Warfarin Dose Requirements Research Articles

Frequency of Common CYP2C9 Polymorphisms and Their Impact on Warfarin Dose Requirement in Pakistani Population.

Polymorphisms in cytochrome P450 (CYP) 2C9 (CYP2C9) gene result in interindividual variability in warfarin dose requirement. There is a need for characterization of genotype frequency distribution in different populations for construction of customized dosing algorithms to enhance the efficacy and reduce the toxicity of warfarin therapy. This study was carried out in Pakistani population to evaluate the contribution of common CYP2C9 polymorphisms to warfarin therapy. A total of 550 stable patients taking warfarin were enrolled after medical history, physical examination, and laboratory investigations. Single blood sample was collected after informed consent. Genomic DNA was extracted, and genotype analysis for CYP2C9*2 and CYP2C9*3 polymorphisms was done by polymerase chain reaction-restriction fragment length polymorphism assay. A number of samples were also analyzed by direct DNA sequencing for validation of the results. Data were analyzed using SPSS version 20. Genotype frequency distribution of CYP2C9*2 and CYP2C9*3 was found to be different from other populations. Of these 2 polymorphisms, CYP2C9*2 did not demonstrate significant effect on warfarin dose requirement, whereas CYP2C9*3 did show significant effect ( P value = .012). It is concluded that there is a need to study genotype frequency distribution and their effect on warfarin dose variability among different populations due to diversity in outcome.

Effect of VKORC1, CYP2C9, CFP4F2, and GGCX Gene Polymorphisms on Warfarin Dose in Japanese Pediatric Patients.

Warfarin dosage requirements show considerable inter-individual variability. There are some reports of warfarin dose regimens correlating with single nucleotide polymorphisms (SNP) for CYP2C9, VKORC1 and other genes in adults. In children, however, reports are scarcer than in adults and the number of genes examined is more limited. We explored the effects of genetic variation on warfarin dose requirement in Japanese pediatric patients. A total of 45 patients who were prescribed warfarin at the Yokohama City University Hospital were included in this study. The influence of genetic polymorphisms on stable warfarin dosage requirement was investigated by genotyping SNPs of the VKORC1, CYP2C9, CYP4F2, and GGCX genes (rs9923231, rs1057910, rs2108622, and rs699664, respectively) in each patient. Patients with the TT genotype in rs9923231 in VKORC1 required significantly lower maintenance dosages than those with the TC genotype (p=0.001). Multiple regression analysis showed that, while VKORC1 status and patient height account for 78.2% of the variability in maintenance warfarin dosage, genetic polymorphisms in VKORC1 account for 27%, although polymorphisms in CYP4F2 and GGCX had no effect on dosage and the effect of CYP2C9 could not be evaluated. Polymorphisms in VKORC1 partially affected daily warfarin dosage requirements. VKORC1 genotype and height are the primary determinants influencing warfarin dosage in Japanese pediatric patients. Further studies with larger sample sizes are needed to confirm our results.

Effect of Left Ventricular Systolic Dysfunction on Response to Warfarin

Candidates for chronic warfarin therapy often have co-morbid conditions, such as heart failure, with reduced left ventricular ejection fraction. Previous reports have demonstrated an increased risk of over-anticoagulation due to reduced warfarin dose requirement in patients with decompensated heart failure. However, the influence of left ventricular systolic dysfunction (LVSD), defined as left ventricular ejection fraction <40%, on warfarin response has not been evaluated. Here, we assess the influence of LVSD on warfarin dose, anticoagulation control (percent time in target range), and risk of over-anticoagulation (international normalized ratio >4) and major hemorrhage. Of the 1,354 patients included in this prospective cohort study, 214 patients (16%) had LVSD. Patients with LVSD required 11% lower warfarin dose compared with those without LVSD (p <0.001) using multivariate linear regression analyses. Using multivariate Cox proportional hazards model, patients with LVSD experienced similar levels of anticoagulation control (percent time in target range: 51% vs 53% p= 0.15), risk of over-anticoagulation (international normalized ratio >4; hazard ratio 1.01, 95% confidence interval 0.82 to 1.25; p= 0.91), and risk of major hemorrhage (hazard ratio 1.11; 95% confidence interval 0.70 to 1.74; p= 0.66). Addition of LVSD variable in the model increased the variability explained from 35% to 36% for warfarin dose prediction. In conclusion, our results demonstrate that patients with LVSD require lower doses of warfarin. Whether warfarin dosing algorithms incorporating LVSD in determining initial doses improves outcomes needs to be evaluated.

