Genome-Wide Association Study of VKORC1 and CYP2C9 on acenocoumarol dose, stroke recurrence and intracranial haemorrhage in Spain

Natalia Cullell; Caty Carrera; Elena Muiño; Nuria-Paz Torres-Aguila; Jara Cárcel-Márquez; Jonathan González-Sánchez; Cristina Gallego-Fabrega; Jessica Molina; Sarah Besora; Javier Sotoca; Maria-Teresa Buongiorno; Jordi Jiménez-Conde; Eva Giralt-Steinhauer; Reyes de Torres-Chacón; Joan Montaner; Fernando Mancha; Juan A Cabezas; Joan Martí-Fàbregas; Luis Prats-Sánchez; Pol Camps-Renom; Francisco Purroy; Serafi Cambray; María Del Mar Freijo; Cristòfol Vives-Bauzá; Silvia Tur; Maria-Àngels Font; Elena López-Cancio; Maria Hernandez-Perez; Victor Obach; Ana Calleja; Juan Arenillas; Manuel Rodríguez-Yáñez; José Castillo; Tomas Sobrino; Israel Fernández-Cádenas; Jerzy Krupinski

doi:10.1038/s41598-020-59641-9

Genome-Wide Association Study of VKORC1 and CYP2C9 on acenocoumarol dose, stroke recurrence and intracranial haemorrhage in Spain

Natalia Cullell, Caty Carrera, Elena Muiño, Nuria-Paz Torres-Aguila, Jara Cárcel-Márquez, Jonathan González-Sánchez, Cristina Gallego-Fabrega, Jessica Molina, Sarah Besora, Javier Sotoca, Maria-Teresa Buongiorno, Jordi Jiménez-Conde, Eva Giralt-Steinhauer, Reyes de Torres-Chacón, Joan Montaner, Fernando Mancha, Juan A Cabezas, Joan Martí-Fàbregas, Luis Prats-Sánchez, Pol Camps-RenomFrancisco Purroy, Serafi Cambray, María Del Mar Freijo, Cristòfol Vives-Bauzá, Silvia Tur, Maria-Àngels Font, Elena López-Cancio, Maria Hernandez-Perez, Victor Obach, Ana Calleja, Juan Arenillas, Manuel Rodríguez-Yáñez, José Castillo, Tomas Sobrino, Israel Fernández-Cádenas, Jerzy Krupinski

School of Biology

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Abstract

Acenocoumarol is an oral anticoagulant with significant interindividual dose variations. Variants in CYP2C9 and VKORC1 have been associated with acenocoumarol maintenance dose. We analysed whether any of the 49 polymorphisms in CYP2C9 and VKORC1 previously associated with acenocoumarol maintenance dose in a Genome-Wide Association study (GWAs) in Dutch population are associated with stroke recurrence, intracranial haemorrhage (ICH) and acenocoumarol maintenance dose in a Spanish population. We performed a GWAs using Human Core Exome-chip (Illumina) in 78 patients stroke patients treated with acenocoumarol for secondary prevention enrolled as part of the prospective investigator-initiated study (IIS) SEDMAN Study. Patients were followed-up a median of 12.8 months. Three and eight patients had recurrent stroke and ICH events, respectively. We found 14 of the 49 published variants associated with acenocoumarol maintenance dose (p < 0.05). Six polymorphisms were associated with stroke recurrence and four variants with ICH (p < 0.05). In conclusion, variants in VKORC1 and CYP2C9 are associated with acenocoumarol maintenance dose, stroke recurrence and ICH in a Spanish cohort. These results highlight the relevance of studying pharmacogenetics associated with efficacy and safety of anticoagulant drugs and justify studies with larger sample size and different ethnic populations.

Original language	English
Article number	2806
Number of pages	7
Journal	Scientific Reports
Volume	10
DOIs	https://doi.org/10.1038/s41598-020-59641-9
Publication status	Published - 18 Feb 2020

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Cullell-2020-Genome-wide-association-VKORC1-SciRep-2806
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Cullell, N., Carrera, C., Muiño, E., Torres-Aguila, N.-P., Cárcel-Márquez, J., González-Sánchez, J., Gallego-Fabrega, C., Molina, J., Besora, S., Sotoca, J., Buongiorno, M.-T., Jiménez-Conde, J., Giralt-Steinhauer, E., de Torres-Chacón, R., Montaner, J., Mancha, F., Cabezas, J. A., Martí-Fàbregas, J., Prats-Sánchez, L., ... Krupinski, J. (2020). Genome-Wide Association Study of VKORC1 and CYP2C9 on acenocoumarol dose, stroke recurrence and intracranial haemorrhage in Spain. Scientific Reports, 10, Article 2806. https://doi.org/10.1038/s41598-020-59641-9

