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

Wakamiya, Takuya; Hokosaki, Tatsunori; Tsujimoto, Shin‐ichi; Kadota, Keisuke; Nakano, Yusuke; Watanabe, S.; Iwamoto, Mari; Yanagimachi, Masakatsu; Ito, Shuichi

doi:10.1007/s40291-016-0212-5

Cited by 13 publications

(10 citation statements)

References 22 publications

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“…We did not find a statistically significant association for CYP4F2, CYP3A4*22, and CYP3A4*1B, which is in line with all other pediatric studies [17,[21][22][23]. Furthermore, there was no statistically significant association between the TR and dose requirement.…”

Section: Discussionsupporting

confidence: 89%

“…This indicated that there is a need for a specific algorithm for pediatric patients. Up to now, several studies have been carried out to create a warfarin pharmacogenetic dosing algorithm for pediatric patients [16][17][18][19][20][21][22][23]. However, to the best of our knowledge, no studies have been carried out to establish an algorithm for acenocoumarol in pediatric patients.…”

Section: Introductionmentioning

confidence: 99%

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The pediatric acenocoumarol dosing algorithm: the Children Anticoagulation and Pharmacogenetics Study

Maagdenberg

Bierings

Ommen

et al. 2018

Journal of Thrombosis and Haemostasis

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To cite this article: Maagdenberg H, Bierings MB, van Ommen CH, van der Meer FJM, Appel IM, Tamminga RYJ, le Cessie S, Swen JJ, van der Straaten T, de Boer A, Maitland-van der Zee AH. The pediatric acenocoumarol dosing algorithm: the Children Anticoagulation and Pharmacogenetics Study. J Thromb Haemost 2018; https://doi.org/10.1111/jth.14211. Essentials• A pediatric pharmacogenetic dosing algorithm for acenocoumarol has not yet been developed.• We conducted a multicenter retrospective follow-up study in children in the Netherlands.• Body surface area and indication explained 45.0% of the variability in dose requirement.• Adding the genotypes of VKORC1, CYP2C9 and CYP2C18 to the algorithm increased this to 61.8%. Summary. Background:The large variability in dose requirement of vitamin K antagonists is well known. For warfarin, pediatric dosing algorithms have been developed to predict the correct dose for a patient; however, this is not the case for acenocoumarol. Objectives: To develop dosing algorithms for pediatric patients receiving acenocoumarol with and without genetic information. Methods: The Children Anticoagulation and Pharmacogenetics Study was designed as a multicenter retrospective follow-up study in Dutch anticoagulation clinics and children's hospitals. Pediatric patients who used acenocoumarol between 1995 and 2014 were selected for inclusion. Clinical information and saliva samples for genotyping of the genes encoding cytochrome P450 (CYP) 2C9, vitamin K epoxide reductase complex subunit 1 (VKORC1), CYP4F2, CYP2C18 and CYP3A4 were collected. Linear regression was used to analyze their association with the log mean stable dose. A stable period was defined as three or more consecutive International Normalized Ratio measurements within the therapeutic range over a period of ≥ 3 weeks. Results: In total, 175 patients were included in the study, of whom 86 had a stable period and no missing clinical information (clinical cohort; median age 8.9 years, and 49% female). For 80 of these 86 patients, genetic information was also available (genetic cohort). The clinical algorithm, containing body surface area and indication, explained 45.0% of the variability in dose requirement of acenocoumarol. After addition of the VKORC1, CYP2C9, and CYP2C18 genotypes to the algorithm, this increased to 61.8%. Conclusions: These findings show that clinical factors had the largest impact on the required dose of acenocoumarol in pediatric patients. Nevertheless, genetic factors, and especially VKORC1, also explained a significant part of the variability.

