Influence of ORM1 polymorphisms on the maintenance stable warfarin dosage

Wang, Lian Sheng; Shang, Junlong; Shi, Shu Ya; Zhang, Yan Qing; Lin, Jian; Guo, Zhihao; Wang, Yi-Chen; Tang, Jie; Liu, Jie; Liu, Ying Zi; Li, Zhi; Tan, Zhi Rong; Zhou, Hong; Jiang, Hai He; Xie, Hai Tang

doi:10.1007/s00228-012-1448-6

Cited by 11 publications

(7 citation statements)

References 39 publications

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“…Therefore, combined contribution of VKORC1 rs9923231, CYP2C9 rs1057910, and ORM1 rs17650 polymorphisms to dosage variation in this study with a narrow participant population of specific genotypes was lower than those in our early study (14.8% vs 25.3%). 9 According to the INR records for our data (Figure 2), current warfarin treatment practices provided effective and safe anticoagulant therapy for the patients with wildtype genotypes in the first month. The INR of these patients rose quickly and remained steady within the target range.…”

Section: Discussionmentioning

confidence: 92%

“…Genotypes for VKORC1 rs9923231 and CYP2C9 rs1057910 were determined by using a pyrosequencing method as described previously, 9 and genotypes for CYP4F2 rs2108622 and ORM1 rs17650 were determined through a Polymerase Chain Reaction (PCR)-restriction fragment length polymorphism method as described previously. 9 The CYP4F2 rs2108622 genotypes were differentiated using PvuII enzyme restriction digestion. The ORM1 rs17650 genotypes were differentiated using EcoNI enzyme restriction digestion.…”

Section: Methodsmentioning

confidence: 99%

“…8 The CYP4F2 rs2108622 polymorphism was reported to cause 2% to 7% of dosage variation, and the ORM1 rs17650 polymorphism accounted for 2% of dosage differences according to our early findings. 9 Based on numerous published reports, the Food and Drug Administration has suggested practicing genotype-guided (pharmacogenetically based) dosing for anticoagulation control with warfarin. 10 However, Kimmel et al found that genotype-guided dosing of warfarin did not improve anticoagulation control.…”

Section: Introductionmentioning

confidence: 99%

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The Impact of Gene Polymorphisms on Anticoagulation Control With Warfarin

Jiang

Liu

Wang

et al. 2017

Clin Appl Thromb Hemost

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Differences in warfarin maintenance dosages based on the presence of polymorphisms in VKORC1, CYP2C9, CYP4F2, and ORM1 can be determined through dosage adjustment according to routine guidelines. Little is known about whether routine therapy could provide consensus anticoagulation control for patients with different genotypes. This study was carried out to compare anticoagulant control in patients with different genotypes. Six hundred seventy patients using warfarin according to Chinese guidelines were enrolled. Warfarin dosages and monitored international normalized ratios (INRs) were recorded. Genotypes of VKORC1 rs9923231, CYP4F2 rs2108622, CYP2C9 rs1057910, and ORM1 rs17650 polymorphisms were determined. Warfarin dosages and INR were compared between genotypes. Patients with the AGCC*F*F*1*1 polymorphism took longer than patients with the AACC*F*F*1*1 polymorphism (20 vs 5 days, P < .001) to achieve the targeted INR range. The INR values of patients with AACC*F*F*1*3 were unstable and did not enter the stable state control phase until after 35 days. The peak INR of patients with the AACC*F*F*1*3 polymorphism was exceedingly high, with some values exceeding the control range limit of 3.0. Patients with the AACC*F*S*1*1 or AACT*F*F*1*1 polymorphisms exhibited similar INR values as the patients with the AACC*F*F*1*1 polymorphism. This study found that routine medication with warfarin provides significantly different levels of anticoagulant control between patients with wild-type genotypes and patients with heterozygous polymorphism genotypes of VKORC1 rs9923231 or CYP2C9 rs1057910. Patients with heterozygous polymorphism genotypes of VKORC1 or CYP2C9 require genotype-directed therapy with warfarin to increase efficacy and safety in anticoagulant treatment.

