Variability In Warfarin Dose Requirements Research Articles

Variants in CDHR3, CACNAC1, and LTA Genes Predisposing Sensitivity and Response to Warfarin in Patients with Cardiovascular Disease.

IntroductionWarfarin has been in use for more than 60 years; however, it has serious side effects including major bleeding. The high interpatient variability in the required dose impacts the sensitivity and responsiveness to warfarin in different patients. This study aims to assess the influence of CDHR3, CACNAC1, and LTA gene polymorphisms on the variability of warfarin dose requirements and susceptibility to coronary heart disease in the Jordanian population.MethodsThis study was conducted in the anti-coagulation clinic in Queen Alia Heart Institute in Amman, with 212 patients in total. Three SNPs were genotyped within CDHR3 (rs10270308), CACNAC1 (rs216013), and LTA (rs1041981) genes.ResultsOur findings revealed that patients with LTA polymorphism are more prone to warfarin sensitivity than others. Furthermore, carriers of the LTA polymorphism needed a lower initial dose of warfarin and are associated with less variation in doses required to achieve target INR.ConclusionThe current study could help in understanding the role of genetic variability in warfarin dosing and matching patients to different treatment options. Clinical applications of these findings for warfarin treatment may also contribute to improving the efficacy and safety of warfarin treatment in Jordanian patients with cardiovascular disease.

Implications of Polymorphisms in the BCKDK and GATA-4 Gene Regions on Stable Warfarin Dose in African Americans.

VKORC1 and CYP2C9 genotypes explain less variability in warfarin dose requirements in African Americans compared with Europeans. Variants in BCKDK and GATA‐4 gene regions, purported to regulate VKORC1 and CYP2C9 expression, have been shown to play an important role in warfarin dose requirements in Europeans and Asians, respectively. We sought to determine whether rs56314408 near BCKDK or GATA‐4 rs2645400 influence warfarin dose requirements in 200 African Americans. Unlike the strong linkage disequilibrium (LD) between rs56314408 and VKORC1 rs9923231 in Europeans, they were not in LD in African Americans. No associations were found on univariate analysis. On multivariable analysis, rs56314408 was associated (P = 0.027) with dose in a regression model excluding VKORC1 rs9923231, and GATA‐4 rs2645400 was associated (P = 0.032) with dose in a model excluding CYP2C (CYP2C9*2, *3, *5, *6, *8, and *11, CYP2C rs12777823) variants. Neither variant contributed to dose in the model that included both VKORC1 rs9923231 and CYP2C variants. Our results do not support contributions of the studied variants to warfarin dose requirements in African Americans. However, they illustrate the value of studies in African descent populations, who have low LD in their genome, in teasing out genetic variation underlying drug response associations. They also emphasize the importance of confirming associations in persons of African ancestry.

The effects of CYP2C9 and VKORC1 gene polymorphisms on warfarin maintenance dose in Turkish cardiac patients.

Aim: Our aim was to examine the effect of CYP2C9 and VKORC1 polymorphisms on warfarin dose requirements in Turkish patients. Materials & methods: 24 warfarin prescribed patients were included and analyzed for eight VKORC1 and 6 CYP2C9 polymorphisms in the study. Results: Patients with CYP2C9 *1/*1 and VKORC1 -1639 GG and GA genotypes required higher warfarin doses in comparison to wild type VKORC1 genotype. Patients with CYP2C9 *1/*3 and VKORC1 -1639 GG genotypes simultaneously, required the lowest dose of warfarin (4.64mg/day). Patients with CYP2C9 *1/*1 and VKORC1 9041 AA genotype were found to require higher warfarin doses. Conclusion: Our results provide additional evidence to support the hypothesis that CYP2C9 *2, *3, VKORC1 9041 G>A polymorphisms explain considerable proportion of inter-individual variability in warfarin dose requirement.