Clinical application of a new warfarin-dosing regimen based on the CYP2C9 and VKORC1 genotypes in atrial fibrillation patients.

The polymorphisms of cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase complex 1 (VKORC1) are important genetic factors for warfarin dose determinations. The present study aimed to investigate the contribution of the CYP2C9 and VKORC1 genotypes to warfarin dose requirement in atrial fibrillation (AF) patients, and to evaluate the clinical application of a warfarin-dosing algorithm. A total of 122 AF patients with a target international normalized ratio of 2.0 to 3.0 were included to determine the genotypes of CYP2C9 (rs1057910) and VKORC1 (rs9923231). A warfarin-dosing algorithm was developed based on age, height, and the CYP2C9 and VKORC1 genotypes of AF patients. The results indicated that the mean warfarin daily dose requirement was lower in the CYP2C9*1/*3 genotype compared with those in the homozygous wild-type CYP2C9*1/*1 patients (P<0.05), and was higher in patients with the VKORC1 AG and GG genotypes compared with those with the AA genotype (P<0.05). The multivariate regression model showed that age, height, and the CYP2C9 and VKORC1 genotypes were the best variables for estimating warfarin dose (R2=56.4%). A new warfarin-dosing algorithm was developed and its validity was confirmed in a second cohort of AF patients. During the 50-day follow-up, 63.3% (19/30) of control group patients and 86.7% (26/30) of patients in the experimental group acquired the warfarin maintenance dose. Among all the patients who acquired the warfarin maintenance dose, the mean time elapse from initiation until warfarin maintenance dose was significantly less in the experimental group (25.8±1.7 day) compared to the control group (33.1±1.9 day) (P<0.05). There was significant linear correlation between predicted warfarin maintenance dose and actual dose (r=0.822, P<0.01). In conclusion, a new warfarin-dosing algorithm was developed based on the CYP2C9 and VKORC1 genotypes, and it can shorten the time elapse from initiation until warfarin maintenance dose in AF patients with warfarin therapy.

Association of apolipoprotein E (APOE) polymorphisms with warfarin maintenance dose in a northern Han Chinese population.

BackgroundApolipoprotein E (apoE) induces the uptake of vitamin K-rich lipoproteins by the liver, which likely affects inter-individual variation of warfarin dosing requirements. Associations between APOE polymorphisms and warfarin dosing were previously reported inconsistently among different ethnic groups, so the present study investigated this association in northern Han Chinese patients with mechanical heart valve prosthesis.MethodsA total of 186 patients who underwent mechanical heart valve replacement and attained a stable warfarin dose were included. APOE single nucleotide polymorphisms (SNPs) rs7412 and rs429358 were genotyped using Illumina SNP GoldenGate Assay. Genotyping results were confirmed by direct sequencing. PHASE v2.1 software was used to construct rs7412 and rs429358 haplotypes. The effects of different APOE genotypes on warfarin dose were analyzed statistically.ResultsThe mean warfarin maintenance dose was 3.10 ± 0.96 mg/day, and the mean international normalized ratio (INR) was 2.09 ± 0.24. APOE E2, E3, and E4 allele frequencies were 11.6 %, 82.5 %, and 5.9 %, respectively. No E2/E2 or E4/E4 genotypes were detected in this population. E2/E3, E3/E3, E2/E4, and E3/E4 genotype frequencies were 21.0 %, 67.2 %, 2.2 %, and 9.7 %, respectively. Significant differences in warfarin dose requirements were observed among patients with E2/E3, E3/E3, and E3/E4 genotypes (p < 0.05). In post hoc comparison, daily warfarin maintenance doses were significantly higher in E2/E3 heterozygotes compared with E3/E3 homozygotes (p < 0.05), but no differences in dose requirements were found between E3/E4 and E3/E3, or E2/E3 and E3/E4 (p > 0.05). Patients were divided into low-intensity anticoagulant treatment group (1.6 ≤ INR <2.0) and relatively high-intensity anticoagulant treatment group (2.0 ≤ INR ≤2.5), and significantly higher warfarin dose requirements were observed in E2/E3 heterozygotes compared with E3/E3 homozygotes in both subgroups (p < 0.05). Multivariable analysis adjusting for other confounders showed that E2/E3 genotype was associated with a significantly higher warfarin dose compared with E3/E3 genotype (p < 0.05).ConclusionsAPOE allele and genotype frequencies in the northern Han Chinese population appear to differ from other racial groups or populations living in other regions of China. The APOE E2 variant was associated with a significantly higher warfarin maintenance dose. Thus, APOE polymorphisms could be one of the predictors influencing warfarin doses in this population.

