , Adulto , Idoso , Canadá/epidemiologia , Clopidogrel/efeitos adversos , Clopidogrel/uso terapêutico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Variantes Farmacogenômicos/genética , Inibidores da Agregação de Plaquetas/efeitos adversos , Cloridrato de Prasugrel/efeitos adversos , Cloridrato de Prasugrel/uso terapêutico , República da Coreia/epidemiologia , Resultado do Tratamento , Estados Unidos/epidemiologia
7.
Lung Cancer ; 128: 20-25, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30642448

RESUMO

OBJECTIVES: Crizotinib is a standard treatment for advanced anaplastic lymphoma kinase (ALK)- or ROS1-fusion-gene-positive non-small cell lung cancer; however, serious adverse events (AEs), including elevated alanine aminotransferase (ALT)/aspartate aminotransferase (AST) and interstitial lung disease (ILD), develop occasionally. Here, we evaluated relationships between clinically significant crizotinib-associated AEs and germline variations. MATERIALS AND METHODS: DNA obtained from 75 patients allowed selection of 147 genes according to function, exon identification and sequencing, and determination of germline single nucleotide variants (SNVs). Correlations between clinically significant AEs and presence of germline variants were estimated by Fisher's exact test. RESULTS: We defined clinically significant AEs as grade 4 hematological toxicity, grade ≥3 non-hematological toxicity, and any grade of ILD. These AEs were observed in 26 patients (35%), with elevated AST/ALT (15%) the most common, followed by neutropenia (5%), ILD (4%), and thromboembolic events (4%). Nonsynonymous SNVs in epoxide hydrolase 1 (EPHX1) [odds ratio (OR): 3.86; p = 0.0009) and transcription factor 7-like 2 (TCF7L2) (OR: 2.51; p = 0.025) were associated with the presence of clinically significant AEs. CONCLUSION: Nonsynonymous EPHX1 and TCF7L2 SNVs might be associated with clinically significant crizotinib-associated AEs. These data indicated that target-gene sequencing could be feasible for predicting anticancer-agent toxicity, and that germline multi-gene information might be useful for predicting patient-specific AEs to promote precision medicine.


Assuntos
Quinase do Linfoma Anaplásico/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Crizotinibe/efeitos adversos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/genética , Neoplasias Pulmonares/genética , Variantes Farmacogenômicos/genética , Inibidores de Proteínas Quinases/efeitos adversos , Adulto , Idoso , Idoso de 80 Anos ou mais , Substituição de Aminoácidos , Carcinoma Pulmonar de Células não Pequenas/complicações , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Crizotinibe/uso terapêutico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/diagnóstico , Feminino , Mutação em Linhagem Germinativa , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Neoplasias Pulmonares/complicações , Neoplasias Pulmonares/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Polimorfismo de Nucleotídeo Único , Inibidores de Proteínas Quinases/uso terapêutico
8.
Basic Clin Pharmacol Toxicol ; 124(1): 84-93, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30098132

RESUMO

Acute coronary syndrome (ACS) has become a vital disease with high mortality worldwide. A combined antiplatelet therapy (aspirin and a P2Y12 antagonist) is commonly used to prevent re-infarction in ACS patients who have undergone percutaneous coronary intervention (PCI). Clopidogrel, a P2Y12 antagonist, plays an important role in the inhibition of platelet aggregation (IPA). However, it is a pro-drug requiring biotransformation by cytochrome P450 (CYP450). The aim of this study is to unravel the effect of clopidogrel-associated genetic variants on inhibition of platelet activity and clinical outcomes in ACS patients. In our study, a total of 196 patients with metabolic gene polymorphism of clopidogrel were enrolled, and their antiplatelet effect as well as their cardiovascular events were collected. Approximately 2 mL of venous blood samples were used for genotype detection and another 4 mL were collected for platelet reactivity with thrombelastography. The primary clinical end-point was defined as a combination of cardiovascular mortality and revascularization for targeted vascular lesion. Based on the results of IPA, the prevalence of high on-treatment platelet reactivity (HPR) was 17.3% and the majority of patients (82.7%) obtained normal on-treatment platelet reactivity (NPR). The HPR group had significantly higher body mass index (BMI) and lower arachidonic acid (AA) induced IPA (P < 0.05). Therapy including Glycoprotein (GP) IIb/IIIa antagonist increased IPA (P < 0.05). ADP-induced IPA effect was lower with the presence of CYP2C19*2, *3 and paraoxonase (PON)1 Q192R loss-of-function (LOF) alleles, respectively (P < 0.05). Multivariate logistic regression analysis demonstrated that aspirin resistance (AA-induced IPA < 50%) had a greater risk of the occurrence of major adverse cardiovascular events (MACE) (OR = 3.817; 95% CI: 1.672-8.700; P = 0.002). CYP2C19*2 LOF alleles were associated with high risk of MACE in 1-year post PCI operations (OR = 2.571; 95% CI: 1.143-5.780; P = 0.030). For the ACS patients, the presence of CYP2C19*2 and PON1 Q192R LOF alleles were the major drivers of HPR.


