TY - JOUR
T1 - Single nucleotide variations in ZBTB46 are associated with post-thrombolytic parenchymal haematoma
AU - The International Stroke Genetic Consortium and the Spanish Stroke Genetic Consortium
AU - Carrera, Caty
AU - Cárcel-Márquez, Jara
AU - Cullell, Natalia
AU - Torres-Águila, Nuria
AU - Muiño, Elena
AU - Castillo, José
AU - Sobrino, Tomás
AU - Campos, Francisco
AU - Rodríguez-Castro, Emilio
AU - Llucià-Carol, Laia
AU - Millán, Mònica
AU - Muñoz-Narbona, Lucía
AU - López-Cancio, Elena
AU - Bustamante, Alejandro
AU - Ribó, Marc
AU - Álvarez-Sabín, José
AU - Jiménez-Conde, Jordi
AU - Roquer, Jaume
AU - Giralt-Steinhauer, Eva
AU - Soriano-Tárraga, Carolina
AU - Mola-Caminal, Marina
AU - Vives-Bauza, Cristófol
AU - Navarro, Rosa Díaz
AU - Tur, Silvia
AU - Obach, Victor
AU - Arenillas, Juan Francisco
AU - Segura, Tomás
AU - Serrano-Heras, Gemma
AU - Martí-Fàbregas, Joan
AU - Delgado-Mederos, Raquel
AU - Freijo-Guerrero, M. Mar
AU - Moniche, Francisco
AU - Cabezas, Juan Antonio
AU - Castellanos, Mar
AU - Gallego-Fabrega, Cristina
AU - González-Sanchez, Jonathan
AU - Krupinsky, Jurek
AU - Strbian, Daniel
AU - Tatlisumak, Turgut
AU - Thijs, Vincent
AU - Lemmens, Robin
AU - Slowik, Agnieszka
AU - Pera, Johanna
AU - Kittner, Steven
AU - Cole, John
AU - Heitsch, Laura
AU - Ibañez, Laura
AU - Cruchaga, Carlos
AU - Lee, Jin Moo
AU - Montaner, Joan
AU - Fernandez-Cadenas, Israel
N1 - Funding: The GENISIS study is funded by the National Institute of Health (K23 NS099487, and R01NIH NS085419). The Neurovascular Research Laboratory is supported by the Spanish stroke research network (INVICTUS plus). The Stroke Pharmacogenomics and Genetics Laboratory is supported by the Spanish stroke research network (INVICTUS plus); the Generation Project (PI15/01978) and the Pre-Test Stroke Project (PMP15/00022) are funded by the Instituto de Salud Carlos III and Fondo Europeo de Desarrollo Regional (ISCIII-FEDER). The Neurovascular Research Group, IMIM is supported by INVICTUS plus (RD16/0019/0002). The Biomedical Research Institute Hospital de la Santa Creu i Sant Pau, IIB Sant Pau is supported by INVICTUS plus (RD16/0019/0010). Ibiostroke (AC19/00106), Maestro Project (PI18/01338) is supported by the Instituto de Salud Carlos III and Fondo Europeo de Desarrollo Regional (ISCIII-FEDER) and the Epigenisis project is supported by Marato TV3 (201711.30). I.F.-C. (CPII17/00021), T.S. (CPII17/00027) and F.C. (CPII19/00020) are recipients of a research contract from the Miguel Servet Program from the Instituto de Salud Carlos III. A.B. is supported by a Juan Rodes research contract from the Carlos III Health Institute (JR16/00008). J.C.-M. is supported by an AGAUR Contract (agencia de gestio d'ajuts universitaris i de recerca; FI_DGR 2019, grant number 2019_FI_B 00853) co-financed with Fons Social Europeu (FSE). The Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health, and by NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS.