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Section: Discussionsupporting

confidence: 89%

Section: Introductionmentioning

confidence: 99%

The pediatric acenocoumarol dosing algorithm: the Children Anticoagulation and Pharmacogenetics Study

Maagdenberg

Bierings

Ommen

et al. 2018

Journal of Thrombosis and Haemostasis

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“…However, the results of these association studies are ambiguous, seem to be population-dependent and cannot be seen separately from variants in other genes, relevant for warfarin metabolism. Hence, the effects of these GGCX variants fall beyond the scope of this systematic review [41,42,43,44]. …”

Section: Introductionmentioning

confidence: 99%

GGCX-Associated Phenotypes: An Overview in Search of Genotype-Phenotype Correlations

Vilder

Debacker

Vanakker

2017

IJMS

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Gamma-carboxylation, performed by gamma-glutamyl carboxylase (GGCX), is an enzymatic process essential for activating vitamin K-dependent proteins (VKDP) with important functions in various biological processes. Mutations in the encoding GGCX gene are associated with multiple phenotypes, amongst which vitamin K-dependent coagulation factor deficiency (VKCFD1) is best known. Other patients have skin, eye, heart or bone manifestations. As genotype–phenotype correlations were never described, literature was systematically reviewed in search of patients with at least one GGCX mutation with a phenotypic description, resulting in a case series of 47 patients. Though this number was too low for statistically valid correlations—a frequent problem in orphan diseases—we demonstrate the crucial role of the horizontally transferred transmembrane domain in developing cardiac and bone manifestations. Moreover, natural history suggests ageing as the principal determinant to develop skin and eye symptoms. VKCFD1 symptoms seemed more severe in patients with both mutations in the same protein domain, though this could not be linked to a more perturbed coagulation factor function. Finally, distinct GGCX functional domains might be dedicated to carboxylation of very specific VKDP. In conclusion, this systematic review suggests that there indeed may be genotype–phenotype correlations for GGCX-related phenotypes, which can guide patient counseling and management.

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“…Certain genetic polymorphisms have been shown to affect the required therapeutic dose of warfarin. These include polymorphisms in the genes VKORC1, CYP2C9 (Alrashid et al, 2016), CYP4F2, GGCX, and EPHX1 (Liu et al, 2015;Sun et al, 2015Sun et al, , 2016Wakamiya et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

Pharmacogenetics-based warfarin dose prediction algorithm for patients with heart valve replacement in Southeast China

Lin¹,

Zhang²,

Qiu³

et al. 2017

Genet. Mol. Res.

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ABSTRACT.This study was designed to analyze the influence of polymorphisms in CYP2C9, VKORC1, CYP4F2, GGCX, and EPHX1 genes on the optimal warfarin dosage in patients who have undergone artificial heart valve replacement and establish an algorithm for use by physicians in Southeast China to predict each patient's optimal steadystate warfarin dose. One-hundred and ninety-six patients scheduled for heart valve replacement in Southeast China were enrolled in this study. Five genotypes, CYP2C9, VKORC1, CYP4F2, GGCX and EPHX1, were detected using time-of-flight mass spectrometry. Correlations of clinical and genetic factors with optimal steady-state dose of warfarin were analyzed. There were significant correlations between the genotypes of CY2C9, VKORC1, CYP4F2 and the warfarin dosage (P = 0.000, 0.000 and 0.015). Multiple stepwise regression analysis was performed to obtain the following algorithm: the observed differences in optimal warfarin dosage among the enrolled patients. A retrospective validation study comparing this algorithm with the published algorithms used in patient populations of other races revealed that the obtained algorithm had the best accuracy (The smallest MRE: 21.11 ± 19.08 mg/day) and applicability (the largest RE proportion of patients in ideal rang: 58.3%). This study 1) defined the relative contributions of age, body surface area, and polymorphisms in CYP2C9, VKORC1, and CYP4F2 to the optimal steady-state dosage of warfarin; 2) established a dose prediction algorithm for populations in this region that takes into account the clinical, pharmacological and genetic polymorphism data; and 3) clarified the advantages of this algorithm over the established prediction equations. Our algorithm can assist clinicians in Southeast China in prescribing appropriate anticoagulation therapy.

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

Abstract: 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.

Cited by 13 publications

References 22 publications

The pediatric acenocoumarol dosing algorithm: the Children Anticoagulation and Pharmacogenetics Study

The pediatric acenocoumarol dosing algorithm: the Children Anticoagulation and Pharmacogenetics Study

GGCX-Associated Phenotypes: An Overview in Search of Genotype-Phenotype Correlations

Pharmacogenetics-based warfarin dose prediction algorithm for patients with heart valve replacement in Southeast China

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