Assuntos
Síndrome Coronariana Aguda/prevenção & controle , Clopidogrel/farmacologia , Variantes Farmacogenômicos/genética , Ativação Plaquetária/efeitos dos fármacos , Complicações Pós-Operatórias/prevenção & controle , Síndrome Coronariana Aguda/sangue , Síndrome Coronariana Aguda/cirurgia , Idoso , Arildialquilfosfatase/genética , Aspirina/uso terapêutico , Biotransformação/genética , Clopidogrel/metabolismo , Clopidogrel/uso terapêutico , Citocromo P-450 CYP2C19/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Intervenção Coronária Percutânea , Complicações Pós-Operatórias/sangue , Recidiva , Resultado do Tratamento
9.
Basic Clin Pharmacol Toxicol ; 124(1): 94-104, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30103286

RESUMO

BACKGROUND: The effect of risperidone treatment in patients with schizophrenia varies according to the dopamine receptor genes. This study aimed to evaluate the relationship between genes of the dopamine receptors (D1, D2, and D3) and the effect of risperidone treatment. METHODS: Three electronic databases (PubMed, Embase, and Cochrane Library) were searched for relevant cohort or case-control studies published before 9 May 2018. A systematic review and meta-analysis was performed for qualitative and quantitative assessment of the relationship between the dopamine receptors D1, D2, and D3 (DRD1, 2, and 3) and the effect of risperidone treatment. The summary odds ratio (OR) and weighted mean difference (WMD) in a random-effects model were used to measure these relationships. RESULTS: Twelve studies involving 24 SNPs were included. DRD2 (Ser311Cys, rs1801028 Ser/Ser) significantly lowered the improvement rate (determined by the PANSS score) unlike Ser/Cys (WMD: -11.58, 95% CI: -17.35 to -5.18). For Asian patients, A241G (rs1799978) AA carriers showed greater improvement after risperidone therapy (P < 0.05). The polymorphisms of 141C Ins/Del (rs1799732), T939C (rs6275), rs6277, and TaqID (rs1800498) may also influence the treatment effect. TaqIA (rs1800497) and TaqIB (rs17294542) were not associated with the rate of response to risperidone. DRD3 was not associated with an improvement in the PANSS total score; however, Ser9Gly might be related to a change in negative symptoms. No significant effect of DRD1 (rs5326, rs4867798, rs4532, and rs11749676) was found. CONCLUSIONS: Our result supported the hypothesis that DRD2 affected risperidone treatment. DRD1 had no significant effect on the response to risperidone, whereas DRD3 might be associated with an improvement in negative symptoms. Larger observational studies are warranted to verify these findings and identify other genetic factors involved.