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Section: Discussionmentioning

confidence: 92%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The Impact of Gene Polymorphisms on Anticoagulation Control With Warfarin

Jiang

Liu

Wang

et al. 2017

Clin Appl Thromb Hemost

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“…These studies have reported substantial prevalence and significant effect on warfarin dose by these gene products. 24,[34][35][36]44,46,62,66,69,72 These polymorphisms may be considered to be prevalent and substantial contributors to warfarin dose variability in Pakistani population. Further studies on such polymorphisms are recommended to identify the major genetic factors in Pakistani population.…”

Section: Discussionmentioning

confidence: 99%

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

Qayyum

Najmi

Mansoor

et al. 2016

Clin Appl Thromb Hemost

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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.

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“…We used next-generation sequencing method to resequence the exons, exon-intron boundaries and gene regulatory regions of 43 target genes or regions that were potentially associated with warfarin dosage. These warfarin dose-associated genes or areas were selected on the basis of the PharmaGKB website, the results of genome-wide association studies, or the results of other published studies [17][18][19][20][21][22]. The details of these genes are shown in Fig linkage disequilibrium (LD) (r 2 > 0.9).…”

Section: Methodsmentioning

confidence: 99%

Identification of novel variants associated with warfarin stable dosage by use of a two‐stage extreme phenotype strategy

Luo

Zhu

et al. 2017

Journal of Thrombosis and Haemostasis

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Essentials• Required warfarin doses for mechanical heart valves vary greatly.• A two-stage extreme phenotype design was used to identify novel warfarin dose associated mutation.• We identified a group of variants significantly associated with extreme warfarin dose.• Four novel identified mutations account for 2.2% of warfarin dose discrepancies.Summary. Background: The variation among patients in warfarin response complicates the management of warfarin therapy, and an improper therapeutic dose usually results in serious adverse events. Objective: To use a twostage extreme phenotype strategy in order to discover novel warfarin dose-associated mutations in heart valve replacement patients. Patients/method: A total of 1617 stable-dose patients were enrolled and divided randomly into two cohorts. Stage I patients were genotyped into three groups on the basis of VKORC1-1639G>A and CYP2C9*3 polymorphisms; only patients with the therapeutic dose at the upper or lower 5% of each genotype group were selected as extreme-dose patients for resequencing of the targeted regions. Evaluation of the accuracy of the sequence data and the potential value of the stage I-identified significant mutations were conducted in a validation cohort of 420 subjects. Results: A group of mutations were found to be significantly associated with the extreme warfarin dose. The validation work finally identified four novel mutations, i.e. DNMT3A rs2304429 (24.74%), CYP1A1 rs3826041 (47.35%), STX1B rs72800847 (7.01%), and NQO1 rs10517 (36.11%), which independently and significantly contributed to the overall variability in the warfarin dose. After addition of these four mutations, the estimated regression equation was able to account for 56.2% (R 2 Adj = 0.562) of the overall variability in the warfarin maintenance dose, with a predictive accuracy of 62.4%. Conclusion: Our study provides evidence linking genetic variations in STX1B, DNMT3A and CYP1A1 to warfarin maintenance dose. The newly identified mutations together account for 2.2% of warfarin dose discrepancy.

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Influence of ORM1 polymorphisms on the maintenance stable warfarin dosage

Abstract: We identified ORM1 as another polymorphic gene affecting warfarin dose requirements. ORM1 S carriers require lower maintenance doses to achieve and maintain an optimal level of anticoagulation.

Cited by 11 publications

References 39 publications

The Impact of Gene Polymorphisms on Anticoagulation Control With Warfarin

The Impact of Gene Polymorphisms on Anticoagulation Control With Warfarin

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

Identification of novel variants associated with warfarin stable dosage by use of a two‐stage extreme phenotype strategy

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