Impact of the CYP4F2 gene polymorphisms on the warfarin maintenance dose: A systematic review and meta-analysis.

Warfarin is an oral anticoagulant with significant interpatient variability in dosage. A large number of studies have confirmed that the individual warfarin dose is mainly affected by the cytochrome P450 complex subunit 2C9 and vitamin K epoxide reductase complex subunit 1. However, the association between cytochrome P450 4F2 (CYP4F2) gene polymorphisms and warfarin dosage in the Asian population remains controversial. To investigate the impact of the CYP4F2 polymorphism rs2108622 (p.V433M) on warfarin dose requirement, a systematic review and meta-analysis were conducted. According to the strict inclusion and exclusion criteria set, a comprehensive literature search was performed, and the studies published before August 5, 2015 were searched for in PubMed, EMBASE and the China National Knowledge Infrastructure databases. The references were checked by two independent reviewers. The association between the warfarin maintenance dose and CYP4F2 polymorphism was analyzed. Twenty-two studies were included in the meta-analysis. Compared with the CYP4F2 genotype CC, carriers of the CT and TT genotypes required a 9 [95% confidence interval (CI): 6.0-13.0] and 20% (95% CI, 13.0-27.0) higher warfarin dose, respectively. In the combined analysis, T carriers (CT+TT) required an 11% (95% CI, 8.0-14.0) higher warfarin dose compared to the CC genotype. In addition, there was a 10% (95% CI, 5.0-15.0) higher warfarin dose in TT carriers compared to the CT genotype (all P<0.05). The results of the meta-analysis suggest that the effects of the CYP4F2 polymorphism on individual warfarin dose have a statistically significant difference, and the effect degree is variable in the subgroups. Further studies are expected to explore whether the pharmacogenetics model including the CYP4F2 polymorphism can strengthen the prediction of warfarin dose.

Novel regulatory variant detected on the VKORC1 haplotype that is associated with warfarin dose.

Warfarin dose requirement is associated with VKORC1 rs9923231, and we studied whether it is a functional variant. We selected variants in linkage disequilibrium with rs9923231 that bind transcription factors in an allele-specific way. Representative haplotypes were cloned or constructed, nuclear protein binding and transcriptional activity were evaluated. rs56314408C>T and rs2032915C>T were detected in a liver enhancer in linkage disequilibrium with rs9923231. The rs56314408-rs2032915 C-C haplotype preferentially bound nuclear proteins and had higher transcriptional activity than T-T and the African-specific T-C. A motif for TFAP2A/C was disrupted by rs56314408T. No difference in transcriptional activity was detected for rs9923231G>A. Our results supported an activating role for rs56314408C, while rs9923231G>A had no evidence of being functional.

Impact of GGCX, STX1B and FPGS Polymorphisms on Warfarin Dose Requirements in European-Americans and Egyptians.