Assuntos
Antipsicóticos/farmacologia , Receptores de Dopamina D1/genética , Receptores de Dopamina D2/genética , Receptores de Dopamina D3/genética , Risperidona/farmacologia , Esquizofrenia/tratamento farmacológico , Antipsicóticos/uso terapêutico , Humanos , Variantes Farmacogenômicos/genética , Polimorfismo de Nucleotídeo Único , Risperidona/uso terapêutico , Esquizofrenia/genética , Resultado do Tratamento
10.
Int J Legal Med ; 133(2): 365-372, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30191314

RESUMO

We present a novel multiplex assay for the simultaneous detection of 12 polymorphisms within the UGT1A9 sequence, which codes for enzymes involved in phase II biotransformation. The assay combines a multiplexed amplification step with single-base extension sequencing. The method described here is fast, cost-effective, and easy-to-use, combining the relevant features of screening methods for research and diagnostics in pharmacogenetics. To validate the assay, we tested reproducibility and sensitivity and analysed allele frequencies of 110 Caucasian individuals. Furthermore, we describe combining genetic information of individuals consuming Cannabis sativa products with respective plasma concentrations of a metabolite.


Assuntos
Dronabinol/farmacocinética , Glucuronosiltransferase/genética , Variantes Farmacogenômicos/genética , Polimorfismo Genético , Psicotrópicos/farmacocinética , Adolescente , Adulto , Feminino , Toxicologia Forense , Frequência do Gene , Haplótipos , Humanos , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Reprodutibilidade dos Testes , Análise de Sequência , Adulto Jovem
11.
Pharmacogenomics J ; 19(2): 127-135, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30214008

RESUMO

More than 1100 genetic loci have been correlated with drug response outcomes but disproportionately few have been translated into clinical practice. One explanation for the low rate of clinical implementation is that the majority of associated variants may be in linkage disequilibrium (LD) with the causal variants, which are often elusive. This study aims to identify and characterize likely causal variants within well-established pharmacogenomic genes using next-generation sequencing data from the 1000 Genomes Project. We identified 69,319 genetic variations within 160 pharmacogenomic genes, of which 8207 variants are in strong LD (r2>0.8) with known pharmacogenomic variants. Of the latter, eight are coding or structural variants predicted to have high impact, with 19 additional missense variants that are predicted to have moderate impact. In conclusion, we identified putatively functional variants within known pharmacogenomics loci that could account for the association signals and represent the missing causative variants underlying drug response phenotypes.


Assuntos
Variação Genética/genética , Farmacogenética , Variantes Farmacogenômicos/genética , Sequenciamento Completo do Genoma , Genoma Humano/genética , Sequenciamento de Nucleotídeos em Larga Escala , Projeto Genoma Humano , Humanos , Desequilíbrio de Ligação , Polimorfismo de Nucleotídeo Único/genética
12.
Pharmacogenomics J ; 19(2): 115-126, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30206299

RESUMO

Prediction of phenotypic consequences of mutations constitutes an important aspect of precision medicine. Current computational tools mostly rely on evolutionary conservation and have been calibrated on variants associated with disease, which poses conceptual problems for assessment of variants in poorly conserved pharmacogenes. Here, we evaluated the performance of 18 current functionality prediction methods leveraging experimental high-quality activity data from 337 variants in genes involved in drug metabolism and transport and found that these models only achieved probabilities of 0.1-50.6% to make informed conclusions. We therefore developed a functionality prediction framework optimized for pharmacogenetic assessments that significantly outperformed current algorithms. Our model achieved 93% for both sensitivity and specificity for both loss-of-function and functionally neutral variants, and we confirmed its superior performance using cross validation analyses. This novel model holds promise to improve the translation of personal genetic information into biological conclusions and pharmacogenetic recommendations, thereby facilitating the implementation of Next-Generation Sequencing data into clinical diagnostics.


Assuntos
Privacidade Genética , Inativação Metabólica/genética , Farmacogenética/tendências , Variantes Farmacogenômicos/genética , Algoritmos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Mutação de Sentido Incorreto/genética , Testes Farmacogenômicos/métodos , Medicina de Precisão
13.
Genet Med ; 21(6): 1345-1354, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30327539

