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

Research output: Contribution to journalArticlepeer-review


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 languageEnglish
Article number2806
Number of pages7
JournalScientific Reports
Publication statusPublished - 18 Feb 2020


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