Genotype‐based algorithms that include VKORC1 and CYP2C9 genotypes are less predictive of warfarin dose variability in Africans as opposed to Europeans. Polymorphisms in GGCX, FPGS, or STX1B are associated with warfarin dose requirements in African‐Americans. We sought to determine if they influenced warfarin dose in European‐Americans, and another African population, specifically Egyptians. We genotyped 529 adults (n = 325 European‐Americans, 204 Egyptians) on a stable warfarin dose for GGCX rs12714145 and rs10654848, FPGS rs7856096, and STX1B rs4889606. Rs12714145, rs10654848, and rs7856096 were not associated with warfarin dose, whereas STX1B rs4889606 was a significant determinant in univariate analysis (P < 0.0001) in both cohorts. However, STX1B rs4889606 was in high linkage disequilibrium with VKORC1‐1639 G>A, and was no longer significant after including VKORC1‐1639 G>A in the regression model. Based on these data, the polymorphisms do not appear to influence, in a clinically important way, warfarin dose requirements in European‐Americans and Egyptians.

The effect of CYP2C9 and VKORC1 genetic polymorphisms on warfarin dose requirements in a pediatric population

The effect of CYP2C9 and VKORC1 genetic polymorphisms on warfarin dose requirements in a pediatric population

Warfarin dose requirement and cytochrome P450 2C9 and Vitamin K epoxide reductase complex subunit 1-1639 genetic polymorphisms in Thai patients

Aims: The purposes of this study were to investigate the influence of genetic polymorphisms of cytochrome P450 2C9 (CYP2C9)*3 and Vitamin K epoxide reductase complex subunit 1-1639 (VKORC1-1639) G >A and patient's characteristics on warfarin dose requirement and to establish an equation for predicting the warfarin maintenance dose in Thai patients. Settings and Design: This is an observational, retrospective study in outpatients. Ninety-one outpatients receiving warfarin at Phaholpolpayuhasena Hospital, Kanchanaburi, were recruited to this study. Subjects and Methods: Whole blood, dose, and demographic data were collected. Blood samples were analyzed for the genetic polymorphism by restriction fragment length polymorphism technique. Statistical Analysis Used: Differences in baseline characteristics among genotypes were evaluated by analysis of variance or Kruskal-Wallis and the Mann-Whitney U-test or Chi-square test for parametric and nonparametric variables, respectively. Association between genetic factors and warfarin dose was based on Eta test, whereas associations between warfarin dose and polymorphisms were evaluated using Pearson correlation test. Stepwise regression was used to identify factors contributing to warfarin dose requirement followed by linear regression model to develop a warfarin dosing algorithm. Results: CYP2C9*1*1 (wild type) genotype was found in 90 patients (98.90%), and CYP2C9*1*3 was found in only 1 patient (1.10%). No CYP2C9*3*3 genotype was observed. Polymorphisms of VKORC1-1639 GG was found in 9 patients (9.89%) while GA and AA genotype were found in 30 patients (32.97%) and in 52 patients (57.14%), respectively. Patients with VKORC1-1639 AA genotype required statistically and significantly lower, average weekly warfarin dose (19.97 ± 7.61 mg) than GG genotype (37.89 ± 12.20 mg) and GA genotype (29.48 ± 11.50 mg) with the P < 0.05. Conclusions: Using stepwise multiple linear regression, VKORC1-1639 AA, age, and weight could explain about 45.3% of the variation of warfarin maintenance dose. Multivariate analysis of the equation indicated a significant negative correlation between warfarin dose and VKORC1-1639 AA and age, but a significant positive correlation between warfarin dose and weight. This suggested that VKORC1 genotyping may be more important in warfarin dose adjustment and should be a priority for genotype measurement.