RESUMO

PURPOSE: Biomedical databases combining electronic medical records and phenotypic and genomic data constitute a powerful resource for the personalization of treatment. To leverage the wealth of information provided, algorithms are required that systematically translate the contained information into treatment recommendations based on existing genotype-phenotype associations. METHODS: We developed and tested algorithms for translation of preexisting genotype data of over 44,000 participants of the Estonian biobank into pharmacogenetic recommendations. We compared the results obtained by genome sequencing, exome sequencing, and genotyping using microarrays, and evaluated the impact of pharmacogenetic reporting based on drug prescription statistics in the Nordic countries and Estonia. RESULTS: Our most striking result was that the performance of genotyping arrays is similar to that of genome sequencing, whereas exome sequencing is not suitable for pharmacogenetic predictions. Interestingly, 99.8% of all assessed individuals had a genotype associated with increased risks to at least one medication, and thereby the implementation of pharmacogenetic recommendations based on genotyping affects at least 50 daily drug doses per 1000 inhabitants. CONCLUSION: We find that microarrays are a cost-effective solution for creating preemptive pharmacogenetic reports, and with slight modifications, existing databases can be applied for automated pharmacogenetic decision support for clinicians.


Assuntos
Farmacogenética/métodos , Variantes Farmacogenômicos/genética , Análise de Sequência de DNA/métodos , Algoritmos , Bancos de Espécimes Biológicos , Bases de Dados Factuais , Registros Eletrônicos de Saúde , Estônia , Testes Genéticos/normas , Genótipo , Humanos , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Testes Farmacogenômicos/métodos , Fenótipo , Medicina de Precisão/métodos
14.
Pharmacogenet Genomics ; 29(2): 23-30, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30531378

RESUMO

INTRODUCTION: In-hospital adverse medication events result in increased morbidity and mortality. Many implicated drugs carry pharmacogenomic information. We hypothesized that comprehensive pre-emptive pharmacogenomic profiling could have high relevance for in-hospital prescribing. PATIENTS AND METHODS: We retrospectively analyzed the in-hospital medications of a genotyped outpatient cohort admitted at our institution from 2012 to 2015. The endpoints were medication changes (new medications initiated, dose adjustments, or medications discontinued) involving drugs with pharmacogenomic annotations from three sources: Clinical Pharmacogenetics Implementation Consortium guidance, Food and Drug Administration label information, and drugs with clinical decision supports in our institutional pharmacogenomic Genomic Prescribing System. RESULTS: Of 867 genotyped outpatients, 20 were hospitalized (mean: 78.2 years, 65% male). This hospitalized cohort was significantly older (78.2 vs. 61.3 years, P<0.0001) and took more medications (8.9 vs. 5.0 medications, P<0.0001). Out of 159 medication changes made, most (67.9%) were new medications (average: 2.5/hospitalization) with one-third of these having clinically annotated pharmacogenomic information. Half of all hospitalizations involved at least one pharmacogenomic medication. Over half (55%) of the hospitalized cohort was newly prescribed at least one of eight key pharmacogenomic medications, including high-risk drugs such as clopidogrel, codeine, and warfarin. CONCLUSION: Our study suggested that older patients and those with polypharmacy were at increased risk for hospitalizations, where many new prescriptions included frequently used pharmacogenomic drugs. Targeting this group for pre-emptive genotyping would facilitate the delivery of highly relevant information to inform inpatient prescribing.


Assuntos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/genética , Farmacogenética , Variantes Farmacogenômicos/genética , Medicamentos sob Prescrição/efeitos adversos , Idoso , Idoso de 80 Anos ou mais , Clopidogrel/efeitos adversos , Clopidogrel/uso terapêutico , Codeína/efeitos adversos , Codeína/genética , Codeína/uso terapêutico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Feminino , Genótipo , Mortalidade Hospitalar , Hospitalização , Humanos , Masculino , Pessoa de Meia-Idade , Medicamentos sob Prescrição/uso terapêutico , Varfarina/efeitos adversos , Varfarina/uso terapêutico
15.
Pharmacogenomics ; 20(2): 95-104, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30520341

