A multitrait genetic study of hemostatic factors and hemorrhagic transformation after stroke treatment
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- dc.contributor.author Gallego Fabrega, Cristina
- dc.contributor.author Jiménez Conde, Jordi
- dc.contributor.author Roquer, Jaume
- dc.contributor.author Spanish Stroke Genetic Consortium
- dc.date.accessioned 2024-10-28T07:21:17Z
- dc.date.available 2024-10-28T07:21:17Z
- dc.date.issued 2024
- dc.description.abstract Background: Thrombolytic recombinant tissue plasminogen activator (r-tPA) treatment is the only pharmacologic intervention available in the ischemic stroke acute phase. This treatment is associated with an increased risk of intracerebral hemorrhages, known as hemorrhagic transformations (HTs), which worsen the patient's prognosis. Objectives: To investigate the association between genetically determined natural hemostatic factors' levels and increased risk of HT after r-tPA treatment. Methods: Using data from genome-wide association studies on the risk of HT after r-tPA treatment and data on 7 hemostatic factors (factor [F]VII, FVIII, von Willebrand factor [VWF], FXI, fibrinogen, plasminogen activator inhibitor-1, and tissue plasminogen activator), we performed local and global genetic correlation estimation multitrait analyses and colocalization and 2-sample Mendelian randomization analyses between hemostatic factors and HT. Results: Local correlations identified a genomic region on chromosome 16 with shared covariance: fibrinogen-HT, P = 2.45 × 10-11. Multitrait analysis between fibrinogen-HT revealed 3 loci that simultaneously regulate circulating levels of fibrinogen and risk of HT: rs56026866 (PLXND1), P = 8.80 × 10-10; rs1421067 (CHD9), P = 1.81 × 10-14; and rs34780449, near ROBO1 gene, P = 1.64 × 10-8. Multitrait analysis between VWF-HT showed a novel common association regulating VWF and risk of HT after r-tPA at rs10942300 (ZNF366), P = 1.81 × 10-14. Mendelian randomization analysis did not find significant causal associations, although a nominal association was observed for FXI-HT (inverse-variance weighted estimate [SE], 0.07 [-0.29 to 0.00]; odds ratio, 0.87; 95% CI, 0.75-1.00; raw P = .05). Conclusion: We identified 4 shared loci between hemostatic factors and HT after r-tPA treatment, suggesting common regulatory mechanisms between fibrinogen and VWF levels and HT. Further research to determine a possible mediating effect of fibrinogen on HT risk is needed.
- dc.format.mimetype application/pdf
- dc.identifier.citation Gallego-Fabrega C, Temprano-Sagrera G, Cárcel-Márquez J, Muiño E, Cullell N, Lledós M, et al. A multitrait genetic study of hemostatic factors and hemorrhagic transformation after stroke treatment. J Thromb Haemost. 2024 Apr;22(4):936-50. DOI: 10.1016/j.jtha.2023.11.027
- dc.identifier.doi http://dx.doi.org/10.1016/j.jtha.2023.11.027
- dc.identifier.issn 1538-7933
- dc.identifier.uri http://hdl.handle.net/10230/68362
- dc.language.iso eng
- dc.publisher Elsevier
- dc.relation.ispartof J Thromb Haemost. 2024 Apr;22(4):936-50
- dc.rights © 2023 The Authors. Published by Elsevier Inc. on behalf of International Society on Thrombosis and Haemostasis. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
- dc.rights.accessRights info:eu-repo/semantics/openAccess
- dc.rights.uri http://creativecommons.org/licenses/by/4.0/
- dc.subject.keyword Fibrinogen
- dc.subject.keyword Hemorrhagic transformation
- dc.subject.keyword Hemostatic factors
- dc.subject.keyword r-tPA treatment
- dc.subject.keyword von Willebrand factor
- dc.title A multitrait genetic study of hemostatic factors and hemorrhagic transformation after stroke treatment
- dc.type info:eu-repo/semantics/article
- dc.type.version info:eu-repo/semantics/publishedVersion