Polymorphisms of vitamin K-related genes (EPHX1 and VKORC1L1) and stable warfarin doses

The aim of this study was to investigate the possible effects of EPHX1 and VKORC1L1 polymorphisms on variability of responses to warfarin. Sixteen single nucleotide polymorphisms (SNPs) in 201 patients with stable warfarin doses were analyzed including genes of VKORC1, CYP2C9, CYP4F2, GGCX, EPHX1 and VKORC1L1. Univariate analysis was conducted for the association of genotypes with stable warfarin doses. Multiple linear regression analysis was used to investigate factors that independently affected the inter-individual variability of warfarin dose requirements. The rs4072879 of VKORC1L1 (A>G) was significantly associated with stable warfarin doses; wild homozygote carriers (AA) required significantly lower stable warfarin doses than those with the variant G allele (5.02±1.56 vs. 5.96±2.01mg; p=0.001). Multivariate analysis showed that EPHX1 rs1877724 and VKORC1L1 rs4072879 accounted for 1.5% and 1.3% of the warfarin dose variability. Adding EPHX1 and VKORC1L1 SNPs to the base model including non-genetic variables (operation age, body weight and the therapy of ACEI or ARB) and genetic variables (VKORC1 rs9934438, CYP2C9 rs1057910, and CYP4F2 rs2108622) gave a number needed to genotype of 34. This study showed that polymorphisms of EPHX1 and VKORC1L1 could be determinants of stable warfarin doses.

Warfarin Pharmacogenomics in Diverse Populations

Genotype-guided warfarin dosing algorithms are a rational approach to optimize warfarin dosing and potentially reduce adverse drug events. Diverse populations, such as African Americans and Latinos, have greater variability in warfarin dose requirements and are at greater risk for experiencing warfarin-related adverse events compared with individuals of European ancestry. Although these data suggest that patients of diverse populations may benefit from improved warfarin dose estimation, the vast majority of literature on genotype-guided warfarin dosing, including data from prospective randomized trials, is in populations of European ancestry. Despite differing frequencies of variants by race/ethnicity, most evidence in diverse populations evaluates variants that are most common in populations of European ancestry. Algorithms that do not include variants important across race/ethnic groups are unlikely to benefit diverse populations. In some race/ethnic groups, development of race-specific or admixture-based algorithms may facilitate improved genotype-guided warfarin dosing algorithms above and beyond that seen in individuals of European ancestry. These observations should be considered in the interpretation of literature evaluating the clinical utility of genotype-guided warfarin dosing. Careful consideration of race/ethnicity and additional evidence focused on improving warfarin dosing algorithms across race/ethnic groups will be necessary for successful clinical implementation of warfarin pharmacogenomics. The evidence for warfarin pharmacogenomics has a broad significance for pharmacogenomic testing, emphasizing the consideration of race/ethnicity in discovery of gene-drug pairs and development of clinical recommendations for pharmacogenetic testing.

Warfarin Anticoagulation Therapy in Caribbean Hispanics of Puerto Rico: A Candidate Gene Association Study.

Existing algorithms account for ~50% of observed variance in warfarin dose requirements after including common polymorphisms. However, they do not perform as well in populations other than Caucasians, in part because some ethno-specific genetic variants are overlooked. The objective of the present study was to identify genetic polymorphisms that can explain variability in warfarin dose requirements among Caribbean Hispanics of Puerto Rico. Next-Generation Sequencing of candidate genes CYP2C9 and VKORC1 and genotyping by DMET® Plus Assay of cardiovascular patients were performed. We also aimed at characterizing the genomic structure and admixture pattern of this study cohort. Our study used the Extreme Discordant Phenotype approach to perform a case-control association analysis. The CYP2C9 variant rs2860905, which was found in all the major haplotypes occurring in the Puerto Rican population, showed stronger association with warfarin sensitivity (<4 mg/day) than common variants CYP2C9*2 and CYP2C9*3. Although, CYP2C9*2 and CYP2C9*3 are separately contained within two of the haplotypes, 10 subjects with the sensitive phenotype were carriers of only the CYP2C9 rs2860905 variant. Other polymorphisms in CES2 and ABCB1 were found to be associated with warfarin resistance. Incorporation of rs2860905 in a regression model (R2 = 0.63, MSE = 0.37) that also includes additional genetics (i.e., VKORC1-1639 G>A; CYP2C9 rs1856908; ABCB1 c.IVS9-44A>G/ rs10276036; CES2 c.269-965A>G/ rs4783745) and non-genetic factors (i.e., hypertension, diabetes and age) showed better prediction of warfarin dose requirements than CYP2C9*2 and CYP2C9*3 combined (partial R2 = 0.132 vs. 0.023 and 0.007, respectively, p < 0.001). The genetic background of Puerto Ricans in the study cohort showed a tri-hybrid admixture pattern, with a slightly higher than expected contribution of Native American ancestry (25%). The genomic diversity of Puerto Ricans is highlighted by the presence of four different major haplotype blocks in the CYP2C9 locus. Although, our findings need further replication, this study contributes to the field by identifying novel genetic variants that increase predictability of stable warfarin dosing among Caribbean Hispanics.

