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1.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 37(4): 401-404, 2020 Apr 10.
Artigo em Chinês | MEDLINE | ID: mdl-32219822

RESUMO

OBJECTIVE: To compare the accuracy of five warfarin-dosing algorithms and warfarin stable dose model (2.5 mg/day) for Shandong population. METHODS: One hundred and twenty five patients who achieved stable warfarin dose were enrolled. Clinical and genetic data were used to evaluate the value of each algorithm by calculating the percentage of patients whose predicted warfarin dose was within 20% of the actual stable therapeutic dose and mean absolute error (MAE). RESULTS: The frequency of patients with CYP2C9*1/*1, CYP2C9*1/*3 and CYP2C9*1/*2 genotype was 92.00%, 7.20%, 0.80%, respectively. That of VKORC1-1639 AA, AG and GG genotype was 82.40%, 15.20%, 2.40%, respectively. CYP4F2*1/*1, *1/*3, *3/*3 genotype was 50.40%, 39.20%, 10.40%, respectively. With the same genotypes for other loci, patients who carried at least one VKORC1-16398G mutant allele had increased warfarin stable daily dose compared with VKORC1-1639AA. Compared with CYP4F2*1/*1, those carrying at least one CYP4F2*3 mutant allele had warfarin stable daily dose increased by 5.9%-13.00%. The percentage of ideal prediction calculated from IWPC model (59.20%), Huang model (57.60%) and Ohno model (52.80%) were higher than others. The MAE were 0.35 (95%CI: 0.11-0.49), 0.15 (95%CI: 0.10-0.32), 0.39 (95%CI: 0.12-0.51), respectively. CONCLUSION: The polymorphisms of CYP2C9, VKORC1 and CYP4F2 genes can influence the stable dose of warfarin in Shandong population. IWPC algorithm is suitable for guiding the use of warfarin in this population.


Assuntos
Anticoagulantes/administração & dosagem , Hidrocarboneto de Aril Hidroxilases , Varfarina/administração & dosagem , Citocromo P-450 CYP2C9/genética , Família 4 do Citocromo P450/genética , Relação Dose-Resposta a Droga , Genótipo , Humanos , Modelos Teóricos , Polimorfismo Genético , Vitamina K Epóxido Redutases/genética
2.
Expert Opin Drug Metab Toxicol ; 16(1): 1-9, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31914334

RESUMO

Background: Warfarin acts in heart valve replacement patients to minimize thromboembolic complications. We investigated whether patients can be distinguished based on their genotypes to efficiently and safely administer warfarin therapy after heart valve replacements.Research design and methods: A retrospective analysis was conducted in patients with warfarin therapy who underwent elective heart valve replacements between January 2013 and September 2018. The patients were divided into normal, sensitive, and highly sensitive bins based on their CYP2C9 and VKORC1 genotypes. The primary endpoints were over-anticoagulation and overt bleeding.Results: 375 patients were enrolled, with 65 classified as normal, 281 as sensitive, and 29 as highly sensitive responders. Compared with normal responders, sensitive and highly sensitive responders spent more time on over-anticoagulation in the first 28 (P < 0.001) and 90 (P = 0.001) days; experienced more frequent bleeding events in the first 28 days (P = 0.029; OR, 2.18; 95% CI, 1.15-4.13); required lower warfarin doses to obtain stable INR (P < 0.001); had higher warfarin sensitivity indices (P < 0.001).Conclusion: Predicting evidence have been obtained with CYP2C9 and VKORC1 genotypes in identifying heart valve replacement patients with higher efficient sensitivity and with a higher risk of bleeding and over-anticoagulation.


Assuntos
Anticoagulantes/administração & dosagem , Citocromo P-450 CYP2C9/genética , Hemorragia/induzido quimicamente , Vitamina K Epóxido Redutases/genética , Varfarina/administração & dosagem , Adulto , Idoso , Anticoagulantes/efeitos adversos , Relação Dose-Resposta a Droga , Feminino , Genótipo , Implante de Prótese de Valva Cardíaca/métodos , Hemorragia/epidemiologia , Hemorragia/genética , Humanos , Coeficiente Internacional Normatizado , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Tromboembolia/prevenção & controle , Varfarina/efeitos adversos
3.
Nutrients ; 11(9)2019 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-31484376

RESUMO

Vitamin K is crucial for many physiological processes such as coagulation, energy metabolism, and arterial calcification prevention due to its involvement in the activation of several vitamin K-dependent proteins. During this activation, vitamin K is converted into vitamin K epoxide, which must be re-reduced by the VKORC1 enzyme. Various VKORC1 mutations have been described in humans. While these mutations have been widely associated with anticoagulant resistance, their association with a modification of vitamin K status due to a modification of the enzyme efficiency has never been considered. Using animal models with different Vkorc1 mutations receiving a standard diet or a menadione-deficient diet, we investigated this association by measuring different markers of the vitamin K status. Each mutation dramatically affected vitamin K recycling efficiency. This decrease in recycling was associated with a significant alteration of the vitamin K status, even when animals were fed a menadione-enriched diet suggesting a loss of vitamin K from the cycle due to the presence of the Vkorc1 mutation. This change in vitamin K status resulted in clinical modifications in mutated rats only when animals receive a limited vitamin K intake totally consistent with the capacity of each strain to recycle vitamin K.


