An evaluation of gene-gene interaction between the CYP2C9 and VKORC1 genotypes affecting the anticoagulant effect of phenprocoumon and acenocoumarol

R M F van Schie; A M V Babajeff; T Schalekamp; J A M Wessels; S le Cessie; A de Boer; F J M van der Meer; E van Meegen; T I Verhoef; F R Rosendaal; A H Maitland-van der Zee; EU-PACT Study Group

doi:10.1111/j.1538-7836.2012.04694.x

An evaluation of gene-gene interaction between the CYP2C9 and VKORC1 genotypes affecting the anticoagulant effect of phenprocoumon and acenocoumarol

R M F van Schie, A M V Babajeff, T Schalekamp, J A M Wessels, S le Cessie, A de Boer, F J M van der Meer, E van Meegen, T I Verhoef, F R Rosendaal, A H Maitland-van der Zee, EU-PACT Study Group

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

BACKGROUND: Previous studies have provided contradictory results regarding the interaction between the CYP2C9 and VKORC1 genotypes affecting various outcome measures.

OBJECTIVES: We aimed to provide a definite answer regarding the question whether there exists a gene-gene interaction between the CYP2C9 and VKORC1 genotypes affecting the anticoagulant effect of phenprocoumon and acenocoumarol.

PATIENTS/METHODS: The EU-PACT cohort dataset, which contains data on 624 phenprocoumon and 471 acenocoumarol patients, was used. Patient characteristics, pharmacogenetic data, International Normalized Ratios (INRs) and dosages were available. We investigated whether there was an interaction between the CYP2C9 and VKORC1 genotypes affecting the maintenance dose, time to severe over-anticoagulation and time to achieve stability during the first 180 days of phenprocoumon and acenocoumarol therapy, in addition to the effect of the separate genotypes. The interaction effect was investigated by adding the product term of the CYP2C9 and VKORC1 genotype classes for four different commonly used CYP2C9 classifications to the linear regression model - for the outcome measure maintenance dose - or to the Cox regression models - for the outcome measures time to severe over-anticoagulation and time to achieve stability.

RESULTS: No significant interactions - all P-values above 0.23 for phenprocoumon and 0.30 for acenocoumarol - were observed for all outcome measures.

CONCLUSIONS: There are no interactions between the CYP2C9 and VKORC1 genotypes affecting the maintenance dose, time to severe over-anticoagulation and time to achieve stability for phenprocoumon and acenocoumarol.

Original language	English
Pages (from-to)	767-772
Number of pages	6
Journal	Journal of Thrombosis and Haemostasis
Volume	10
Issue number	5
DOIs	https://doi.org/10.1111/j.1538-7836.2012.04694.x
Publication status	Published - 2012

Bibliographical note

Keywords

Acenocoumarol
Adult
Aged
Aged, 80 and over
Anticoagulants
Aryl Hydrocarbon Hydroxylases
Blood Coagulation
Cytochrome P-450 CYP2C9
Drug Monitoring
Female
Genotype
Humans
International Normalized Ratio
Linear Models
Male
Middle Aged
Mixed Function Oxygenases
Netherlands
Pharmacogenetics
Phenotype
Phenprocoumon
Proportional Hazards Models
Vitamin K Epoxide Reductases

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10.1111/j.1538-7836.2012.04694.x

Cite this

van Schie, R. M. F., Babajeff, A. M. V., Schalekamp, T., Wessels, J. A. M., le Cessie, S., de Boer, A., van der Meer, F. J. M., van Meegen, E., Verhoef, T. I., Rosendaal, F. R., Maitland-van der Zee, A. H., & EU-PACT Study Group (2012). An evaluation of gene-gene interaction between the CYP2C9 and VKORC1 genotypes affecting the anticoagulant effect of phenprocoumon and acenocoumarol. Journal of Thrombosis and Haemostasis, 10(5), 767-772. https://doi.org/10.1111/j.1538-7836.2012.04694.x