Integrated analysis of genetic variation and gene expression reveals novel variant for increased warfarin dose requirement in African Americans

Background Warfarin is commonly used to control and prevent thromboembolic disorders. However, because of warfarin's complex dose-requirement relationship, safe and effective use is challenging. Pharmacogenomics-guided warfarin dosing algorithms that include the well-established VKORC1 and CYP2C9 polymorphisms explain only a small proportion of inter-individual variability in African Americans (AAs). Objectives We aimed to assess whether transcriptomic analyses could be used to identify regulatory variants associated with warfarin dose response in AAs. Patients/Methods We identified a total of 56 expression quantitative trait loci (eQTLs) for CYP2C9, VKORC1 and CALU derived from human livers and evaluated their association with warfarin dose response in two independent AA warfarin patient cohorts. Results We found that rs4889606, a strong cis-eQTL for VKORC1 (log10 Bayes Factor = 12.02), is significantly associated with increased warfarin daily dose requirement (β = 1.1; 95% confidence interval [CI] 0.46 to 1.8) in the discovery cohort (n = 305) and in the replication cohort (β = 1.04; 95% CI 0.33 -1.7; n = 141) after conditioning on relevant covariates and the VKORC1 -1639G>A (rs9923231) variant. Inclusion of rs4889606 genotypes, along with CYP2C9 alleles, rs9923231 genotypes and clinical variables, explained 31% of the inter-patient variability in warfarin dose requirement. We demonstrate different linkage disequilibrium patterns in the region encompassing rs4889606 and rs9923231 between AAs and European Americans, which may explain the increased dose requirement found in AAs. Conclusion Our approach of interrogating eQTLs identified in liver has revealed a novel predictor of warfarin dose response in AAs. Our work highlights the utility of leveraging information from regulatory variants mapped in the liver to uncover novel variants associated with drug response and the importance of population-specific research.

Predictors of warfarin dose requirements in South African patients attending an anticoagulation clinic

Warfarin is the most common oral anticoagulant for the treatment and prevention of thromboembolic disease. However, it has a wide interpatient variability in dose requirements due to various genetic and clinical factors. This study investigated the effect of clinical and genetic factors on the variability of warfarin dose requirements in 147 South African patients (81 white and 66 black). The study was performed at a University Hospital Anticoagulation Clinic managed by nursing sisters at the Charlotte Maxeke Johannesburg Academic Hospital. The most common indication for anticoagulation was atrial fibrillation (n=55, 37.4%). The mean warfarin dose was significantly higher in black patients as compared to white patients (5.4±2.9mg/day and 3.8±2.1mg/day, respectively; P<0.001). Older age was significantly associated with a lower maintenance warfarin dose (P<0.001). Drugs which decreased the international normalized ratio (INR) were significantly associated with a higher maintenance warfarin dose of 6.4±3.4mg/day (P<0.034). In contrast, there was no significant difference in warfarin dosage requirements in the presence of CYP2C9 and VKORC1 variant alleles (P>0.05). Patients, however, homozygous for CYP2C9 *1,*3, and VKORC1 required less than 5mg/day of warfarin to maintain the INR within the therapeutic range. In conclusion, this study indicates that clinical characteristics including; age, ethnic group, and drugs which decrease the INR might help to predict better dose requirements in this population group and thereby reduce the risk of bleeding and thrombotic complications.