RESUMO

AIM: First, evaluate if patients carrying putatively diminished activity CYP2C8 genotype have longer paclitaxel exposure (e.g., time above threshold concentration of 0.05 µM [Tc >0.05]). Second, screen additional pharmacogenes for associations with Tc >0.05. Methods: Pharmacogene panel genotypes were translated into genetic phenotypes for associations with Tc >0.05 (n = 58). RESULTS: Patients with predicted low-activity CYP2C8 had shorter Tc >0.05 after adjustment for age, body surface area and race (9.65 vs 11.03 hrs, ß = 5.47, p = 0.02). This association was attributed to CYP2C8*3 (p = 0.006), not CYP2C8*4 (p = 0.58). Patients with predicted low-activity SLCO1B1 had longer Tc >0.05 (12.12 vs 10.15 hrs, ß = 0.85, p = 0.012). CONCLUSION: Contrary to previous publications, CYP2C8*3 may confer increased paclitaxel metabolic activity. SLCO1B1 and CYP2C8 genotype may explain some paclitaxel pharmacokinetic variability.


Assuntos
Citocromo P-450 CYP2C8/genética , Transportador 1 de Ânion Orgânico Específico do Fígado/genética , Neoplasias/tratamento farmacológico , Paclitaxel/efeitos adversos , Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/efeitos adversos , Feminino , Estudos de Associação Genética , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/genética , Neoplasias/patologia , Paclitaxel/administração & dosagem , Variantes Farmacogenômicos/genética , Fenótipo
16.
Int J Legal Med ; 133(2): 353-363, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30173302

RESUMO

Depression is known to be a risk factor for suicide. Currently, the most used antidepressants are selective serotonin reuptake inhibitors (SSRIs). Not all users, however, benefit from them. In such cases, treatment failure can be explained in part by genetic differences. In this study, we investigated the role of pharmacogenetic factors in citalopram-positive completed suicides (n = 349). Since citalopram is metabolized by CYP2C19 and CYP2D6 enzymes, the study population was genotyped for clinically relevant CYP2C19 and CYP2D6 polymorphisms and CYP2D6 copy number variation. To assess genetic differences between suicide cases and Finns in general, Finnish population samples (n = 855) were used as controls. Also, the role of drug interactions among suicide cases was evaluated. We found enrichment of a combined group of genetically predicted poor and ultrarapid metabolizer phenotypes (gMPs) of CYP2C19 among suicide victims compared to controls 0.356 [0.31-0.41] vs. 0.265 [0.24-0.30] (p = 0.0065). In CYP2D6 gMPs, there was no difference between cases and controls when the study population was analyzed as a whole. However, there were significantly more poor metabolizers among females who committed suicide by poisoning compared to female controls. In 8% of all drug poisoning deaths, lifetime drug-drug interaction was evaluated having a contribution to the fatal outcome. From clinical perspective, pharmacogenetic testing prior to initiation of SSRI drug could be beneficial. It may also be useful in medico-legal settings as it may elucidate obscure poisoning cases. Also, the possibility of unintentional drug interactions should be taken into account in drug poisoning deaths.


Assuntos
Citalopram/envenenamento , Citocromo P-450 CYP2C19/genética , Citocromo P-450 CYP2D6/genética , Genótipo , Variantes Farmacogenômicos/genética , Inibidores de Captação de Serotonina/envenenamento , Suicídio , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Citalopram/farmacocinética , Variações do Número de Cópias de DNA , Interações de Medicamentos/genética , Feminino , Finlândia , Toxicologia Forense , Frequência do Gene , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Inibidores de Captação de Serotonina/farmacocinética
17.
São Paulo; s.n; s.n; 2019. 140 p. tab, graf, ilus.
Tese em Português | LILACS | ID: biblio-1007576