Abstract 18405: Warfarin Dose Requirements and Polymorphisms in MicroRNA and Nuclear Receptor Genes

Background and Aim: The marked inter-individual variability in warfarin dose requirement is mainly attributed to the variants of the main target genes across the warfarin pharmacological pathway, i.e. cytochrome P-450 (CYP) 2C9, CYP3A4, ABCB1, vitamin K epoxide reductase complex subunit 1 (VKORC1) and epoxide hydrolase 1 (EPHX1). The expression of these genes is primarily regulated by a complex network of nuclear receptors (NR) which are encoded, in turn, by polymorphic genes. Furthermore, microRNAs (miRNA) can reduce the expression of both warfarin target genes and the genes encoding NRs. We investigated whether the variants of genes encoding i) warfarin targets, ii) NRs involved in the regulation of the targets and iii) miRNA involved in the regulation of NRs and the targets, are associated with warfarin dose requirements. Methods and Results: The study was performed using the Quebec Warfarin Cohort consisting of 988 new warfarin users who were recruited over a period of 3 years and were followed-up for 12 months. The candidate genes were selected according to the literature and included 5 warfarin target genes, 9 NRs genes and 29 miRNA genes. SNPs with MAF&gt;0.01 within these genes were selected for the present study from the NCBI database. Genotyping was previously performed using Omni 2.5 array (Illumina, CA) and iPLEX ADME CYP2C9/VKORC1 panel (Agena, CA) and missing SNPs were imputed. We tested the effect of SNPs on the log-transformed values of dose at 3-month post-initiation using multivariate linear regression analysis, and the adjusted significance threshold was set to 2.49 x 10-4. A total of 3970 SNPs, including 702 in target genes, 3162 in NRs and 106 in miRNA genes were studied. For the association with warfarin dose, 137 SNPs in CYP2C9 and VKORC1 were significant, as well as 3 SNPs in nuclear vitamin D receptor (VDR) gene: rs4760658, β = -0,0852, P = 7,32x10-5; rs11168293, β = -0,0809, P = 1,78x10-4; rs4760655, β = -0,0799, P = 2,15x10-4. None of the variants in miRNA genes showed a significant association with warfarin dose. Conclusions: Variants in the gene encoding VDR, a nuclear receptor which has been previously shown to be involved in the regulation of CYP2C9, CYP3A4 and ABCB1, may contribute to the variability in response to warfarin.

Influence of UDP-Glucuronosyltransferase Polymorphisms on Stable Warfarin Doses in Patients with Mechanical Cardiac Valves.

This study aimed to evaluate the effect of uridine diphosphate (UDP)-glucuronosyltransferase (UGT) polymorphisms on warfarin dosing requirements in patients with mechanical cardiac valves. A total of 191 patients with stable warfarin doses from the EAST Group of Warfarin were included in this study. The influence of genetic polymorphisms on stable warfarin doses was investigated by genotyping 6 single nucleotide polymorphisms (SNPs): vitamin K epoxide reductase complex 1 (VKORC1) rs9934438, cytochrome P450 (CYP) 2C9 rs1057910, CYP4F2 rs2108622, and UGT1A1 (rs887829, rs4148323, and rs4124874). An additional subgroup analysis was carried out using patients with wild-type homozygote carriers of CYP2C9. One UGT1A1 SNP of rs887829 (C>T) exhibited significant association with stable warfarin doses in the study population and subgroup. Patients with the T allele in UGT1A1 rs887829 (CT or TT) required higher doses than those with the CC genotype in the study population (6.3 ± 2.4 mg vs. 5.2 ± 1.6 mg, P = 0.003). Similarly, in the subpopulation of AA carriers in the CYP2C9 gene, patients with the T allele required significantly higher doses of warfarin than those with other genotypes of rs887829 (6.5 ± 2.4 vs. 5.3 ± 1.5 mg, P = 0.002). Approximately 45.1% of overall interindividual variability in warfarin dose requirement was explained by the multivariate regression model. VKORC1, CYP2C9, UGT1A1 rs887829, age, and CYP4F2 accounted for 28.2%, 6.6%, 5.5%, 3.0%, and 1.8% of the variability, respectively. Our results suggest that UGT1A1 could be a determinant of stable warfarin doses.

