RESUMO
OBJECTIVE: This study was intended to determine the incidence rate of warfarin-related adverse events (e.g., bleeding) in Puerto Ricans and whether a genetic association between warfarin pharmacogenes and any of these adverse events was observed over the initiation period (i.e., the first 90 days of therapy). METHODS: We conducted an observational, retrospective cohort study of pharmacogenetic association in 122 warfarin-treated, male, Puerto Rican patients (69.9 +/- 9.6 years) from the Veterans Affair Caribbean Healthcare System (VACHS) who consented to participate. Genotyping was performed using the CYP2C9 and VKORC1 assays by Luminex. Event-free survival curves were estimated using the Kaplan-Meier method and analyzed by log-rank test. Cox regression models were constructed and hazard ratios (HR) calculated. RESULTS: Carriers of functional CYP2C9 and VKORC1 polymorphisms demonstrated a higher incidence rate of multiple adverse events (i.e., 5.2 vs. 1.0 cases per 100 patient-months; RR = 4.8, p = 0.12) than did wild types. A significant association was observed between multiple adverse events and carrier status (HR = 2.5; 95% CI: 1.0-6.3, p = 0.04). However, no significant associations between genotypes and individual outcomes over the first 90 days of therapy were found. CONCLUSION: The association of CYP2C9 and VKORC1 genotypes and risks for adverse events due to exposure to warfarin was examined for the first time in Puerto Ricans. Despite a lack of association with individual events in this study population, our findings revealed a potential utility of genotyping for the prevention of multiple adverse events during warfarin therapy.
Assuntos
Anticoagulantes/administração & dosagem , Anticoagulantes/efeitos adversos , Hemorragia/induzido quimicamente , Hemorragia/genética , Varfarina/administração & dosagem , Varfarina/efeitos adversos , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Genótipo , Humanos , Pessoa de Meia-Idade , Porto Rico , Estudos RetrospectivosRESUMO
BACKGROUND: The influence of CYP2C9 and VKORC1 polymorphisms on warfarin dose has been investigated in white, Asian, and African American populations but not in Puerto Rican Hispanic patients. OBJECTIVE: To test the associations between genotypes, international normalized ratio (INR) measurements, and warfarin dosing and gauge the impact of these polymorphisms on warfarin dose, using a published algorithm. METHODS: A retrospective warfarin pharmacogenetic association study in 106 Puerto Rican patients was performed. DNA samples from patients were assayed for 12 variants in both CYP2C9 and VKORC1 loci by HILOmet PhyzioType assay. Demographic and clinical nongenetic data were retrospectively collected from medical records. Allele and genotype frequencies were determined and Hardy-Weinberg equilibrium (HWE) was tested. RESULTS: Sixty-nine percent of patients were carriers of at least one polymorphism in either the CYP2C9 or the VKORC1 gene. Double, triple, and quadruple carriers accounted for 22%, 5%, and 1%, respectively. No significant departure from HWE was found. Among patients with a given CYP2C9 genotype, warfarin dose requirements declined from GG to AA haplotypes; whereas, within each VKORC1 haplotype, the dose decreased as the number of CYP2C9 variants increased. The presence of these loss-of-function alleles was associated with more out-of-range INR measurements (OR = 1.38) but not with significant INR >4 during the initiation phase. Analyses based on a published pharmacogenetic algorithm predicted dose reductions of up to 4.9 mg/day in carriers and provided better dose prediction in an extreme subgroup of highly sensitive patients, but also suggested the need to improve predictability by developing a customized model for use in Puerto Rican patients. CONCLUSIONS: This study laid important groundwork for supporting a prospective pharmacogenetic trial in Puerto Ricans to detect the benefits of incorporating relevant genomic information into a customized DNA-guided warfarin dosing algorithm.