Assuntos
Mutação Puntual , Deficiência de Vitamina K , Vitamina K Epóxido Redutases/genética , Vitamina K Epóxido Redutases/metabolismo , Vitamina K/sangue , Animais , Cálcio/metabolismo , Dieta , Esquema de Medicação , Regulação Enzimológica da Expressão Gênica , Genótipo , Masculino , Microssomos Hepáticos , Tempo de Protrombina , Ratos , Vitamina K 3/administração & dosagem
4.
BMJ ; 366: l4410, 2019 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-31371314

RESUMO

OBJECTIVE: To determine if genetically increased serum calcium levels are associated with improved bone mineral density and a reduction in osteoporotic fractures. DESIGN: Mendelian randomisation study. SETTING: Cohorts used included: the UK Biobank cohort, providing genotypic and estimated bone mineral density data; 25 cohorts from UK, USA, Europe, and China, providing genotypic and fracture data; and 17 cohorts from Europe, providing genotypic and serum calcium data (summary level statistics). PARTICIPANTS: A genome-wide association meta-analysis of serum calcium levels in up to 61 079 individuals was used to identify genetic determinants of serum calcium levels. The UK Biobank study was used to assess the association of genetic predisposition to increased serum calcium with estimated bone mineral density derived from heel ultrasound in 426 824 individuals who had, on average, calcium levels in the normal range. A fracture genome-wide association meta-analysis comprising 24 cohorts and the UK Biobank including a total of 76 549 cases and 470 164 controls, who, on average, also had calcium levels in the normal range was then performed. RESULTS: A standard deviation increase in genetically derived serum calcium (0.13 mmol/L or 0.51 mg/dL) was not associated with increased estimated bone mineral density (0.003 g/cm2, 95% confidence interval -0.059 to 0.066; P=0.92) or a reduced risk of fractures (odds ratio 1.01, 95% confidence interval 0.89 to 1.15; P=0.85) in inverse-variance weighted mendelian randomisation analyses. Sensitivity analyses did not provide evidence of pleiotropic effects. CONCLUSIONS: Genetic predisposition to increased serum calcium levels in individuals with normal calcium levels is not associated with an increase in estimated bone mineral density and does not provide clinically relevant protection against fracture. Whether such predisposition mimics the effect of short term calcium supplementation is not known. Given that the same genetically derived increase in serum calcium is associated with an increased risk of coronary artery disease, widespread calcium supplementation in the general population could provide more risk than benefit.


Assuntos
Densidade Óssea/genética , Cálcio/sangue , Predisposição Genética para Doença , Fraturas por Osteoporose/sangue , Fraturas por Osteoporose/genética , Adenosina Trifosfatases/genética , Diacilglicerol Quinase/genética , Feminino , Fator de Transcrição GATA3/genética , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Masculino , Análise da Randomização Mendeliana , Polimorfismo de Nucleotídeo Único , Receptores de Detecção de Cálcio/genética , Medição de Risco , Vitamina D3 24-Hidroxilase/genética , Vitamina K Epóxido Redutases/genética
5.
Biomed Res Int ; 2019: 3794876, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31341897

RESUMO

Leptospirosis is a reemerging zoonosis and ranges in severity from benign to sometimes fatal. In cattle, infection may be responsible for abortion and infertility cases causing economic losses. Humans may be contaminated through direct contact with urine of infected animals or indirectly though interaction with urine-contaminated environment. Many wildlife species living close to cattle, especially commensal rodents may play a role in the transmission of leptospires. Because little is known on the epidemiology of nonmaintenance Leptospira serovars, appropriate management is still limited. On a French farm where human and cattle leptospirosis were detected, the transmission cycle was explored to propose appropriate mitigation measures. For that, commensal rodents present on the farm were trapped and their leptospires carriage was studied by molecular methods. Trapped mice were shown to carry two pathogenic Leptospira species (L. interrogans and L. kirschneri). Since these 2 serogroups were simultaneously detected in the trapped mice and in the cows of this farm, we suspected an initial Leptospira transmission from mice to cows requiring an effective management of mice on this farm. Because resistance to anticoagulant rodenticides due to Vkorc1 mutations has been largely described in rodents and first-generation anticoagulant rodenticides seemed to be inefficient in controlling mice on this farm, susceptibility of these mice to anticoagulants has been characterized by Vkorc1 sequencing. 50% of the trapped mice carried mutations in the Vkorc1 gene leading to severe resistance to first-generation anticoagulants. The management of such mice that are a real sanitary threat can be achieved only by using the most toxic second-generation anticoagulants or nonanticoagulant solutions.