Impact of regular physical activity on weekly warfarin dose requirement.

Warfarin is an oral anticoagulant agent with a narrow therapeutic index. There is a marked inter- and intra-patient variability in warfarin dose requirement. All factors influencing warfarin response are not known and this study aims to evaluate if regular physical activity (RPA) is a determining factor. RPA level was collected with the Stanford Brief Activity Survey in 1064 incident warfarin users, as part of the Quebec Warfarin Cohort (QWC), and with the Global Physical Activity Questionnaire in 618 patients from the Montreal Heart Institute (MHI) Biobank. Linear regression was performed to model relationship of warfarin dose after 3 months of therapy in the QWC with RPA, while controlling for height, weight, age, CYP2C9 (*2 and *3 alleles) and VKORC1 (*2 allele) genotype. Warfarin dose of prevalent users was modeled in the MHI Biobank for replication. A higher level of physical activity was associated with higher doses of warfarin in both cohorts. In the QWC, physical activity could explain 5.4 % (P < 0.001) and 0.9 % (P = 3.23 × 10−5) of variance in dose, in univariate and multivariable models, respectively. Similarly, RPA was found to be associated with 1.7 % (P = 0.0012) and 0.5 % (P = 0.0391) of inter-individual variability in warfarin dose requirement before and after adjustment for other covariables, respectively. RPA is associated with higher warfarin dose requirement. The relevance of clinical recommendations on RPA to maintain a steady response to warfarin should be assessed in further studies.Electronic supplementary materialThe online version of this article (doi:10.1007/s11239-015-1248-9) contains supplementary material, which is available to authorized users.

Improvements in CYP2C9 Genotyping Accuracy Are Needed: A Report of the First Proficiency Testing for Warfarin-related CYP2C9 and VKORC1 Genotyping in China.

Warfarin is the most commonly used oral anticoagulant in clinical practice. The cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase complex 1 (VKORC1) genotypes have been confirmed to be associated with warfarin dose requirements. Accurate genotyping results are of particular importance for obtaining reliable genotype-guided warfarin dosing information. This study aims to determine analytic performance of laboratories offering CYP2C9 and VKORC1 testing in China. A proficiency panel of 15 validated cell samples covering common CYP2C9 and VKORC1 genetic polymorphisms was provided to 31 participating laboratories, and their genotyping results were evaluated. Fourteen data sets (45.2%) performed well with the entire panel of samples, and 17 data sets (54.8%) reported at least one genotyping error. For VKORC1 (-1639G>A), participating laboratories were 100% successful in detecting genotypes of GG, GA, and AA. For CYP2C9, participants were greater than 90% successful in detecting genotypes of *1/*1, *1/*2, *1/*3, *2/*3, and *3/*3. However, 15 laboratories failed to detect rarely encountered variant genotype *2/*2. The poor performance of CYP2C9 genotyping may be because of the limitation of methodologies used for detecting CYP2C9*2 allele. The proficiency testing survey highlighted the need for improving genotyping accuracy for some laboratories in this field.

Effects of single nucleotide polymorphisms in c-Myc on stable warfarin doses in patients with cardiac valve replacements.

This study aimed to investigate an association between c-Myc SNPs and stable warfarin doses. The influences of genetic polymorphisms on dose requirements were investigated by genotyping ten SNPs in 201 patients with stable warfarin doses; VKORC1 (rs9923231), CYP2C9 (rs1057910), CYP4F2 (rs2108622), GATA4 (rs10090884), c-Myc (rs4645962, rs4645943, rs4645948 and rs4645974) and 8q24 (rs1447295 and rs16901979). Around 44.3% of the overall interindividual variability in warfarin dose requirements was explained by the multivariate regression model; VKORC1 genotype accounted for 26.4%, CYP2C9 genotype for 4.9%, age for 3.4%, c-Myc genotypes for 5.2% (rs4645974 for 2.4% and rs4645943 for 2.8%), CYP4F2 genotype for 2.9% and diuretic use for 1.5%. Our results revealed that c-Myc could be a determinant of stable warfarin doses.

