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

Abstract

Hemorrhagic transformation is a complication of recombinant tissue-plasminogen activator (rtPA) treatment. The most severe form, parenchymal hematoma, can result in neurological deterioration, disability, and death. Our objective is to identify single nucleotide variations associated with a risk of parenchymal hematoma following thrombolytic therapy in acute ischemic stroke patients. A fixed-effect genome-wide metanalysis was performed combining two-stage Genome Wide Association studies (GWAs) (n = 1,904). The Discovery Stage (3 cohorts) comprised 1,324 ischemic stroke individuals, of whom 5.4% had a parenchymal hematoma. Genetic variants yielding a p-value <1x10-5 were analyzed in the Validation Stage (6 cohorts), formed by 580 ischemic stroke patients with 12.1% hemorrhagic events. All the participants received rtPA; cases were parenchymal hematoma type 1 or 2 as defined by the ECASS criteria. Genome-wide significant findings (p < 5x10-8) were characterized by in-silico functional annotation, gene expression, and DNA regulatory elements. We analyzed 7,989,272 single nucleotide polymorphisms (SNPs) 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 Chrosome 20. The top SNP was rs76484331 in the ZBTB46 gene (p = 2.49x10-8; 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 hematoma (p = 0.01), and the overall association after meta-analysis increased (p = 1.61x10-8; 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 conculsion, we identified single nucleotide variants in the ZBTB46 gene associated with a higher risk of parenchymal hematoma following rtPA treatment.