Integrated analysis of genetic variation and gene expression reveals novel variant for increased warfarin dose requirement in African Americans (original) (raw)
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Clinical Pharmacology and Therapeutics, 2011
it is well recognized that the genetic variants VKORC1-1639, CYP2C9*2, and CYP2C9*3 contribute to warfarin dose response. This has led to warfarin dosing algorithms that include these polymorphisms and explains between 47% and 56% of variability in dose in Caucasians. however, these polymorphisms explain significantly less of the variance in dose among African Americans. In order to identify novel variations that affect warfarin dose in African Americans, we used a targeted resequencing strategy that examined evolutionarily conserved sequences and regions of putative transcriptional binding. Through ethnicity-specific warfarin dose model building in 330 African Americans, we identified two novel genetic associations with higher warfarin dose, namely, VKORC1-8191 (rs61162043, P = 0.0041) and 18786 in CYP2C9 (rs7089580, P = 0.035). These novel finds are independent of the previous associations with these genes. Our regression model, encompassing both genetic and clinical variables, explained 40% of the variability in warfarin dose in African-American subjects, significantly more than any model thus far. Warfarin, which is used to prevent thrombotic disorders, 1 is available as a racemic mixture, with the majority of the pharmacologic effect attributed to the S-isomer. 2,3 Given the role of cytochrome P-450 2C9 (CYP2C9) in the hydroxylation of (S)-warfarin, 4,5 the function of this enzyme is crucial to the therapeutic response and adverse-effect profile of this drug. Warfarin produces its therapeutic effect through the inhibition of vitamin K epoxide reductase (encoded by the gene VKORC1), which results in decreased production of the reduced form of vitamin K, an essential cofactor in vitamin K-dependent clotting factor activation. The variations in warfarin dose have been attributed to several factors such as age, 6,7 diet, 8-10 and concomitant medications 11,12 as well as to genetic factors. 13 Single-nucleotide polymorphisms (SNPs) in both CYP2C9 and VKORC1 have reproducibly been found to affect warfarin dose, leading to the development of pharmacogenetically guided warfarin dosing algorithms. 14,15 The warfarin drug label was recently revised to reflect these
Pharmacogenomics, 2011
Aim: Warfarin is a widely used therapeutic agent for long-term oral anticoagulation worldwide. Its administration is challenging owing to its narrow therapeutic range and serious adverse effects. Several environmental factors and numerous genes, of which CYP2C9 and VKORC1 are the most important, have been associated with interindividual dosage variability. Many studies have been conducted to understand warfarin dosage variability better, the majority of which have been focused on the Caucasian and African–American populations. Very little information is available regarding genetic influences of warfarin dosage variability in the South African black population. Materials & methods: In this study, we genotyped 213 South African black individuals for CYP2C9 and VKORC1 variants and a small subset of environmental factors that may be responsible for warfarin dosage variability. Results: We observed 26 novel SNPs and seven previously described CYP2C9 variants and three previously describe...
Pacific Symposium on Biocomputing. Pacific Symposium on Biocomputing, 2016
The blood thinner warfarin has a narrow therapeutic range and high inter- and intra-patient variability in therapeutic doses. Several studies have shown that pharmacogenomic variants help predict stable warfarin dosing. However, retrospective and randomized controlled trials that employ dosing algorithms incorporating pharmacogenomic variants under perform in African Americans. This study sought to determine if: 1) including additional variants associated with warfarin dose in African Americans, 2) predicting within single ancestry groups rather than a combined population, or 3) using percentage African ancestry rather than observed race, would improve warfarin dosing algorithms in African Americans. Using BioVU, the Vanderbilt University Medical Center biobank linked to electronic medical records, we compared 25 modeling strategies to existing algorithms using a cohort of 2,181 warfarin users (1,928 whites, 253 blacks). We found that approaches incorporating additional variants inc...
Clinical and Applied Thrombosis-hemostasis, 2010
Warfarin is the most prescribed oral anticoagulant worldwide. Because of the complexity of warfarin therapy, we attempted to dissect genetic from bioenvironmental factors influencing warfarin dose responses in individuals of a genetic isolate of Hispanic ancestry. A total of 191 patients with standard values of international normalized ratio were recruited. Three groups with a significantly different warfarin dose response were identified, that is, sensitive (2.28 + 0.50 mg/d), intermediate (4.2 + 0.76 mg/d), and resistant (7.40 + 1.54 mg/d; Tukey test, P < .001). Age had a significant inverse correlation with warfarin dose (P < .001; effective dose diminished 0.56 mg/d/decade). Required doses were higher for individuals with CYP2C9 variants containing the allele *1 compared to those individuals with variants composed of other alleles (P ¼ .006). Similarly, individuals with VKORC1-1639GG and VKORC1-1639GA genotypes also required higher doses compared to the AA genotype (P < .001). Evaluation of potential gene-gene interactions between CYP2C9 and VKORC1 polymorphisms showed significant differences in dosing for CYP2C9 genotypes within the VKORC1-1639G/A subgroup (P ¼ .013). A stepwise multivariate linear regression analysis showed that 38.2% of the warfarin dose response variance was accounted for by a model involving age (20.9%), VKORC1-1639G/A (11.3%), and CYP2C9*1, *2, and *3 variants (7.1%). These results corroborate previous findings on warfarin pharmacogenetics and define a contrastable gene-bioenvironment interaction model suited to be used in Hispanic populations.