RESUMO

A Hipercolesterolemia Familial (HF) é uma doença genética do metabolismo das lipoproteínas, caracterizada pelo aumento do colesterol plasmático, transportado principalmente pela lipoproteína de baixa densidade (LDL). A HF é causada principalmente por mutações nos genes LDLR, APOB e PCSK9. As mutações conhecidas na PCSK9 podem levar ao aumento ou diminuição da função proteolítica da proteína, as quais são associadas ao aumento ou diminuição da LDL-c plasmática, respectivamente. Com o projeto genoma humano surgiram novos métodos de sequenciamento, o que resultou em um grande número de novas variantes genéticas relacionadas à HF. Entretanto, os mecanismos pelos quais essas variantes influenciam na concentração do colesterol e sua interferência na resposta terapêutica não estão totalmente elucidados. O objetivo do presente trabalho foi avaliar in vitro o efeito de variantes na região codificadora e reguladora do gene PCSK9 identificadas em pacientes HF utilizando sequenciamento de nova geração. Para a caracterização funcional das variantes na região codificadora da PCSK9, primeiramente foi avaliado o impacto dessas variantes na interação PCSK9-LDLR via Docking molecular. Células HEK293FT foram transfectadas com as diferentes construções da PCSK9, e posteriormente, foram utilizadas em ensaios para avaliar a atividade do LDLR e a internalização de LDL por citometria de fluxo. Para as variantes na região reguladora da PCSK9, foi realizado uma predição in silico do possível efeito de variantes na região 3UTR na ligação de miRNAs. A avalição da interação entre os miRNAs preditos, e a região 3UTR da PCSK9, e o possível impacto nessa interação na presença de variantes na região 3UTR, foi realizada em células HEK293FT transfectadas com um plasmídeo contendo a 3UTR da PCSK9 e um gene repórter da Gaussia luciferase, juntamente com um plasmídeo de expressão contendo os miRNAs de interesse. Foi também estudado o efeito dos miRNAs preditos sobre a expressão, RNAm e proteína, da PCSK9 via RT-qPCR e Western blot, em células HepG2. Foram identificadas 9 variantes na região codificadora da PCSK9, e duas, E32K e R469W, foram selecionadas para os ensaios posteriores. Para a R469W foi observada uma possível alteração conformacional a qual poderia aumentar a afinidade da PCSK9 pelo LDLR. Para a E32K, uma possível associação com HF foi observada em uma família brasileira com ascendência japonesa. As variantes E32K e R469W apresentaram uma redução na atividade do LDLR de 5 e 11%, respectivamente em comparação a PCSK9-WT. Entretanto, não foram observadas reduções estaticamente significativas na atividade do LDLR e na internalização da LDL em células transfectadas com ambas as variantes. Dez variantes foram encontradas na região 3UTR da PCSK9, entre elas três foram selecionadas por impactar a ligação de quatro miRNAs. Nossos dados demonstraram uma redução significativa na expressão da PCSK9 em células HepG2 transfectadas com os miR-4721 e miR-564 (p=0,036 e p=0,010, respectivamente). Porém, não foi observada diferenças na expressão da luciferase em células transfectadas com esses miRNAs, não sendo possível validar a interação miRNA-RNAm. As variantes no gene PCSK9 identificadas no nosso estudo podem não explicar individualmente o fenótipo HF, mas podem contribuir para a severidade da doença juntamente com outras variantes em outros genes


Familial Hypercholesterolemia (FH) is a genetic disorder of lipoprotein metabolism, characterized by elevated plasma cholesterol levels, mostly carried by low-density lipoprotein (LDL). FH is mainly caused by mutations in three genes, LDLR, APOB, and PCSK9. Gain-of-function mutations in PCSK9 reduce LDL receptor levels, resulting in high levels of LDL cholesterol in the plasma. Loss-of-function mutations lead to higher levels of the LDL receptor, resulting in lower LDL cholesterol levels. The Human Genome Project led to a faster technological development related to sequencing methods, which allowed identifying many novel variants associated with FH. However, the mechanisms by which these variants influence cholesterol levels and their interference in therapeutic response are not fully understood. The aim of the present study was to perform an in vitro characterization of the effect of PCSK9 variants identified in FH patients using Next-Generation Sequencing. For the functional characterization of variants in the coding region of PCSK9, the impact of these variants on PCSK9-LDLR interaction was evaluated by molecular docking. HEK293FT cells were transiently transfected with different PCSK9 constructs, and the amount of cell surface LDLR and LDL internalization were determined by flow cytometry. For the variants in PCSK9 3UTR region, an in silico prediction of PCSK9 3UTR variants in miRNA seed regions and target sites was performed. To determine whether the predicted miRNAs directly interact with PCSK9 3UTR region, HEK293FT cells were co-transfected with a vector containing a PCSK9 3'UTR region and a Gaussia luciferase reporter gene, together with an expression plasmid containing the miRNAs of interest. The effect of the predicted miRNAs on the expression of PCSK9 was evaluated using RT-qPCR and Western blot in HepG2 cells transiently transfected with miRNA mimics. Nine missense variants were identified in PCSK9 gene. E32K e R469W were chosen for further analysis. For R469W, a possible conformational change was observed that could increase the affinity of PCSK9 for LDLR, when compared to the wild-type. For E32K, a possible association with FH in a Brazilian family with Japanese ancestry was observed. E32K and R469W had a 5% and 11% decreased level of cell surface LDLR, respectively, as compared with WT-PCSK9. However, no significant reduction in the number of cell surface LDLR and LDL internalization was observed in transfected cells for both variants. Ten variants were found in PCSK9 3'UTR region, of which three were selected for affecting the binding of four miRNAs. Our data demonstrated a significant downregulation of PCSK9 in cells transfected with miR-4721 and miR-564 miRNA mimics, compared to cells transfected with a scramble control (p=0,036 and p=0,010, respectively). However, no differences in luciferase expression were observed in cells transfected with these miRNAs, therefore, it was not possible to experimentally validate miRNA-mRNA interaction. PCSK9 variants found in our study may not fully explain FH phenotype but may contribute to the severity of the disease together with other variants in other genes


