Single nucleotide variations in ZBTB46 are associated with post-thrombolytic parenchymal haematoma

The International Stroke Genetic Consortium and the Spanish Stroke Genetic Consortium, Caty Carrera, Jara Cárcel-Márquez, Natalia Cullell, Nuria Torres-Águila, Elena Muiño, José Castillo, Tomás Sobrino, Francisco Campos, Emilio Rodríguez-Castro, Laia Llucià-Carol, Mònica Millán, Lucía Muñoz-Narbona, Elena López-Cancio, Alejandro Bustamante, Marc Ribó, José Álvarez-Sabín, Jordi Jiménez-Conde, Jaume Roquer, Eva Giralt-SteinhauerCarolina Soriano-Tárraga, Marina Mola-Caminal, Cristófol Vives-Bauza, Rosa Díaz Navarro, Silvia Tur, Victor Obach, Juan Francisco Arenillas, Tomás Segura, Gemma Serrano-Heras, Joan Martí-Fàbregas, Raquel Delgado-Mederos, M. Mar Freijo-Guerrero, Francisco Moniche, Juan Antonio Cabezas, Mar Castellanos, Cristina Gallego-Fabrega, Jonathan González-Sanchez, Jurek Krupinsky, Daniel Strbian, Turgut Tatlisumak, Vincent Thijs, Robin Lemmens, Agnieszka Slowik, Johanna Pera, Steven Kittner, John Cole, Laura Heitsch, Laura Ibañez, Carlos Cruchaga, Jin Moo Lee, Joan Montaner, Israel Fernandez-Cadenas*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

10 Citations (Scopus)

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 < 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.

Original languageEnglish
Pages (from-to)2416-2426
Number of pages11
JournalBrain
Volume144
Issue number8
Early online date16 Mar 2021
DOIs
Publication statusPublished - 1 Aug 2021

Keywords

  • GWAS
  • Ischaemic stroke
  • Parenchymal haematoma
  • Pharmacogenetics
  • Thrombolysis

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