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title = "An evaluation of gene-gene interaction between the CYP2C9 and VKORC1 genotypes affecting the anticoagulant effect of phenprocoumon and acenocoumarol",

abstract = "BACKGROUND: Previous studies have provided contradictory results regarding the interaction between the CYP2C9 and VKORC1 genotypes affecting various outcome measures.OBJECTIVES: We aimed to provide a definite answer regarding the question whether there exists a gene-gene interaction between the CYP2C9 and VKORC1 genotypes affecting the anticoagulant effect of phenprocoumon and acenocoumarol.PATIENTS/METHODS: The EU-PACT cohort dataset, which contains data on 624 phenprocoumon and 471 acenocoumarol patients, was used. Patient characteristics, pharmacogenetic data, International Normalized Ratios (INRs) and dosages were available. We investigated whether there was an interaction between the CYP2C9 and VKORC1 genotypes affecting the maintenance dose, time to severe over-anticoagulation and time to achieve stability during the first 180 days of phenprocoumon and acenocoumarol therapy, in addition to the effect of the separate genotypes. The interaction effect was investigated by adding the product term of the CYP2C9 and VKORC1 genotype classes for four different commonly used CYP2C9 classifications to the linear regression model - for the outcome measure maintenance dose - or to the Cox regression models - for the outcome measures time to severe over-anticoagulation and time to achieve stability.RESULTS: No significant interactions - all P-values above 0.23 for phenprocoumon and 0.30 for acenocoumarol - were observed for all outcome measures.CONCLUSIONS: There are no interactions between the CYP2C9 and VKORC1 genotypes affecting the maintenance dose, time to severe over-anticoagulation and time to achieve stability for phenprocoumon and acenocoumarol.",

keywords = "Acenocoumarol, Adult, Aged, Aged, 80 and over, Anticoagulants, Aryl Hydrocarbon Hydroxylases, Blood Coagulation, Cytochrome P-450 CYP2C9, Drug Monitoring, Female, Genotype, Humans, International Normalized Ratio, Linear Models, Male, Middle Aged, Mixed Function Oxygenases, Netherlands, Pharmacogenetics, Phenotype, Phenprocoumon, Proportional Hazards Models, Vitamin K Epoxide Reductases",

author = "{van Schie}, {R M F} and Babajeff, {A M V} and T Schalekamp and Wessels, {J A M} and {le Cessie}, S and {de Boer}, A and {van der Meer}, {F J M} and {van Meegen}, E and Verhoef, {T I} and Rosendaal, {F R} and {Maitland-van der Zee}, {A H} and {EU-PACT Study Group}",

note = "{\textcopyright} 2012 International Society on Thrombosis and Haemostasis.",

year = "2012",

doi = "10.1111/j.1538-7836.2012.04694.x",

language = "English",

volume = "10",

pages = "767--772",

journal = "Journal of Thrombosis and Haemostasis",

issn = "1538-7933",

publisher = "Elsevier BV",

number = "5",

}

van Schie, RMF, Babajeff, AMV, Schalekamp, T, Wessels, JAM, le Cessie, S, de Boer, A, van der Meer, FJM, van Meegen, E, Verhoef, TI, Rosendaal, FR, Maitland-van der Zee, AH & EU-PACT Study Group 2012, 'An evaluation of gene-gene interaction between the CYP2C9 and VKORC1 genotypes affecting the anticoagulant effect of phenprocoumon and acenocoumarol', Journal of Thrombosis and Haemostasis, vol. 10, no. 5, pp. 767-772. https://doi.org/10.1111/j.1538-7836.2012.04694.x

TY - JOUR

T1 - An evaluation of gene-gene interaction between the CYP2C9 and VKORC1 genotypes affecting the anticoagulant effect of phenprocoumon and acenocoumarol

