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.

RP11-362K2.2:RP11-767I20.1 Genetic Variation Is Associated with Post-Reperfusion Therapy Parenchymal Hematoma. A GWAS Meta-Analysis

“…In a previous work by our group, we explored which SNVs were associated with hemorrhagic transformation through a GWAS, analyzing extreme phenotypes: PH vs. non hemorrhagic transformation in patients undergoing only IVT [ 10 ]. This led to the finding that rs7648433, located in ZBTB46 gene, was associated with this phenotype and it has been implicated in mechanisms such as shear stress and atherosclerosis in other studies.…”

“…Studies genotyped on the same platforms were combined in the discovery cohort. For the replication cohorts data were already imputed [ 10 ].…”

“…There is a genetic predisposition for HTs following intravenous thrombolysis (IVT). This genetic contribution has been explored through candidate genes [ 8 , 9 ] or more recently through a Genome Wide Association Study (GWAS), carried out by our own group [ 10 ]. In this last study, we found that single nucleotide variants (SNVs) in the ZBTB46 gene were associated with PH in patients who underwent IVT [ 10 ].…”

“…This genetic contribution has been explored through candidate genes [ 8 , 9 ] or more recently through a Genome Wide Association Study (GWAS), carried out by our own group [ 10 ]. In this last study, we found that single nucleotide variants (SNVs) in the ZBTB46 gene were associated with PH in patients who underwent IVT [ 10 ]. For this purpose, we studied the extreme phenotype, patients with PH vs. patients without HT, excluding patients with petechial infarction (HI) subtype.…”

“…In the article we mentioned above, published by our group, we found that PH shared a genetic background with deep intracerebral hemorrhage (ICH), lobar ICH, and white matter hyperintensities (WMH) [ 10 ]. After Bonferroni correction, only lobar ICH remained significantly correlated.…”