Single nucleotide variations in ZBTB46 are associated with post-thrombolytic parenchymal haematoma
Authors: Carrera Caty , Cárcel-Márquez Jara , Cullell Natalia , Torres-Águila Nuria , Muiño Elena , Castillo José , Sobrino Tomás , Campos Francisco , Rodríguez-Castro Emilio , Llucià-Carol Laia , Millán Mònica , Muñoz-Narbona Lucía , López-Cancio Elena , Bustamante Alejandro , Ribó Marc , Álvarez-Sabín José , Jiménez-Conde Jordi , Roquer Jaume , Giralt-Steinhauer Eva , Soriano-Tárraga Carolina , Mola-Caminal Marina , Vives-Bauza Cristófol , Navarro Rosa Díaz , Tur Silvia , Obach Victor , Arenillas Juan Francisco , Segura Tomás , Serrano-Heras Gemma , Martí-Fàbregas Joan , Delgado-Mederos Raquel , Freijo-Guerrero M Mar , Moniche Francisco , Cabezas Juan Antonio , Castellanos Mar , Gallego-Fabrega Cristina , González-Sanchez Jonathan , Krupinsky Jurek , Strbian Daniel , Tatlisumak Turgut , Thijs Vincent , Lemmens Robin , Slowik Agnieszka , Pera Johanna , Kittner Steven , Cole John , Heitsch Laura , Ibañez Laura , Cruchaga Carlos , Lee Jin-Moo , Montaner Joan , Fernández-Cadenas Israel 
Published: March 2021

Abstract
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 &lt; 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 &lt; 5 × 10−8) were characterized by in silico functional annotation, gene expression, and DNA regulatory elements. We analysed 7 989 272 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.