Assuntos
Doenças dos Bovinos/transmissão , Leptospirose/transmissão , Camundongos/microbiologia , Animais , Anticoagulantes , Bovinos , Doenças dos Bovinos/epidemiologia , Doenças dos Bovinos/microbiologia , Feminino , Humanos , Leptospira/isolamento & purificação , Leptospira interrogans/isolamento & purificação , Leptospirose/epidemiologia , Leptospirose/veterinária , Proteínas de Membrana/genética , Roedores , Rodenticidas , Sorogrupo , Vitamina K Epóxido Redutases/genética , Zoonoses/transmissão
6.
Croat Med J ; 60(3): 212-220, 2019 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-31187948

RESUMO

AIM: To investigate the prevalence of common genetic variants that can serve as markers of thrombophilia and warfarin pharmacogenetics in Bosnia and Herzegovina. METHODS: The study was performed between August and October 2017 on 130 healthy unrelated adult volunteers from Bosnian-Herzegovinian population sample. The prevalence of the following genetic variants was determined: F5 c.1601G>A (factor V Leiden), F2 c.*97G>A (factor II or prothrombin mutation), F13A1 (factor XIII) c.103G>T, MTHFR (methylenetetrahydrofolate reductase) c.665C>T and c.1286A>C, as well as PAI-1 (plasminogen activator inhibitor 1) c.-816A>G and c.-844G>A as markers of thrombophilia risk, and *2 and *3 alleles of CYP2C9 (cytochrome P450 2C9) and five variants of VKORC1 (vitamin K epoxide reductase complex subunit 1) as markers of warfarin pharmacogenetics. DNA was isolated from buccal swabs using salting out method, while genotyping was performed using matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry. RESULTS: Minor allele frequencies for two main thrombophilia risk factors, F5 c.1601G>A and F2 c.*97G>A were 0.023 and 0.008, respectively. Combined data for the markers of warfarin pharmacogenetics imply that 57.4% study participants can be expected to metabolize warfarin at an extensive, 40.3% at intermediate, and 2.3% at a poor rate. CONCLUSION: This study reports the first extensive population genetic data for thrombophilia and warfarin pharmacogenetic markers in Bosnia and Herzegovina. Allele frequencies of genetic variants are within the general average for European populations, and their presence implies the necessity of introduction of personalized medicine in warfarin-mediated antithrombotic therapy.


Assuntos
Anticoagulantes/metabolismo , Fatores de Coagulação Sanguínea/genética , Trombofilia/genética , Varfarina/metabolismo , Adolescente , Adulto , Alelos , Biomarcadores , Bósnia e Herzegóvina , Citocromo P-450 CYP2C9/genética , Fator V/genética , Fator XIII/genética , Feminino , Frequência do Gene , Genótipo , Humanos , Masculino , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Pessoa de Meia-Idade , Inibidor 1 de Ativador de Plasminogênio/genética , Gravidez , Protrombina/genética , Vitamina K Epóxido Redutases/genética , Adulto Jovem
7.
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
8.
Mol Med Rep ; 19(6): 5361-5367, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31059093

RESUMO

A substantial body of research has confirmed that Vitamin K epoxide reductase complex subunit 1 (VKORC1) plays a role in contributing to the high interpatient variability in the warfarin maintenance dose. The aim of the present study was to examine the impact of SNPs of miR­137 on the warfarin maintenance dose. Computational analysis and luciferase assay were used to search the targets of miR­137, and luciferase assay was also used to confirm the effect of the polymorphisms on the transcription of the promoter. The regulatory relationship between miR­137 and VKORC1 was detected using real­time PCR. We then performed statistical analysis to find the warfarin maintenance dose in the different groups. A total of 155 subjects were enrolled in our research, and the characteristics of the patients were collected. Using computational analysis, we identified that miR­137 binds to the VKORC1 3'untranslated region (3'UTR) and regulates the expression of VKORC1. This hypothesis was confirmed by luciferase reporter assay as miR­137 significantly reduced the VKORC1 3'UTR luciferase activity, while the luciferase activity of mutant VKORC1 3'UTR was similar to the scramble control. According to the result of the luciferase reporter assay, we found that miR­137 SNP with the presence of the A allele apparently reduced the luciferase activity. Using real­time PCR, we revealed that miR­137 negatively regulated the expression of VKORC1 in a concentration­dependent manner in liver cells. Furthermore, no difference was noted regarding the warfarin maintenance dose between the different age or gender groups, and furthermore AC + AA carriers showed a markedly higher warfarin maintenance dose than CC carriers. These findings collectively provide support that VKORC1 is a direct target of miR­137 and the miR­137 rs2660304 polymorphism is associated with warfarin maintenance dose in patients with atrial fibrillation. The rs2660304 polymorphism is a potential biomarker for predicting the clinical efficacy of warfarin in these patients.