Assuntos
Técnicas In Vitro/instrumentação , Pró-Proteína Convertase 9/análise , Variantes Farmacogenômicos/genética , Hiperlipoproteinemia Tipo II/diagnóstico
18.
Medicine (Baltimore) ; 97(52): e13674, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30593137

RESUMO

Individual differences in drug clinical response are related to pharmacogenomics. The genetic variation of drug-metabolizing enzymes, drug receptors, and their downstream protein genes is the main factor causing individual differences in drug response. The genetic backgrounds among different ethnic groups are quite different. In this study, we aimed to detect the distribution difference of genotype frequency in very important pharmacogenetic (VIP) gene variants in the Lisu.Using the chi-squared test, we compared the genotype frequencies of the VIP variants in 105 Lisu people with those in 26 populations from the 1000 Genome project separately. Bonferroni's multiple adjustment was also conducted (P < .05/(26*49)). Moreover, Arlequin v3.5 and Structure v2.3.4 software were used to analyze the genetic distance and genetic structure.There were 9, 9, 11, 12, 11, 11, 9, 17, 13, 13, 16, 5, 3, 5, 3, 4, 17, 14, 16, 17, 16, 10, 13, 12, 10, and 9 single nucleotide polymorphisms that differed in frequency distribution, when Lisu people compared with the 26 populations separately. Only CYP2E1 rs2070676 was different in the Lisu population compared with the 26 groups from the 1000 Genome project. PTGS2 rs5275 and CYP2D6 rs1065852 were different in the Lisu population compared with most of the populations. Additionally, genetic backgrounds of Lisu and Han Chinese in Beijing were closest according to the lowest F-statistics value and resemblance in genetic structures.Our results complete the information of the Lisu population in pharmacogenomics database.


Assuntos
Grupos Étnicos/genética , Variantes Farmacogenômicos/genética , China/etnologia , Ciclo-Oxigenase 2/genética , Citocromo P-450 CYP2E1/genética , Feminino , Frequência do Gene , Genética Populacional , Genótipo , Voluntários Saudáveis , Humanos , Masculino , Testes Farmacogenômicos , Polimorfismo de Nucleotídeo Único
19.
Breast Cancer Res ; 20(1): 149, 2018 12 10.
Artigo em Inglês | MEDLINE | ID: mdl-30526633