Quantitative Assessment of CYP2C9 Genetic Polymorphisms Effect on the Oral Clearance of S-Warfarin in Healthy Subjects.

Genetic polymorphisms in CYP2C9 account for 10-20% of the variability in warfarin dose requirement. As such CYP2C9 genetic polymorphisms are commonly included in algorithms aimed to optimize warfarin therapy as a way to account for variability in warfarin responsiveness that is due to altered pharmacokinetics. However, most of the currently available pharmacokinetic data were derived from studies among patients on chronic warfarin therapy and therefore suffer from the confounding effects of disease states and drug interactions. The purpose of the present study was to provide an accurate quantitative estimate of S-warfarin oral clearance (CLS) among healthy subjects carrying different CYP2C9 genotypes. Single dose of warfarin was administered to 150 non-smokers, age (mean±SD) 23.3±4.5years, 60% male, non-obese, healthy subjects. Blood samples were taken for up to 168h and urine was collected over the entire study period. Compared with carriers of the wild-type CYP2C9*1/*1 genotype (n=69), CLS was reduced by 25, 39 and 47% among heterozygote for CYP2C9*2 (n=41) CYP2C9*3 (n=26) and carriers of 2 variant alleles (n=14), respectively (p<0.001). The corresponding decrease in the formation clearance of 6 and 7 S-hydroxy-warfarin was 45, 65 and 75%, respectively (p<0.001). The current study provides an estimate concerning the effect of CYP2C9 polymorphisms on S-warfarin pharmacokinetics among healthy subjects. As such it is free of the confounding effects of disease states and drug interactions. Further research is needed to evaluate whether the incorporation of quantitative data obtained in the present study into pharmacogenetic warfarin algorithm may enhance its precision. Clinicaltrials.gov Identifier NCT00162474.

Frequency of Common VKORC1 Polymorphisms and Their Impact on Warfarin Dose Requirement in Pakistani Population.

Polymorphisms in vitamin K epoxide reductase complex subunit 1 (VKORC1) gene lead to interindividual variability in warfarin dose requirement. The characterization of genotype frequency distribution is required 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 VKORC1 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 VKORC1 1173C>T and VKORC1-1639G>A 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 results. Data were analyzed using SPSS version 20. Genotype frequency distributions of VKORC1 1173C>T and VKORC1-1639G>A were found to be different from other populations. Both of these polymorphisms did not demonstrate significant effect on warfarin dose requirement. Although Cytochrome P450 2C9 (CYP2C9) and VKORC1 polymorphisms together attributed only 3.8% variability in warfarin dose but it was statistically significant ( p value = .004). 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. At the same time, no effect on warfarin dose variation explained by VKORC1 polymorphisms and small variability explained by studied genotypes stresses the need for exploration of more genetic and nongenetic factors in Pakistani population.

Genetic determinants of variability in warfarin response after the dose-titration phase.

Genetic factors contribute considerably toward variability in warfarin dose requirements and are important in the dose-titration phase; their effects on the stability of anticoagulation later in therapy are not known. Using deidentified electronic medical records linked to a DNA-biobank, we studied 140 African-Americans and 943 European-Americans after the warfarin dose-titration phase. We genotyped 12 single nucleotide polymorphisms in genes (CYP2C9, VKORC1, CYP4F2, GGCX, EPHX1, CALU) associated with altered warfarin dose requirements and tested their associations with international normalized ratio variability (INRVAR) and percent time in therapeutic range in European-Americans and African-Americans. One allele copy of rs2108622 in CYP4F2 was associated with a 15% [95% confidence interval (CI): 1-26, P=0.03] decrease in the median INRVAR in European-Americans. In African-Americans, GGCX variants rs11676382 and rs699664 were associated with 4.16-fold (95% CI: 1.45-11.97, P=0.009) and 1.50-fold (95% CI: 1.07-2.08, P=0.02) changes in the median INRVAR per variant allele copy, respectively; rs11676382 was also significantly associated with a 23.19% (95% CI: 5.89-40.48, P=0.01) decrease in time in therapeutic range. The total variation in INRVAR explained by both clinical factors and rs2108622 was 5.2% for European-Americans. In African-Americans, the inclusion of GGCX variants rs11676382 and rs699664, and the CYP2C9*8 variant rs7900194 explained ∼29% of the variation in INRVAR. The stability of anticoagulation after the warfarin dose-titration phase is differentially affected by variants in CYP4F2 in European-Americans and GGCX loci in African-Americans.