Assuntos
Anticoagulantes/uso terapêutico , Fibrilação Atrial/tratamento farmacológico , Variação Genética , MicroRNAs/genética , Varfarina/uso terapêutico , Regiões 3' não Traduzidas , Adulto , Alelos , Antagomirs/metabolismo , Fibrilação Atrial/genética , Fibrilação Atrial/patologia , Relação Dose-Resposta a Droga , Feminino , Genótipo , Células Hep G2 , Humanos , Coeficiente Internacional Normatizado , Masculino , MicroRNAs/antagonistas & inibidores , MicroRNAs/metabolismo , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Regiões Promotoras Genéticas , Vitamina K Epóxido Redutases/química , Vitamina K Epóxido Redutases/genética , Vitamina K Epóxido Redutases/metabolismo
9.
Arterioscler Thromb Vasc Biol ; 39(7): 1351-1368, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31144989

RESUMO

Aortic aneurysm is a vascular disease whereby the ECM (extracellular matrix) of a blood vessel degenerates, leading to dilation and eventually vessel wall rupture. Recently, it was shown that calcification of the vessel wall is involved in both the initiation and progression of aneurysms. Changes in aortic wall structure that lead to aneurysm formation and vascular calcification are actively mediated by vascular smooth muscle cells. Vascular smooth muscle cells in a healthy vessel wall are termed contractile as they maintain vascular tone and remain quiescent. However, in pathological conditions they can dedifferentiate into a synthetic phenotype, whereby they secrete extracellular vesicles, proliferate, and migrate to repair injury. This process is called phenotypic switching and is often the first step in vascular pathology. Additionally, healthy vascular smooth muscle cells synthesize VKDPs (vitamin K-dependent proteins), which are involved in inhibition of vascular calcification. The metabolism of these proteins is known to be disrupted in vascular pathologies. In this review, we summarize the current literature on vascular smooth muscle cell phenotypic switching and vascular calcification in relation to aneurysm. Moreover, we address the role of vitamin K and VKDPs that are involved in vascular calcification and aneurysm. Visual Overview- An online visual overview is available for this article.


Assuntos
Aneurisma Aórtico/etiologia , Músculo Liso Vascular/fisiologia , Miócitos de Músculo Liso/fisiologia , Calcificação Vascular/etiologia , Vitamina K/fisiologia , Elastina/metabolismo , Humanos , Músculo Liso Vascular/citologia , Estresse Oxidativo , Fenótipo , Fator de Crescimento Transformador beta/fisiologia , Vitamina K Epóxido Redutases/genética
10.
Clinics (Sao Paulo) ; 74: e739, 2019 03 14.
Artigo em Inglês | MEDLINE | ID: mdl-30892416

RESUMO

OBJECTIVE: In this study, the relationship between osteoporotic vertebral fractures and 9041 Guanine/Adenine and 3673 Guanine/Adenine polymorphisms related to the vitamin K epoxide reductase complex subunit-1 (VKORC1) gene in postmenopausal women with osteoporosis was investigated. METHOD: DNA was isolated from blood samples collected from 150 women with postmenopausal osteoporosis. Genotyping of the two polymorphic regions (9041 Guanine/Adenine and 3673 Guanine/Adenine) in VKORC1 was performed using polymerase chain reaction-restriction fragment length polymorphism analysis. The presence of radiographic fractures among the 150 patients was ascertained by using the Genant method. RESULT: At least one fracture was detected in 98 patients, and no fracture was observed in 52 patients on radiological images. We found no association between the 9041 Guanine/Adenine (p=0.283) and 3673 Guanine/Adenine (p=0.232) polymorphisms of the VKORC1 gene and the development of secondary postosteoporotic fractures in our study. CONCLUSION: There was no relationship between osteoporotic vertebral fracture and VKORC1 gene polymorphism in a postmenopausal Turkish population.


Assuntos
Osteoporose Pós-Menopausa/genética , Fraturas por Osteoporose/genética , Polimorfismo Genético/genética , Fraturas da Coluna Vertebral/genética , Vitamina K Epóxido Redutases/genética , Idoso , Densidade Óssea , Feminino , Frequência do Gene/genética , Estudos de Associação Genética , Humanos , Pessoa de Meia-Idade , Projetos Piloto , Estudos Retrospectivos , Turquia
11.
Eur J Clin Pharmacol ; 75(7): 913-920, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30848333

