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- Carrera, C., et al.
(författare)
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Single nucleotide variations in ZBTB46 are associated with post-thrombolytic parenchymal haematoma
- 2021
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Ingår i: Brain. - : Oxford University Press (OUP). - 0006-8950 .- 1460-2156. ; 144, s. 2416-2426
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Tidskriftsartikel (refereegranskat)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 x 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 x 10(-8)) were characterized by in silica 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 x 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 x 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 silica 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.
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- Lozano, Manuel, et al.
(författare)
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Prenatal Metals Exposure and pre-adolescents’ Emotional and Behavioral Problems
- 2023
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Ingår i: Exposure and Health. - 2451-9766.
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Tidskriftsartikel (refereegranskat)abstract
- Emotional and behavioral problems during childhood raise the risk of subsequent developmental of mental disorders. Our aim was to study the association between maternal metal and trace element concentrations during gestation and these problems in 9 year-old children. The study sample comprised Spanish mother-child pairs in the INMA project (n = 1003). Metals and trace elements (As, Cd, Co, Cu, Mo, Ni, Pb, Sb, Se, Tl and Zn) were measured in urine samples collected during pregnancy. Inorganic As metabolites were speciated in a subsample (n = 729). Emotional and behavioral problems were assessed using the Child Behavior Checklist (CBCL) composed of three scales: internalizing, externalizing and total problems. Sociodemographic, dietary and exposure to other environmental pollutants were obtained through questionnaires. Single nucleotide polymorphisms in brain- and metabolism-related genes APOE, BDNF, GSTP1, and PON1 were determined in cord blood. Multivariate negative binomial models were used. The interaction with sex and genotypes was evaluated including interaction terms. A multi-element analysis was carried out by a principal component analysis. Higher concentrations of Cu, monomethylarsonic acid, and Pb during pregnancy were associated with an increased incidence ratio risk (IRR) between 4.6 and 7.5% for internalizing and externalizing problems for all three CBCL scales in the children. Increasing Mo, Ni and Co concentrations were associated with higher IRR for internalizing problems (up to 8%), and Cd for externalizing problems (6.7%). Modifications by sex and genotypes were found for several associations. Multi-element analysis associated multiple metals and trace elements (Ni, Cu, Se, Cd and Pb) with higher internalizing problems.
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