PY - 2021/8/1
Y1 - 2021/8/1
N2 - Haemorrhagic transformation is a complication of recombinant tissue-plasminogen activator treatment. The most severe form, parenchymal haematoma, can result in neurological deterioration, disability, and death. Our objective was to identify single nucleotide variations associated with a risk of parenchymal haematoma following thrombolytic therapy in patients with acute ischaemic stroke. A fixed-effect genome-wide meta-analysis was performed combining two-stage genome-wide association studies (n = 1904). The discovery stage (three cohorts) comprised 1324 ischaemic stroke individuals, 5.4% of whom had a parenchymal haematoma. Genetic variants yielding a P-value < 0.05 1 × 10-5 were analysed in the validation stage (six cohorts), formed by 580 ischaemic stroke patients with 12.1% haemorrhagic events. All participants received recombinant tissue-plasminogen activator; cases were parenchymal haematoma type 1 or 2 as defined by the European Cooperative Acute Stroke Study (ECASS) criteria. Genome-wide significant findings (P < 5 × 10-8) were characterized by in silico functional annotation, gene expression, and DNA regulatory elements. We analysed 7989272 single nucleotide polymorphisms and identified a genome-wide association locus on chromosome 20 in the discovery cohort; functional annotation indicated that the ZBTB46 gene was driving the association for chromosome 20. The top single nucleotide polymorphism was rs76484331 in the ZBTB46 gene [P = 2.49 × 10-8; odds ratio (OR): 11.21; 95% confidence interval (CI): 4.82-26.55]. In the replication cohort (n = 580), the rs76484331 polymorphism was associated with parenchymal haematoma (P = 0.01), and the overall association after meta-analysis increased (P = 1.61 × 10-8; OR: 5.84; 95% CI: 3.16-10.76). ZBTB46 codes the zinc finger and BTB domain-containing protein 46 that acts as a transcription factor. In silico studies indicated that ZBTB46 is expressed in brain tissue by neurons and endothelial cells. Moreover, rs76484331 interacts with the promoter sites located at 20q13. In conclusion, we identified single nucleotide variants in the ZBTB46 gene associated with a higher risk of parenchymal haematoma following recombinant tissue-plasminogen activator treatment.
AB - Haemorrhagic transformation is a complication of recombinant tissue-plasminogen activator treatment. The most severe form, parenchymal haematoma, can result in neurological deterioration, disability, and death. Our objective was to identify single nucleotide variations associated with a risk of parenchymal haematoma following thrombolytic therapy in patients with acute ischaemic stroke. A fixed-effect genome-wide meta-analysis was performed combining two-stage genome-wide association studies (n = 1904). The discovery stage (three cohorts) comprised 1324 ischaemic stroke individuals, 5.4% of whom had a parenchymal haematoma. Genetic variants yielding a P-value < 0.05 1 × 10-5 were analysed in the validation stage (six cohorts), formed by 580 ischaemic stroke patients with 12.1% haemorrhagic events. All participants received recombinant tissue-plasminogen activator; cases were parenchymal haematoma type 1 or 2 as defined by the European Cooperative Acute Stroke Study (ECASS) criteria. Genome-wide significant findings (P < 5 × 10-8) were characterized by in silico functional annotation, gene expression, and DNA regulatory elements. We analysed 7989272 single nucleotide polymorphisms and identified a genome-wide association locus on chromosome 20 in the discovery cohort; functional annotation indicated that the ZBTB46 gene was driving the association for chromosome 20. The top single nucleotide polymorphism was rs76484331 in the ZBTB46 gene [P = 2.49 × 10-8; odds ratio (OR): 11.21; 95% confidence interval (CI): 4.82-26.55]. In the replication cohort (n = 580), the rs76484331 polymorphism was associated with parenchymal haematoma (P = 0.01), and the overall association after meta-analysis increased (P = 1.61 × 10-8; OR: 5.84; 95% CI: 3.16-10.76). ZBTB46 codes the zinc finger and BTB domain-containing protein 46 that acts as a transcription factor. In silico studies indicated that ZBTB46 is expressed in brain tissue by neurons and endothelial cells. Moreover, rs76484331 interacts with the promoter sites located at 20q13. In conclusion, we identified single nucleotide variants in the ZBTB46 gene associated with a higher risk of parenchymal haematoma following recombinant tissue-plasminogen activator treatment.
KW - GWAS
KW - Ischaemic stroke
KW - Parenchymal haematoma
KW - Pharmacogenetics
KW - Thrombolysis
U2 - 10.1093/brain/awab090
DO - 10.1093/brain/awab090
M3 - Article
C2 - 33723576
AN - SCOPUS:85114073971
SN - 0006-8950
VL - 144
SP - 2416
EP - 2426
JO - Brain
JF - Brain
IS - 8
ER -