RESUMO

PURPOSE: We previously demonstrated that the rational pediatric dosage of warfarin can be well-described by a SIZE parameter that includes an allometry exponent of weight. On the other hand, allometry alone is considered to be insufficient to predict drug clearance in neonates and infants. The primary purpose of the present study was to evaluate the effects of incorporation of the maturation process into the analysis model for the dose-response relationship of warfarin in Japanese children. In addition, we evaluated the effect of chronic heart failure (CHF) on the response to warfarin as an independent risk factor for increased anticoagulant effects. METHODS: Thirty-eight patients with stable anticoagulation by warfarin were enrolled. During a mean follow-up period of 4.74 ± 3.51 years, 1092 data points including prothrombin time-international normalized ratio (PT-INR) were obtained. The data were subjected to multiple regression analysis to identify covariates related to the anticoagulant effects. RESULTS: Two different models describing the maturation process did not improve the predictive performance for the dose-response relationship in pediatric patients. In addition to the SIZE-normalized daily dose, the vitamin K epoxide reductase complex 1 (VKORC1) genotype, and concomitant use of bosentan, CHF was identified as a covariate increasing the anticoagulant effects of warfarin to 118%. CONCLUSION: The SIZE parameter was useful even without incorporation of maturation models to describe the response to warfarin in pediatric patients, and our longitudinal follow-up study design with multiple observations was beneficial to detect changes within individual subjects.


Assuntos
Envelhecimento/metabolismo , Anticoagulantes/administração & dosagem , Coagulação Sanguínea/efeitos dos fármacos , Insuficiência Cardíaca/tratamento farmacológico , Modelos Biológicos , Vitamina K Epóxido Redutases/genética , Varfarina/administração & dosagem , Administração Oral , Adolescente , Grupo com Ancestrais do Continente Asiático/genética , Criança , Pré-Escolar , Doença Crônica , Relação Dose-Resposta a Droga , Feminino , Genótipo , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/metabolismo , Humanos , Lactente , Masculino
12.
Eur J Clin Pharmacol ; 75(7): 901-911, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30852642

RESUMO

PURPOSE: Large inter-individual differences in warfarin maintenance dose are mostly due to the effect of genetic polymorphisms in multiple genes, including vitamin K epoxide reductase complex 1 (VKORC1), cytochromes P450 2C9 (CYP2C9), and cytochrome P450 4F2 (CYP4F2). Thus, several algorithms for predicting the warfarin dose based on pharmacogenomics data with clinical characteristics have been proposed. Although these algorithms consider these genetic polymorphisms, the formulas have different coefficient values that are critical in this context. In this study, we assessed the mutual validity among these algorithms by specifically considering racial differences. METHODS: Clinical data including actual warfarin dose (AWD) of 125 Japanese patients from our previous study (Eur J Clin Pharmacol 65(11):1097-1103, 2009) were used as registered data that provided patient characteristics, including age, sex, height, weight, and concomitant medications, as well as the genotypes of CYP2C9 and VKORC1. Genotyping for CYP4F2*3 was performed by the PCR method. Five algorithms that included these factors were selected from peer-reviewed articles. The selection covered four populations, Japanese, Chinese, Caucasian, and African-American, and the International Warfarin Pharmacogenetics Consortium (IWPC). RESULTS: For each algorithm, we calculated individual warfarin doses for 125 subjects and statistically evaluated its performance. The algorithm from the IWPC had the statistically highest correlation with the AWD. Importantly, the calculated warfarin dose (CWD) using the algorithm from African-Americans was less correlated with the AWD as compared to those using the other algorithms. The integration of CYP4F2 data into the algorithm did not improve the prediction accuracy. CONCLUSION: The racial difference is a critical factor for warfarin dose predictions based on pharmacogenomics.


Assuntos
Algoritmos , Anticoagulantes/administração & dosagem , Grupo com Ancestrais do Continente Asiático/genética , Citocromo P-450 CYP2C9/genética , Família 4 do Citocromo P450/genética , Vitamina K Epóxido Redutases/genética , Varfarina/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Farmacogenética
13.
Int J Mol Sci ; 20(5)2019 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-30866412

RESUMO

Here, we describe a Dutch family with idiopathic pulmonary fibrosis (IPF). We hypothesized that there might be an association between the presence of Vitamin K epoxide reductase complex 1 (VKORC1) and/or cytochrome P450 2C9 (CYP2C9) variant alleles and the early onset of IPF in the members of this family. VKORC1 (rs9923231 and rs9934438) and CYP2C9 (rs1799853 and rs1057910) were genotyped in this family, which includes a significant number of pulmonary fibrosis patients. In all family members, at least one of the variant alleles tested was present. The presence of the VKORC1 variant alleles in all of the IPF cases and CYP2C9 variants in all but one, which likely leads to a phenotype that is characterized by the early onset and progressive course of IPF. Our findings indicate a role of these allelic variants in (familial) IPF. Therefore, we suggest that the presence of these variants, in association with other pathogenic mutations, should be evaluated during genetic counselling. Our findings might have consequences for the lifestyle of patients with familial IPF in order to prevent the disease from becoming manifest.