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.

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.

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.

Effects of Pregnane X Receptor Genetic Polymorphisms on Stable Warfarin Doses

Pregnane X receptor (PXR) is a transcriptional regulator of many drug-metabolizing enzymes including cytochrome P450 (CYP) 2C9. The objective of this study was to assess the possible association between PXR single-nucleotide polymorphisms (SNPs) and stable warfarin doses. A total of 201 patients with stable warfarin doses from the EwhA-Severance Treatment (EAST) Group of Warfarin were included in this study. The influence of genetic polymorphisms on stable warfarin doses was investigated by genotyping 11 SNPs, that is, vitamin K epoxide reductase complex 1 (VKORC1) rs9934438, CYP2C9 rs1057910, CYP4F2 rs2108622, constitutive androstane receptor (CAR) rs2501873, hepatocyte nuclear factor 4α (HNF4α) rs3212198, and PXR (rs3814055, rs1403526, rs3732357, rs3732360, rs2276707 and rs2472682). Subgroup analysis was conducted on CYP2C9 wild-type homozygote allele (AA) carriers. One PXR SNP of rs2472682 (A>C) exhibited significant association with stable warfarin doses in study population and the subgroup; variant homozygote carriers required significantly lower daily doses of warfarin than those carrying wild allele by about 0.8 mg. Approximate 43.7% of overall interindividual variability in warfarin dose requirement was explained by multivariate regression model. VKORC1, CYP2C9, age, CYP4F2, PXR rs2472682, and CAR/HNF4α rs2501873/rs3212198 accounted for 29.6%, 5.9%, 3.7%, 2.3%, 1.3%, and 0.9% of the variability, respectively. PXR SNP of rs2472682 remained a significant factor in CYP2C9 wild-type homozygote carriers based on univariate and multivariate analyses. The combination of CAR/HNF4α/PXR SNPs of rs2501873/rs3212198/rs2472682 showed about 1 mg dose difference between grouped genotypes in study population and subgroup. Our results revealed that PXR could be a determinant of stable warfarin doses.

Combined effects of hepatocyte nuclear factor 4α and constitutive androstane receptor on stable warfarin doses.

A possible association between the combination of genetic variations in hepatocyte nuclear factor 4α (HNF4α) and constitutive androstane receptor (CAR) and the stable doses of warfarin was examined in patients from the Ewha-Severance Treatment (EAST) Group of Warfarin. Around 42.5% of the overall interindividual variability in warfarin dose requirements was explained by the multivariate regression model; the vitamin K epoxide reductase complex 1 (VKORC1) genotype accounted for 29.6%, the cytochrome P450 (CYP) 2C9 genotype for 4.3%, age for 3.6%, the CYP4F2 genotype for 3.3%, and CAR/HNF4α (rs2501873/rs3212198) for 1.7%. Our results showed that the combination of CAR and HNF4α genotypes could be determinants of stable warfarin doses.

Genes affecting warfarin response-interactive or additive?

Genotypes for cytochrome P450 (CYP) 2C9 and vitamin K epoxide reductase complex 1 (VKORC1) contribute significantly to the inter-patient variability in warfarin dose requirements. These genotypes in addition to clinical factors explain approximately 50% of the dose variability in Europeans, but less in other populations. Thus, a large portion of the variability remains unexplained and has been the focus of on-going research. Trials evaluating the clinical utility of genotype-guided warfarin dosing have shown a benefit in Europeans, but not in an ethnically diverse cohort. Identifying and accounting for variants important in non-European populations will likely be necessary before a benefit with genotype-guided dosing will be realized in these populations.