@article{ab177f85f7da48b89ca76df6e0aa39d2,

title = "Genome-Wide Association Study of VKORC1 and CYP2C9 on acenocoumarol dose, stroke recurrence and intracranial haemorrhage in Spain",

abstract = "Acenocoumarol is an oral anticoagulant with significant interindividual dose variations. Variants in CYP2C9 and VKORC1 have been associated with acenocoumarol maintenance dose. We analysed whether any of the 49 polymorphisms in CYP2C9 and VKORC1 previously associated with acenocoumarol maintenance dose in a Genome-Wide Association study (GWAs) in Dutch population are associated with stroke recurrence, intracranial haemorrhage (ICH) and acenocoumarol maintenance dose in a Spanish population. We performed a GWAs using Human Core Exome-chip (Illumina) in 78 patients stroke patients treated with acenocoumarol for secondary prevention enrolled as part of the prospective investigator-initiated study (IIS) SEDMAN Study. Patients were followed-up a median of 12.8 months. Three and eight patients had recurrent stroke and ICH events, respectively. We found 14 of the 49 published variants associated with acenocoumarol maintenance dose (p < 0.05). Six polymorphisms were associated with stroke recurrence and four variants with ICH (p < 0.05). In conclusion, variants in VKORC1 and CYP2C9 are associated with acenocoumarol maintenance dose, stroke recurrence and ICH in a Spanish cohort. These results highlight the relevance of studying pharmacogenetics associated with efficacy and safety of anticoagulant drugs and justify studies with larger sample size and different ethnic populations.",

author = "Natalia Cullell and Caty Carrera and Elena Mui{\~n}o and Nuria-Paz Torres-Aguila and Jara C{\'a}rcel-M{\'a}rquez and Jonathan Gonz{\'a}lez-S{\'a}nchez and Cristina Gallego-Fabrega and Jessica Molina and Sarah Besora and Javier Sotoca and Maria-Teresa Buongiorno and Jordi Jim{\'e}nez-Conde and Eva Giralt-Steinhauer and {de Torres-Chac{\'o}n}, Reyes and Joan Montaner and Fernando Mancha and Cabezas, {Juan A} and Joan Mart{\'i}-F{\`a}bregas and Luis Prats-S{\'a}nchez and Pol Camps-Renom and Francisco Purroy and Serafi Cambray and {Del Mar Freijo}, Mar{\'i}a and Crist{\`o}fol Vives-Bauz{\'a} and Silvia Tur and Maria-{\`A}ngels Font and Elena L{\'o}pez-Cancio and Maria Hernandez-Perez and Victor Obach and Ana Calleja and Juan Arenillas and Manuel Rodr{\'i}guez-Y{\'a}{\~n}ez and Jos{\'e} Castillo and Tomas Sobrino and Israel Fern{\'a}ndez-C{\'a}denas and Jerzy Krupinski",

year = "2020",

month = feb,

day = "18",

doi = "10.1038/s41598-020-59641-9",

language = "English",

volume = "10",

journal = "Scientific Reports",

issn = "2045-2322",

publisher = "Nature publishing group",

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Cullell, N, Carrera, C, Muiño, E, Torres-Aguila, N-P, Cárcel-Márquez, J, González-Sánchez, J, Gallego-Fabrega, C, Molina, J, Besora, S, Sotoca, J, Buongiorno, M-T, Jiménez-Conde, J, Giralt-Steinhauer, E, de Torres-Chacón, R, Montaner, J, Mancha, F, Cabezas, JA, Martí-Fàbregas, J, Prats-Sánchez, L, Camps-Renom, P, Purroy, F, Cambray, S, Del Mar Freijo, M, Vives-Bauzá, C, Tur, S, Font, M-À, López-Cancio, E, Hernandez-Perez, M, Obach, V, Calleja, A, Arenillas, J, Rodríguez-Yáñez, M, Castillo, J, Sobrino, T, Fernández-Cádenas, I & Krupinski, J 2020, 'Genome-Wide Association Study of VKORC1 and CYP2C9 on acenocoumarol dose, stroke recurrence and intracranial haemorrhage in Spain', Scientific Reports, vol. 10, 2806. https://doi.org/10.1038/s41598-020-59641-9

TY - JOUR

T1 - Genome-Wide Association Study of VKORC1 and CYP2C9 on acenocoumarol dose, stroke recurrence and intracranial haemorrhage in Spain