Assuntos
Citocromo P-450 CYP2C9/genética , Fibrose Pulmonar Idiopática/genética , Polimorfismo de Nucleotídeo Único , Vitamina K Epóxido Redutases/genética , Adulto , Idade de Início , Idoso de 80 Anos ou mais , Progressão da Doença , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Países Baixos , Linhagem , Regiões Promotoras Genéticas , Estudos Retrospectivos
14.
Medicine (Baltimore) ; 98(6): e14365, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30732170

RESUMO

Prosthetic Valve Thrombosis (PVT), in spite of the advances in the valve design and the material used, remains a serious complication of mechanical cardiac valve replacement. The factors influencing the development of PVT are: thrombogenicity of the valve, hemodynamics of the transprosthetic blood flow and ineffective anticoagulation. Genetic polymorphism of the genes VKORC1 (-1639 G > A and 1173 C > T), CYP2C9 (*2 & *3 alleles) and CYP4F2 (1347 G > A) are known to influence the anticoagulant dose-effect response. Since there has not been any earlier study on the direct influence of gene polymorphism on the development of PVT, we investigated into this association.Genotyping for the genes VKORC1, CYP2C9 and CYP4F2 was carried out by conventional PCR-RFLP method for 91 consecutive PVT patients. Subjects of our earlier study served as controls (n = 136).Female patients and patients with smaller prosthetic valve size were more prone to developing PVT (68%, n = 62). Patients bearing A allele of CYP4F2 1347 G > A polymorphism exhibited a fivefold increased risk of PVT (OR = 5.022 (1.39-18.04), P = .013). G allele of VKORC1 when analyzed in combination of genotypes showed a fourteen fold increased risk for developing PVT (OR = 14.25 (5.52-36.77), P = 0.001). CYP2C9 (*2&*3) gene polymorphism did not show any significant association with PVT (OR = 1.54 (0.128 - 18.82), P = .731).Patients bearing A allele of CYP4F2 showed an increased risk of developing PVT in our case - control study.


Assuntos
Citocromo P-450 CYP2C9/genética , Família 4 do Citocromo P450/genética , Próteses Valvulares Cardíacas/efeitos adversos , Trombose/genética , Vitamina K Epóxido Redutases/genética , Adolescente , Adulto , Idoso , Alelos , Anticorpos Antifosfolipídeos/sangue , Estudos de Casos e Controles , Feminino , Genótipo , Humanos , Índia , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Estudos Prospectivos , Fatores Sexuais , Adulto Jovem
15.
Mol Biol Rep ; 46(2): 1825-1833, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30712247

RESUMO

It was aimed to underline the importance and explain the meaning of genetic testing in warfarin dosing and investigate and evaluate the contributions of the CYP2C9, VKORC1, and CYP4F2 variants in a Turkish population. Two hundred patients were genotyped for CYP2C9 (rs1799853, rs1057910 and rs56165452), VKORC1 (rs9934438, rs8050894, rs9923231, rs7294 and rs2359612) and CYP4F2 (rs2108622), yet, only 127 patients were found suitable for further evaluation in terms of their personal response to warfarin due to long term usage and available INR and dose usage information. The DNA sequences were determined by the ABI PRISM 3100 Genetic Analyzer to 3130xl System (Applied Biosystems, Foster City, California). Warfarin dose application suggestions by warfaringdosing.org, FDA and MayoClinic were followed. Dose requirements in the Turkish population were found higher than the suggested doses by warfarindosing.org. The multivariate logistic regression analysis reveals the utilization of VCORC1 genetic evaluation is valuable in warfarin dosing (low and moderate vs. high) in this study (p < 0.001). The present study provides findings for clinicians to adapt the genetic data to the daily practice. We observed that the VKORC1 variant showed a more potent impact in warfarin dosing in this study.


Assuntos
Citocromo P-450 CYP2C9/metabolismo , Família 4 do Citocromo P450/metabolismo , Vitamina K Epóxido Redutases/metabolismo , Varfarina/farmacologia , Adulto , Idoso , Biomarcadores Farmacológicos , Citocromo P-450 CYP2C9/genética , Família 4 do Citocromo P450/genética , Relação Dose-Resposta a Droga , Feminino , Frequência do Gene , Variação Genética/genética , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Farmacogenética , Polimorfismo de Nucleotídeo Único , Turquia , Vitamina K Epóxido Redutases/genética , Varfarina/administração & dosagem
16.
Genet Test Mol Biomarkers ; 23(3): 209-214, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30758238