AU - van Schie, R M F

AU - Babajeff, A M V

AU - Schalekamp, T

AU - Wessels, J A M

AU - le Cessie, S

AU - de Boer, A

AU - van der Meer, F J M

AU - van Meegen, E

AU - Verhoef, T I

AU - Rosendaal, F R

AU - Maitland-van der Zee, A H

AU - EU-PACT Study Group

PY - 2012

Y1 - 2012

N2 - BACKGROUND: Previous studies have provided contradictory results regarding the interaction between the CYP2C9 and VKORC1 genotypes affecting various outcome measures.OBJECTIVES: We aimed to provide a definite answer regarding the question whether there exists a gene-gene interaction between the CYP2C9 and VKORC1 genotypes affecting the anticoagulant effect of phenprocoumon and acenocoumarol.PATIENTS/METHODS: The EU-PACT cohort dataset, which contains data on 624 phenprocoumon and 471 acenocoumarol patients, was used. Patient characteristics, pharmacogenetic data, International Normalized Ratios (INRs) and dosages were available. We investigated whether there was an interaction between the CYP2C9 and VKORC1 genotypes affecting the maintenance dose, time to severe over-anticoagulation and time to achieve stability during the first 180 days of phenprocoumon and acenocoumarol therapy, in addition to the effect of the separate genotypes. The interaction effect was investigated by adding the product term of the CYP2C9 and VKORC1 genotype classes for four different commonly used CYP2C9 classifications to the linear regression model - for the outcome measure maintenance dose - or to the Cox regression models - for the outcome measures time to severe over-anticoagulation and time to achieve stability.RESULTS: No significant interactions - all P-values above 0.23 for phenprocoumon and 0.30 for acenocoumarol - were observed for all outcome measures.CONCLUSIONS: There are no interactions between the CYP2C9 and VKORC1 genotypes affecting the maintenance dose, time to severe over-anticoagulation and time to achieve stability for phenprocoumon and acenocoumarol.

AB - BACKGROUND: Previous studies have provided contradictory results regarding the interaction between the CYP2C9 and VKORC1 genotypes affecting various outcome measures.OBJECTIVES: We aimed to provide a definite answer regarding the question whether there exists a gene-gene interaction between the CYP2C9 and VKORC1 genotypes affecting the anticoagulant effect of phenprocoumon and acenocoumarol.PATIENTS/METHODS: The EU-PACT cohort dataset, which contains data on 624 phenprocoumon and 471 acenocoumarol patients, was used. Patient characteristics, pharmacogenetic data, International Normalized Ratios (INRs) and dosages were available. We investigated whether there was an interaction between the CYP2C9 and VKORC1 genotypes affecting the maintenance dose, time to severe over-anticoagulation and time to achieve stability during the first 180 days of phenprocoumon and acenocoumarol therapy, in addition to the effect of the separate genotypes. The interaction effect was investigated by adding the product term of the CYP2C9 and VKORC1 genotype classes for four different commonly used CYP2C9 classifications to the linear regression model - for the outcome measure maintenance dose - or to the Cox regression models - for the outcome measures time to severe over-anticoagulation and time to achieve stability.RESULTS: No significant interactions - all P-values above 0.23 for phenprocoumon and 0.30 for acenocoumarol - were observed for all outcome measures.CONCLUSIONS: There are no interactions between the CYP2C9 and VKORC1 genotypes affecting the maintenance dose, time to severe over-anticoagulation and time to achieve stability for phenprocoumon and acenocoumarol.

KW - Acenocoumarol

KW - Adult

KW - Aged

KW - Aged, 80 and over

KW - Anticoagulants

KW - Aryl Hydrocarbon Hydroxylases

KW - Blood Coagulation

KW - Cytochrome P-450 CYP2C9

KW - Drug Monitoring

KW - Female

KW - Genotype

KW - Humans

KW - International Normalized Ratio

KW - Linear Models

KW - Male

KW - Middle Aged

KW - Mixed Function Oxygenases

KW - Netherlands

KW - Pharmacogenetics

KW - Phenotype

KW - Phenprocoumon

KW - Proportional Hazards Models

KW - Vitamin K Epoxide Reductases

U2 - 10.1111/j.1538-7836.2012.04694.x

DO - 10.1111/j.1538-7836.2012.04694.x

M3 - Article

C2 - 22409277

SN - 1538-7933

VL - 10

SP - 767

EP - 772

JO - Journal of Thrombosis and Haemostasis

JF - Journal of Thrombosis and Haemostasis

IS - 5

ER -

An evaluation of gene-gene interaction between the CYP2C9 and VKORC1 genotypes affecting the anticoagulant effect of phenprocoumon and acenocoumarol

Abstract

Bibliographical note

Keywords

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