Assuntos
Hidrocarboneto de Aril Hidroxilases/genética , Oxigenases de Função Mista/genética , Varfarina/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticoagulantes/administração & dosagem , Citocromo P-450 CYP2C9 , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Porto Rico/etnologia , Vitamina K Epóxido RedutasesRESUMO
Polymorphisms in the cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase complex subunit 1 (VKORC1) genes significantly alter the effective warfarin dose. We determined the frequencies of alleles, single carriers, and double carriers of single nucleotide polymorphisms (SNPs) in the CYP2C9 and VKORC1 genes in a Puerto Rican cohort and gauged the impact of these polymorphisms on warfarin dosage using a published algorithm. A total of 92 DNA samples were genotyped using Luminex x-MAP technology. The polymorphism frequencies were 6.52%, 5.43% and 28.8% for CYP2C9 *2, *3 and VKORC1-1639 C>A polymorphisms, respectively. The prevalence of combinatorial genotypes was 16% for carriers of both the CYP2C9 and VKORC1 polymorphisms, 9% for carriers of CYP2C9 polymorphisms, 35% for carriers of the VKORC1 polymorphism, and the remaining 40% were non-carriers for either gene. Based on a published warfarin dosing algorithm, single, double and triple carriers of functionally deficient polymorphisms predict reductions of 1.0-1.6, 2.0-2.9, and 2.9-3.7 mg/day, respectively, in warfarin dose. Overall, 60% of the population carried at least a single polymorphism predicting deficient warfarin metabolism or responsiveness and 13% were double carriers with polymorphisms in both genes studied. Combinatorial genotyping of CYP2C9 and VKORC1 can allow for individualized dosing of warfarin among patients with gene polymorphisms, potentially reducing the risk of stroke or bleeding.
Assuntos
Hidrocarboneto de Aril Hidroxilases/genética , Metagenômica , Oxigenases de Função Mista/genética , Anticoagulantes/administração & dosagem , Anticoagulantes/metabolismo , Citocromo P-450 CYP2C9 , Genótipo , Humanos , Polimorfismo de Nucleotídeo Único , Prevalência , Porto Rico , Estudos Soroepidemiológicos , Vitamina K Epóxido Redutases , Varfarina/administração & dosagem , Varfarina/metabolismoRESUMO
Warfarin continues to be the mainstay therapy for preventing thrombus formation. Although pharmacogenetic algorithms have shown higher predictability of the optimal warfarin dose and lower occurrence of bleeding episodes, they often do not include ethno-specific genetic variants relevant to non-Europeans. This case report describes a rare missense variant at exon 9 of CYP2C9 (rs202201137; c.1370A>G transition; p.Asn457Ser) found in a Puerto Rican patient with low warfarin dose requirements (3 mg/day). The haplotype characterized by two amino acid changes, Asn457Ser and Arg144Cys (rs1799853; c.430C>T), has been designated CYP2C9*61 by the Pharmacogene Variation Consortium. According to prediction scores assessed with the Combined Annotation Dependent Depletion tool, CYP2C9*61 (p.Asn457Ser) was classified as nondeleterious, therefore its impact on CYP2C9 enzymatic activity cannot be postulated.
Assuntos
Anticoagulantes/administração & dosagem , Citocromo P-450 CYP2C9/genética , Hispânico ou Latino/genética , Mutação de Sentido Incorreto/genética , Varfarina/administração & dosagem , Idoso , Genótipo , Humanos , Masculino , Farmacogenética/métodosRESUMO
PURPOSE: To describe and compare ocular findings in patients with Hermansky-Pudlak syndrome (HPS) type 1 and 3. METHODS: This is a retrospective case series of 64 patients with HPS from 1999 to 2009 evaluated at an outpatient private ophthalmologic clinic. Patients underwent genetic analysis of selected albinism (Tyrosine and P gene) and HPS genes (HPS-1 and HPS-3) by screening for common mutations and exon sequencing with DNA screening. Descriptive and non-parametric statistical analyses were carried out. RESULTS: Nearly 70% of the patients were homozygous for common Puerto Rican mutations leading to the HPS1 gene (16-BP DUP, 53.6%), while 30% had the 3904-BP DEL HPS3 gene mutation. Best corrected visual acuity (BCVA) was poorer in patients with type 1 HPS than in patients with type 3 HPS (p < 0.001), esotropia was more common among type 1 HPS patients (p < 0.018), while exotropia was more common among patients with type 3 HPS. Total iris transillumination was more common in patients with type 1 HPS and minimal iris transillumination in patients with type 3 HPS (p < 0.001). The maculae were translucent in patients with type 1 HPS, while patients with type 3 HPS had opaque maculae (p < 0.001). CONCLUSIONS: Patients with type 1 HPS had poorer BCVA, increased incidence of esotropia, lighter iris and macular appearance. In contrast, patients with type 3 HPS had more exotropia. In addition, to our knowledge this is the largest series type 3 HPS ever reported.