RESUMO

AIMS: This study was designed to develop a high-resolution melting (HRM) analysis-based cardiovascular (CV) pharmacogenetics (PGx) genotyping panel for the Canon DNA Genetic Analyzer multiplex genotyping platform and cross-validate its performance with the TaqMan®-based OpenArray® method. METHODS: The CV PGx genotyping panel containing 17 single nucleotide polymorphisms (SNPs) selected from 5 genes (CYP2C9, CYP2C19, CYP4F2, SLCO1B1, and VKORC1) and the CYP2C cluster was used to compare genotyping results between analysis methods. Genomic DNA from 223 clinical samples was used to genotype the 17 SNPs on the Canon DNA Genetic Analyzer and TaqMan OpenArray Quant Studio Real-Time PCR (polymerase chain reaction) System. RESULTS: The concordance between the Canon DNA analyzer and TaqMan-based OpenArray genotyping results for the 17 SNPs ranged from 99.10% to 100% where SNPs (rs4244285, rs12248560, rs4986893, rs72552267, rs28399504, rs4149056, rs28371686, rs9332131, rs72558189, rs9923231, rs12777823), (rs41291556, rs1799853, rs7900194, rs28371685, rs2108622), and (rs1057910) showed 100%, 99.60%, and 99.10% concordance, respectively. CONCLUSION: These results show that the HRM analysis-based CV PGx genotyping panel performed well when compared with TaqMan-based OpenArray. The multiple genetic variant testing capability, efficient turnaround time and reproducibility of both assays formats suggest that the PGx panel with the DNA analyzer or other real-time PCR instruments with HRM assay analysis capability can be used for PGx testing in both research and clinical practice settings.


Assuntos
Doenças Cardiovasculares/genética , Testes Genéticos/métodos , Farmacogenética/métodos , Adulto , Citocromo P-450 CYP2C19/genética , Feminino , Genótipo , Técnicas de Genotipagem/métodos , Voluntários Saudáveis , Humanos , Transportador 1 de Ânion Orgânico Específico do Fígado/genética , Masculino , Desnaturação de Ácido Nucleico/genética , Polimorfismo de Nucleotídeo Único , Reação em Cadeia da Polimerase em Tempo Real , Reprodutibilidade dos Testes , Vitamina K Epóxido Redutases/genética
17.
Clin Pharmacol Ther ; 105(2): 411-416, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30652304

RESUMO

The US Food and Drug Administration (FDA) reference-scaled average bioequivalence approach scales the bioequivalence (BE) limits of narrow therapeutic index drugs (NTIDs) to the intrasubject or within-subject variability (WSV) of the reference-listed drug. A clinical study was conducted to evaluate the WSV of warfarin (Coumadin), 10 mg, administered to 10 healthy volunteers exhibiting similar cytochrome P450 2C9 and vitamin K epoxide reductase alleles on 3 study days. Individual intrasubject coefficients of variation for maximum plasma concentration and area under the curve (0-72 hour) ranged from 3.7-15% and from 4.3-16.2%, respectively (R-warfarin) and from 5.4-19.1% and from 2.5-11.9%, respectively (S-warfarin). Two BE tests were performed on a WSV distribution obtained by bootstrapping 1,000 replicates of the clinical data, yielding passing rates of 95-97% for the mean comparison and 84-87% for the variability comparison. The variability comparison passing rate was lower than expected for an NTID product tested against itself, but it may provide further assurance of BE.


Assuntos
Tratamento Farmacológico , Adulto , Anticoagulantes/efeitos adversos , Anticoagulantes/farmacocinética , Área Sob a Curva , Estudos Cross-Over , Citocromo P-450 CYP2C9/genética , Feminino , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Estereoisomerismo , Equivalência Terapêutica , Vitamina K Epóxido Redutases/genética , Varfarina/efeitos adversos , Varfarina/farmacocinética
18.
Hepatol Int ; 13(2): 214-221, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30617764

RESUMO

INTRODUCTION: Anticoagulation is universally recommended in Budd-Chiari syndrome [BCS]. Vitamin K epoxide reductase complex 1 (VKORC1) and CYP2C9 are involved in the metabolism of warfarin. The present study was done to assess whether these mutations are associated with the risk of bleeding in patients with BCS receiving warfarin. PATIENTS AND METHODS: Patients diagnosed with BCS underwent genotyping for three single nucleotide polymorphisms [SNPs]-two for the CYP2C9 and one for the VKORC1 haplotype. The patients were followed up for at least 12 months and all bleeding episodes were recorded. Patients with and without mutations were compared for bleeding complications and a crude odds ratio [crude OR] was derived for the association between bleeding and presence or absence of mutant alleles. RESULTS: Eighty patients [mean (SD) age 27.47 (8.93) years, 35 male] with BCS underwent genetic testing. 37/80 (46.2%) patients had mutation of CYP2C9 and/or VKORC1; 22/80 (27.5%) had either of the mutant alleles of CYP2C9 and, similarly, 22/80 (27.5%) had the VKORC mutation. Over a median follow-up of 20 (range 12-96) months, 21/80 (26.3%) patients had bleeding complications. Patients with mutant SNPs had a higher risk of bleeding than those without [14/37 vs. 7/43, p = 0.04, crude OR (95% CI) 3.13 (1.1-8.9)]. CONCLUSION: The presence of mutations in VKORC1 or CYP2C9 is associated with increased risk of bleeding in patients with BCS on warfarin. Such patients with SNPs of CY2C9 or VKORC1 haplotype should be monitored intensively while receiving warfarin.