Impact of CYP2C9 and VKORC1 genetic polymorphisms upon warfarin dose requirements in Egyptian patients with acute coronary syndrome.

Warfarin is the most widely prescribed anticoagulant drugs. Cytochrome P450-2C9 (CYP2C9) and vitamin K epoxide reductase-oxidaxe complex subunit 1 (VKORC1) contribute significantly to the variability of warfarin dose requirements among patients. We investigated the impact of CYP2C9 and VKORC1 polymorphisms on the variability of warfarin dosage requirements in Egyptian patients with acute coronary syndrome and their association with other nongenetic factors. Eighty participants with acute coronary syndrome were enrolled in this cross-sectional study. Associations between CYP2C9 and VKORC1 gene variants together with daily warfarin dose, demographic data, clinical status of patients and time to target international normalized ratio were assessed. Mean warfarin dose among patients with wild-type CYP2C91/1 genotype was significantly higher than heterozygous CYP2C91/2 and CYP2C91/3 variants (P ≤ 0.001). Patients with wild VKORC1 (G/G) genotype were treated with significantly higher daily warfarin dosages than homozygous (A/A) and heterozygous (G/A) genotypes. Patients carrying VKORC1 (G/G) genotype in combination with the CYP2C91/1 type alleles had the highest daily warfarin dosage, whereas the lowest daily warfarin dosage to achieve the required clinical effect was found among patients having CYP2C91/2 and CYP2C91/3 genotypes combined with VKORC1 (A/A) genotype (P ≤ 0.001). Regression analysis revealed that age, height, CYP2C9 and VKORC1 genotypes were significantly associated with warfarin dose. Genetic polymorphisms in VKORC1, CYP2C9 along with age and height are determinants of warfarin dose requirements in Egyptian population acute coronary syndrome. Higher warfarin loading dose is required for both wild CYP2C9 and VKORC1 gene variants which may contribute to warfarin-resistant cases.

Genome-wide association study of warfarin maintenance dose in a Brazilian sample.

Extreme discordant phenotype and genome-wide association (GWA) approaches were combined to explore the role of genetic variants on warfarin dose requirement in Brazilians. Patients receiving low (≤ 20 mg/week; n = 180) or high stable warfarin doses (≥ 42.5 mg/week; n = 187) were genotyped with Affymetrix Axiom(®) Biobank arrays. Imputation was carried out using data from the combined 1000 Genomes project. Genome-wide signals (p ≤ 5 × 10(-8)) were identified in the well-known VKORC1 (lead SNP, rs749671; OR: 20.4; p = 1.08 × 10(-33)) and CYP2C9 (lead SNP, rs9332238, OR: 6.8 and p = 4.4 × 10(-13)) regions. The rs9332238 polymorphism is in virtually perfect LD with CYP2C9*2 (rs1799853) and CYP2C9*3 (rs1057910). No other genome-wide significant regions were identified in the study. We confirmed the important role of VKORC1 and CYP2C9 polymorphisms in warfarin dose. Original submitted 14 January 2015; Revision submitted 26 May 2015.

Variation in genes controlling warfarin disposition and response in American Indian and Alaska Native people: CYP2C9, VKORC1, CYP4F2, CYP4F11, GGCX.