Assuntos
Síndrome de Hermanski-Pudlak/diagnóstico , Doenças da Íris/diagnóstico , Doenças Retinianas/diagnóstico , Estrabismo/diagnóstico , Transtornos da Visão/diagnóstico , Adolescente , Adulto , Idoso , Proteínas de Transporte/genética , Criança , Análise Mutacional de DNA , Éxons , Cor de Olho , Feminino , Síndrome de Hermanski-Pudlak/genética , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Doenças da Íris/genética , Masculino , Proteínas de Membrana/genética , Proteínas de Membrana Transportadoras/genética , Pessoa de Meia-Idade , Mutação , Reação em Cadeia da Polimerase , Doenças Retinianas/genética , Estudos Retrospectivos , Estrabismo/genética , Tirosina/genética , Transtornos da Visão/genética , Acuidade Visual , Adulto JovemRESUMO
AIM: This study was aimed at developing a pharmacogenetic-driven warfarin-dosing algorithm in 163 admixed Puerto Rican patients on stable warfarin therapy. PATIENTS & METHODS: A multiple linear-regression analysis was performed using log-transformed effective warfarin dose as the dependent variable, and combining CYP2C9 and VKORC1 genotyping with other relevant nongenetic clinical and demographic factors as independent predictors. RESULTS: The model explained more than two-thirds of the observed variance in the warfarin dose among Puerto Ricans, and also produced significantly better 'ideal dose' estimates than two pharmacogenetic models and clinical algorithms published previously, with the greatest benefit seen in patients ultimately requiring <7 mg/day. We also assessed the clinical validity of the model using an independent validation cohort of 55 Puerto Rican patients from Hartford, CT, USA (R(2) = 51%). CONCLUSION: Our findings provide the basis for planning prospective pharmacogenetic studies to demonstrate the clinical utility of genotyping warfarin-treated Puerto Rican patients.
Assuntos
Hidrocarboneto de Aril Hidroxilases/genética , Relação Dose-Resposta a Droga , Oxigenases de Função Mista/genética , Varfarina/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Algoritmos , Anticoagulantes/administração & dosagem , Citocromo P-450 CYP2C9 , Feminino , Hispânico ou Latino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Análise de Regressão , Vitamina K Epóxido RedutasesRESUMO
BACKGROUNDS: Admixture is of great relevance to the clinical application of pharmacogenetics and personalized medicine, but unfortunately these studies have been scarce in Puerto Ricans. Besides, allele frequencies for clinically relevant genetic markers in warfarin response (i.e., CYP2C9 and VKORC1) have not yet been fully characterized in this population. Accordingly, this study is aimed at investigating whether a correlation between overall genetic similarity and CYP2C9 and/or VKORC1 genotypes could be established. METHODS: 98 DNA samples from Puerto Ricans were genotyped for major CYP2C9 and VKORC1 polymorphisms and tested on a physiogenomic (PG)-array to infer population structure and admixture pattern. RESULTS: Analysis affirmed that Puerto Ricans are broadly admixed. A genetic distance dendrogram was constructed by clustering those subjects with similar genetic profiles. Individual VKORC1 and CYP2C9 genotypes were visually overlaid atop the three dendrogram sectors. Sector-1, representing Amerindian ancestry, showed higher VKORC1 -1639G>A variant frequency than the rest of the population (p=0.051). Although CYP2C9*3 allele frequencies matched the expected HapMap values, admixture may explain deviations from published findings regarding VKORC1 -1639G>A and CYP2C9*2 allele frequencies in sector-3. CONCLUSIONS: Results suggest that the observed inter-individual variations in ancestral contributions have significant implications for the way each Puerto Rican responds to warfarin therapy. Our findings provide valuable evidence on the importance of controlling for admixture in pharmacogenetic studies of Puerto Rican Hispanics.