Assuntos
Anticoagulantes/efeitos adversos , Síndrome de Budd-Chiari/tratamento farmacológico , Citocromo P-450 CYP2C9/genética , Hemorragia/genética , Vitamina K Epóxido Redutases/genética , Varfarina/efeitos adversos , Adolescente , Adulto , Alelos , Síndrome de Budd-Chiari/etiologia , Feminino , Haplótipos , Hemorragia/induzido quimicamente , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Polimorfismo de Nucleotídeo Único , Índice de Gravidade de Doença , Adulto Jovem
19.
OMICS ; 23(1): 36-44, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30566377

RESUMO

Warfarin is a widely prescribed anticoagulant with a narrow therapeutic index. The rs12777823G>A single-nucleotide polymorphism (SNP) in the CYP2C gene cluster has been shown to influence optimal warfarin doses in African Americans. We report here effects of rs12777823G>A SNP on warfarin dose requirements in two South African population groups, black Africans (BA) and mixed ancestry (MA). A total of 425 participants on warfarin treatment were enrolled in the study. The age group of the studied population ranged between 44 and 66 years, with 69% females enrolled. Genetic characterization of the rs12777823G>A was done using the TaqMan SNP genotyping assay. To further compare effects of rs12777823G>A to those of other SNPs, VKORC1 g.-1639G>A and 4 SNPs in CYP2C9 gene (i.e., CYP2C9 c.430C>T, c.1075A>C, c.449G>A, and c.1003C>T) were analyzed. The rs12777823A variant allele frequencies were 0.28 and 0.25 in the BA and MA, respectively. The rs12777823A/A genotype was associated with significantly (p = 0.002) reduced mean warfarin dosage (27 ± 5.3 mg/week) compared with the G/G genotype (45 ± 16.1 mg/week) among BA, but not among the MA. The rs12777823G>A is located in a nongenomic region, suggesting that this SNP might be in linkage disequilibrium with another, likely causal SNP that is present in BA only. Given ongoing worldwide efforts to identify clinically relevant human genetic variation impacting on optimal warfarin dose selection, the African ancestry-specific genetic variant in the CYP2C cluster and others warrant further research and consideration in development of future warfarin dosing algorithms for precision medicine guidelines.


Assuntos
Afro-Americanos/genética , Grupo com Ancestrais do Continente Africano/genética , Anticoagulantes/uso terapêutico , Citocromo P-450 CYP2C9/genética , Família Multigênica/genética , Polimorfismo de Nucleotídeo Único/genética , Varfarina/uso terapêutico , Adulto , Idoso , Frequência do Gene/genética , Genótipo , Humanos , Desequilíbrio de Ligação/genética , Pessoa de Meia-Idade , Vitamina K Epóxido Redutases/genética
20.
Eur J Clin Pharmacol ; 75(3): 343-350, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30411147

RESUMO

BACKGROUND: The initial rise in INR following warfarin is attributed to rapid decline in coagulation factor VII (F7). The R353Q polymorphism in F7 accounts for approximately 1/3 of the variability in F7 activity (FVIIc). OBJECTIVE: Evaluate the role of R353Q in the initial response to warfarin. METHODS: Twenty-eight healthy, males, carrying CYP2C9*1/*1 (n = 14), CYP2C9*1/*2 (n = 4) or CYP2C9*1/*3 (n = 10) genotypes, received single 20 mg warfarin. S&R-warfarin concentrations, INR, and FVIIc were monitored periodically for 7 days. RESULTS: Baseline and maximal INR were 5.6% and 33.5% higher among carriers of the RQ (n = 12) as compared with those carrying the RR (n = 16) genotype (p = 0.032, p = 0.003, respectively). Baseline and nadir FVIIc were 21.6% and 42.0% lower among subjects carrying the RQ as compared with carriers of the RR genotype (p = 0.001, p = 0.007 respectively). In multiple regression analysis, R353Q predicted 36.6% of the variability in peak INR whereas 20.2%, 9.9%, and 5.9% were attributed to VKORC1 genetic polymorphism, cholesterol concentration, and S Warfarin concentration after 24 h, respectively. CONCLUSIONS: R353Q genetic polymorphism plays a key role in determining the initial response to warfarin. The incorporation of this genetic variant into warfarin loading algorithm should be further investigated.


Assuntos
Anticoagulantes/sangue , Coagulação Sanguínea/genética , Fator VII/análise , Polimorfismo de Nucleotídeo Único , Varfarina/sangue , Adulto , Anticoagulantes/administração & dosagem , Arginina/genética , Citocromo P-450 CYP2C9/genética , Monitoramento de Medicamentos , Genótipo , Glutamina/genética , Humanos , Coeficiente Internacional Normatizado , Modelos Lineares , Masculino , Análise Multivariada , Vitamina K Epóxido Redutases/genética , Varfarina/administração & dosagem , Adulto Jovem
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