AU - Cullell, Natalia

AU - Carrera, Caty

AU - Muiño, Elena

AU - Torres-Aguila, Nuria-Paz

AU - Cárcel-Márquez, Jara

AU - González-Sánchez, Jonathan

AU - Gallego-Fabrega, Cristina

AU - Molina, Jessica

AU - Besora, Sarah

AU - Sotoca, Javier

AU - Buongiorno, Maria-Teresa

AU - Jiménez-Conde, Jordi

AU - Giralt-Steinhauer, Eva

AU - de Torres-Chacón, Reyes

AU - Montaner, Joan

AU - Mancha, Fernando

AU - Cabezas, Juan A

AU - Martí-Fàbregas, Joan

AU - Prats-Sánchez, Luis

AU - Camps-Renom, Pol

AU - Purroy, Francisco

AU - Cambray, Serafi

AU - Del Mar Freijo, María

AU - Vives-Bauzá, Cristòfol

AU - Tur, Silvia

AU - Font, Maria-Àngels

AU - López-Cancio, Elena

AU - Hernandez-Perez, Maria

AU - Obach, Victor

AU - Calleja, Ana

AU - Arenillas, Juan

AU - Rodríguez-Yáñez, Manuel

AU - Castillo, José

AU - Sobrino, Tomas

AU - Fernández-Cádenas, Israel

AU - Krupinski, Jerzy

PY - 2020/2/18

Y1 - 2020/2/18

N2 - Acenocoumarol is an oral anticoagulant with significant interindividual dose variations. Variants in CYP2C9 and VKORC1 have been associated with acenocoumarol maintenance dose. We analysed whether any of the 49 polymorphisms in CYP2C9 and VKORC1 previously associated with acenocoumarol maintenance dose in a Genome-Wide Association study (GWAs) in Dutch population are associated with stroke recurrence, intracranial haemorrhage (ICH) and acenocoumarol maintenance dose in a Spanish population. We performed a GWAs using Human Core Exome-chip (Illumina) in 78 patients stroke patients treated with acenocoumarol for secondary prevention enrolled as part of the prospective investigator-initiated study (IIS) SEDMAN Study. Patients were followed-up a median of 12.8 months. Three and eight patients had recurrent stroke and ICH events, respectively. We found 14 of the 49 published variants associated with acenocoumarol maintenance dose (p < 0.05). Six polymorphisms were associated with stroke recurrence and four variants with ICH (p < 0.05). In conclusion, variants in VKORC1 and CYP2C9 are associated with acenocoumarol maintenance dose, stroke recurrence and ICH in a Spanish cohort. These results highlight the relevance of studying pharmacogenetics associated with efficacy and safety of anticoagulant drugs and justify studies with larger sample size and different ethnic populations.

AB - Acenocoumarol is an oral anticoagulant with significant interindividual dose variations. Variants in CYP2C9 and VKORC1 have been associated with acenocoumarol maintenance dose. We analysed whether any of the 49 polymorphisms in CYP2C9 and VKORC1 previously associated with acenocoumarol maintenance dose in a Genome-Wide Association study (GWAs) in Dutch population are associated with stroke recurrence, intracranial haemorrhage (ICH) and acenocoumarol maintenance dose in a Spanish population. We performed a GWAs using Human Core Exome-chip (Illumina) in 78 patients stroke patients treated with acenocoumarol for secondary prevention enrolled as part of the prospective investigator-initiated study (IIS) SEDMAN Study. Patients were followed-up a median of 12.8 months. Three and eight patients had recurrent stroke and ICH events, respectively. We found 14 of the 49 published variants associated with acenocoumarol maintenance dose (p < 0.05). Six polymorphisms were associated with stroke recurrence and four variants with ICH (p < 0.05). In conclusion, variants in VKORC1 and CYP2C9 are associated with acenocoumarol maintenance dose, stroke recurrence and ICH in a Spanish cohort. These results highlight the relevance of studying pharmacogenetics associated with efficacy and safety of anticoagulant drugs and justify studies with larger sample size and different ethnic populations.

U2 - 10.1038/s41598-020-59641-9

DO - 10.1038/s41598-020-59641-9

M3 - Article

C2 - 32071341

SN - 2045-2322

VL - 10

JO - Scientific Reports

JF - Scientific Reports

M1 - 2806

ER -

Genome-Wide Association Study of VKORC1 and CYP2C9 on acenocoumarol dose, stroke recurrence and intracranial haemorrhage in Spain

Abstract

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