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 7â989â272 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.
Subject(s)
Cerebral Hemorrhage/chemically induced , Cerebral Hemorrhage/genetics , Ischemic Stroke/drug therapy , Polymorphism, Single Nucleotide , Thrombolytic Therapy/adverse effects , Tissue Plasminogen Activator/adverse effects , Transcription Factors/genetics , Aged , Aged, 80 and over , Female , Fibrinolytic Agents/adverse effects , Genome-Wide Association Study , Humans , Ischemic Stroke/genetics , Male , Middle Aged , Treatment OutcomeABSTRACT
Introducción. La relación del nivel socioeconómico con las tasas de incidencia y de mortalidad por ictus está bien establecida. La evidencia de la relación con la supervivencia de los pacientes tras el ictus es menos concluyente. El nivel educativo es una medida de nivel socioeconómico muy utilizada en estudios con personas de edad avanzada. Objetivo. Estudiar la relación de la supervivencia en el primer año tras el ictus con el nivel de estudios. Pacientes y métodos. Se analizaron los datos de 544 pacientes con ictus isquémico agudo ingresados en los hospitales públicos de Bizkaia (España), seleccionados consecutivamente. Se obtuvieron datos por entrevista a pacientes o acompañantes y de historia clínica. Se estudiaron variables sobre situación funcional previa, gravedad del ictus, factores de riesgo cardiovascular y de atención al ictus. Se hizo un seguimiento de 12 meses para registrar, en su caso, la fecha de fallecimiento. Se realizó un análisis univariado y multivariado para identificar la relación del nivel de estudios con la supervivencia. Resultados. Tras 12 meses, sobrevivían 203 mujeres (86%) y 273 hombres (88,6%). En ambos sexos, las personas con menos estudios tuvieron peor situación funcional previa, mayor gravedad y fallecieron en mayor proporción. En el análisis multivariado, el nivel de estudios se mantuvo asociado con la supervivencia en el modelo ajustado para los hombres. Conclusiones. La diversidad de nivel educativo marca diferencias en la supervivencia de los pacientes con ictus isquémico en nuestro entorno. El impacto de este factor fue mayor en los hombres que en las mujeres
Aim. To assess the relationship between one-year survival after stroke and level of education. Patients and methods. We analysed data on 544 consecutively recruited patients admitted for acute ischaemic stroke in one the public hospitals of Bizkaia (Spain). Data were obtained through interviews with patients or accompanying persons and from medical records. We studied variables concerning previous functional status, stroke severity, cardiovascular risk factors and stroke care provided. Patients were followed up for 12 months and the dates of any deaths were recorded. Univariate and multivariate analyses were carried out to assess the relationship between level of education and survival. Results. A total of 203 (86%) women and 273 (88.6%) men were alive at 12 months. In both sexes, individuals with a lower level of education had poorer previous functional status, more severe strokes and higher mortality rates. In the multivariate analysis, the association between level of education and survival remained significant in the adjusted model in men. Conclusions. In our setting, there are differences in the survival of patients with ischaemic stroke as a function of level of education. The impact of this factor was greater in men than women