Pharmacogenetic testing is projected to improve health outcomes and reduce the cost of care by increasing therapeutic efficacy and minimizing drug toxicity. American Indian and Alaska Native (AI/AN) people historically have been excluded from pharmacogenetic research and its potential benefits, a deficiency we sought to address. The vitamin K antagonist warfarin is prescribed for prevention of thromboembolic events, although its narrow therapeutic index and wide interindividual variability necessitate close monitoring of drug response. Therefore, we were interested in variation in CYP2C9, VKORC1, CYP4F2, CYP4F11, and GGCX, which encode enzymes important for the activity of warfarin and synthesis of vitamin K-dependent blood clotting factors. We resequenced these genes in 188 AI/AN people in partnership with Southcentral Foundation in Anchorage, Alaska and 94 Yup'ik people living in the Yukon-Kuskokwim Delta of southwest Alaska to identify known or novel function-disrupting variation. We conducted genotyping for specific single nucleotide polymorphisms in larger cohorts of each study population (380 and 350, respectively). We identified high frequencies of the lower-warfarin dose VKORC1 haplotype (-1639G>A and 1173C>T) and the higher-warfarin dose CYP4F2*3 variant. We also identified two relatively common, novel, and potentially function-disrupting variants in CYP2C9 (M1L and N218I), which, along with CYP2C9*3, CYP2C9*2, and CYP2C9*29, predict that a significant proportion of AI/AN people will have decreased CYP2C9 activity. Overall, we predict a lower average warfarin dose requirement in AI/AN populations in Alaska than that seen in non-AI/AN populations of the USA, a finding consistent with clinical experience in Alaska.

Variation in warfarin prescribing and dosing in the UK: a national survey of anticoagulation clinics

Clinical practice in the initiation, prescribing, dosing and monitoring of warfarin in the UK varies, but this has not been adequately documented. The objective was to undertake a survey on current clinical practice in this area, and how it compares with national guidelines that have been developed by the British Committee for Standards in Haematology. A national online survey of anticoagulation clinics was performed using Survey Monkey(®) . The survey was designed to capture data for prescribing, dosing and monitoring of anticoagulation with warfarin. Of 85 clinics who responded to the survey, most were run by secondary care (68%), facilitated by specialist nurses (58%) and followed standard guidelines for the management of warfarin (87%). The majority of clinics indicated their target international normalized ratio (INR) for patients with atrial fibrillation (AF) (69/73; 94·5%) was between 2·0 and 3·0, but the indicated target INR for mechanical heart valves was more variable. Initiation and loading dosing regimens were a major source of variability with uncertainty surrounding individual patient factors such as age, ethnicity and BMI. Current practice amongst UK anticoagulation clinics largely follows current national guidelines but better guidance on dosing, taking into account factors that determine interindividual variability in daily warfarin dose requirements would improve and standardize oral anticoagulation with warfarin.

Pharmacogenomics in cardiology--genetics and drug response: 10 years of progress.

10.2217/FCA.15.20 © 2015 Future Medicine Ltd History of pharmacogenomics in cardiology: where have we been? Following completion of the Human Genome Project in 2003, Dr Francis Collins and others on behalf of the National Human Genome Research Institute announced their vision for the future of genomics research [1]. A number of grand challenges were identified, and among these were developing strategies to identify genetic contributions to drug response, creating genome-based approaches to predict drug response, and applying discoveries to promote the use of genomic information into clinical practice. The NIH has invested significant resources in addressing these challenges, including funding the International HapMap and 1000 Genomes Projects, which have enabled genome-wide association studies (GWAS) of drug response. Through GWAS, investigators have identified genetic contributors to statininduced myopathy, clopidogrel effectiveness and warfarin dose requirements. While most GWAS of drug response have been conducted in European populations, a recent GWAS in African–Americans revealed a novel association between the rs12777823 polymorphism and warfarin dose requirements in this population, demonstrating the importance of conducting pharmacogenomic studies in different ethnic groups [2]. Other NIH-funded initiatives include the Pharmacogenomics Research Network (PGRN), whose broad objective is to elucidate genetic variants contributing to drug response, and the Pharmacogenomics Knowledge Base (PharmGKB), which is a comprehensive resource of pharmacogenomic information for researchers and clinicians. Specific projects within the PGRN have focused on the pharmacogenomics of antihypertensive response, arrhythmia therapy, antiplatelet interventions and cardiovascular disease risk. The Translational Pharmacogenetics Project was formed as a network-wide PGRN effort to translate actionable pharmacogenetic discoveries into clinical practice. More recently, the NIH-funded Implementing Genomics in Practice Network was formed to further enhance and accelerate the incorporation of genomic information into clinical care. Commentary