Genetic and clinical predictors of warfarin dose requirements in African Americans
Clinical pharmacology and therapeutics, 2010
The objective of this study was to determine whether, in African-American patients, additional vitamin K oxidoreductase complex subunit 1 (VKORC1), cytochrome P450 2C9 (CYP2C9), CYP4F2, or apolipoprotein E (APOE) polymorphisms contribute to variability in the warfarin maintenance dose beyond what is attributable to the CYP2C9*2 and *3 alleles and the VKORC1 -1639G>A genotype. In a cohort of 226 African-American patients, weekly warfarin dose requirements were lower in those with the CYP2C9*8 allele (34 (30-47) mg; P = 0.023) and the CYP2C9 *2, *3, *5, *6, or *11 allele (33(28-40 mg); P < 0.001) as compared with those with the CYP2C9*1/*1 genotype (43 (35-56) mg). The combination of CYP2C9 alleles, VKORC1 -1639G>A genotype, and clinical variables explained 36% of the interpatient variability in warfarin dose requirements. By comparison, a model without the CYP2C9*5, *6, *8, and *11 alleles explained 30% of the variability in dose. No other VKORC1, CYP4F2, or APOE polymorphis...
Pharmacogenomics, 2008
Background: Although the influence of VKORC1 and CYP2C9 polymorphisms on warfarin response has been studied, variability in dose explained by CYP2C9 and VKORC1 is lower among African–Americans compared with European–Americans. This has lead investigators to hypothesize that assessment of VKORC1 haplotypes may help capture a greater proportion of the variability in dose for this under-represented group. However, the inadequate representation of African–Americans and the assessment of a few VKORC1 polymorphisms have hindered this effort. Methods: To determine if VKORC1 haplotypes or haplotype groups explain a higher variability in warfarin dose, we comprehensively assessed VKORC1 polymorphisms in 273 African–Americans and 302 European–Americans. The influence of VKORC1 polymorphisms, race-specific haplotypes and haplotype groups on warfarin dose was evaluated in race-stratified multivariable analyses after accounting for CYP2C9 (*2, *3, *5, *6 and *11) and clinical covariates. Results...
Clinical Pharmacology and Therapeutics, 2010
Background-Warfarin demonstrates wide interindividual variability that is partly mediated by variants in CYP2C9 and VKORC1. Whether variants in CALU (vitamin K reductase regulator) influence warfarin dose is unknown. Methods and Results-We resequenced CALU regions in a discovery cohort of dose-outliers: patients with high(>90th percentile, n=55) or low(<10th percentile, n=53) dose requirements(after accounting for known genetic and nongenetic variables). One CALU variant, rs339097, was associated with high-doses(p=0.01). We validated this variant as a predictor of higher warfarin doses in two replication cohorts: 1)496 patients of mixed ethnicity, 2)194 African-American patients. The G allele of rs339097(African-American and Caucasian allele frequency 0.14 and 0.002, respectively), was associated with a 14.5%(SD±7%) greater therapeutic dose(p=0.03) in the first replication cohort and a higher than predicted dose in the second replication cohort(allele frequency=0.14, one-sided p=0.03). Conclusions-CALU rs339097 A>G is associated with higher warfarin dose requirements independent of known genetic and nongenetic predictors of warfarin dose in African-Americans.
Ethnicity-specific pharmacogenetics: the case of warfarin in African Americans
The Pharmacogenomics Journal, 2013
Using a derivation cohort (N=349), we developed the first warfarin dosing algorithm that includes recently discovered polymorphisms in VKORC1 and CYP2C9 associated with warfarin dose requirement in African Americans (AAs). We tested our novel algorithm in an independent cohort of 129 AAs and compared the dose prediction to the International Warfarin Pharmacogenetics Consortium (IWPC) dosing algorithms.
Annals of Pharmacotherapy, 2012
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. Keywords CYP2C9; genotyping; pharmacogenomics; VKORC1; warfarin Warfarin is considered to be the standard-of-care therapy for many thromboembolic disorders. 1,2 In 2010, there were more than 32 million warfarin prescriptions in the US. 3 Warfarin is frequently associated with unpredictable pharmacologic responses, ranging from occult bleeding to hemorrhage, due in part to its narrow therapeutic index. 4 Therefore, its action is closely monitored by means of frequent blood testing for the international normalized ratio (INR) determination, and dosage adjustments are often necessary. 2,5,6 The difference in successful outcomes during warfarin therapy is a multifactorial issue. 7-9 Apart from the clinical and environmental variables, the individual's unique genetic makeup plays a fundamental role in the warfarin response. 10,11 In January 2010, the Food and Drug Administration revised the warfarin label to include dosing recommendations based on genetic polymorphisms in genome-wide association studies and identified CYP2C9 and vitamin K epoxide reductase subunit C1 (VKORC1) as candidate genes. b CYP2C9 encodes the cytochrome P450, subfamily IIC, polypeptide 9, an enzyme responsible for metabolizing
Annals of Pharmacotherapy, 2012
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. Keywords CYP2C9; genotyping; pharmacogenomics; VKORC1; warfarin Warfarin is considered to be the standard-of-care therapy for many thromboembolic disorders. 1,2 In 2010, there were more than 32 million warfarin prescriptions in the US. 3 Warfarin is frequently associated with unpredictable pharmacologic responses, ranging from occult bleeding to hemorrhage, due in part to its narrow therapeutic index. 4 Therefore, its action is closely monitored by means of frequent blood testing for the international normalized ratio (INR) determination, and dosage adjustments are often necessary. 2,5,6 The difference in successful outcomes during warfarin therapy is a multifactorial issue. 7-9 Apart from the clinical and environmental variables, the individual's unique genetic makeup plays a fundamental role in the warfarin response. 10,11 In January 2010, the Food and Drug Administration revised the warfarin label to include dosing recommendations based on genetic polymorphisms in genome-wide association studies and identified CYP2C9 and vitamin K epoxide reductase subunit C1 (VKORC1) as candidate genes. b CYP2C9 encodes the cytochrome P450, subfamily IIC, polypeptide 9, an enzyme responsible for metabolizing