RESUMO

BACKGROUND: Tamoxifen treatment greatly reduces a woman's risk of developing a second primary breast cancer. There is, however, substantial variability in treatment response, some of which may be attributed to germline genetic variation. CYP2D6 is a key enzyme in the metabolism of tamoxifen to its active metabolites, and variants in this gene have been associated with reduced tamoxifen metabolism. The impact of variation on risk of contralateral breast cancer (CBC) is unknown. METHODS: Germline DNA from 1514 CBC cases and 2203 unilateral breast cancer controls was genotyped for seven single nucleotide polymorphisms, one three-nucleotide insertion-deletion, and a full gene deletion. Each variant has an expected impact on enzyme activity, which in combination allows for the classification of women as extensive, intermediate, and poor metabolizers (EM, IM, and PM respectively). Each woman was assigned one of six possible diplotypes and a corresponding CYP2D6 activity score (AS): EM/EM (AS = 2), EM/IM (AS = 1.5), EM/PM (AS = 1), IM/IM (AS = 0.75), IM/PM (AS = 0.5), and PM/PM (AS = 0). We also collapsed categories of the AS to generate an overall phenotype (EM, AS ≥ 1; IM, AS = 0.5-0.75; PM, AS = 0). Rate ratios (RRs) and 95% confidence intervals (CIs) for the association between tamoxifen treatment and risk of CBC in our study population were estimated using conditional logistic regression, stratified by AS. RESULTS: Among women with AS ≥ 1 (i.e., EM), tamoxifen treatment was associated with a 20-55% reduced RR of CBC (AS = 2, RR = - 0.81, 95% CI 0.62-1.06; AS = 1.5, RR = 0.45, 95% CI 0.30-0.68; and AS = 1, RR = 0.55, 95% CI 0.40-0.74). Among women with no EM alleles and at least one PM allele (i.e., IM and PM), tamoxifen did not appear to impact the RR of CBC in this population (AS = 0.5, RR = 1.08, 95% CI 0.59-1.96; and AS = 0, RR = 1.17, 95% CI 0.58-2.35) (p for homogeneity = - 0.02). CONCLUSION: This study suggests that the CYP2D6 phenotype may contribute to some of the observed variability in the impact of tamoxifen treatment for a first breast cancer on risk of developing CBC.


Assuntos
Antineoplásicos Hormonais/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Citocromo P-450 CYP2D6/genética , Segunda Neoplasia Primária/genética , Tamoxifeno/uso terapêutico , Adulto , Idoso , Antineoplásicos Hormonais/metabolismo , Neoplasias da Mama/genética , Neoplasias da Mama/prevenção & controle , Estudos de Casos e Controles , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Segunda Neoplasia Primária/epidemiologia , Segunda Neoplasia Primária/prevenção & controle , Variantes Farmacogenômicos/genética , Polimorfismo de Nucleotídeo Único , Tamoxifeno/metabolismo , Resultado do Tratamento
20.
Nutrients ; 10(10)2018 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-30257492

RESUMO

Emerging research has demonstrated that genetic variation may impact physiological responses to caffeine consumption. The purpose of the present review was to systematically recognize how select single nucleotide polymorphisms (SNPs) impact habitual use of caffeine as well as the ergogenic and anxiogenic consequences of caffeine. Two databases (PubMed and EBSCO) were independently searched using the same algorithm. Selected studies involved human participants and met at least one of the following inclusion criteria: (a) genetic analysis of individuals who habitually consume caffeine; (b) genetic analysis of individuals who underwent measurements of physical performance with the consumption of caffeine; (c) genetic analysis of individuals who underwent measurements of mood with the consumption of caffeine. We included 26 studies (10 randomized controlled trials, five controlled trials, seven cross-sectional studies, three single-group interventional studies and one case-control study). Single nucleotide polymorphisms in or near the cytochrome P450 (CYP1A2) and aryl hydrocarbon receptor (AHR) genes were consistently associated with caffeine consumption. Several studies demonstrated that the anxiogenic consequences of caffeine differed across adenosine 2a receptor (ADORA2A) genotypes, and the studies that investigated the effects of genetic variation on the ergogenic benefit of caffeine reported equivocal findings (CYP1A2) or warrant replication (ADORA2A).


Assuntos
Ansiedade/induzido quimicamente , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Cafeína/farmacologia , Citocromo P-450 CYP1A2/genética , Variantes Farmacogenômicos/genética , Receptor A2A de Adenosina/genética , Receptores de Hidrocarboneto Arílico/genética , Adulto , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Substâncias para Melhoria do Desempenho , Polimorfismo de Nucleotídeo Único
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