TY - JOUR
T1 - A multitrait genetic study of hemostatic factors and hemorrhagic transformation after stroke treatment
AU - Gallego-Fabrega, Cristina
AU - Temprano-Sagrera, Gerard
AU - Cárcel-Márquez, Jara
AU - Muiño, Elena
AU - Cullell, Natalia
AU - Lledós, Miquel
AU - Llucià-Carol, Laia
AU - Martin-Campos, Jesús M.
AU - Sobrino, Tomás
AU - Castillo, José
AU - Millán, M. nica
AU - Muñoz-Narbona, Lucía
AU - López-Cancio, Elena
AU - Ribó, Marc
AU - Alvarez-Sabin, Jose
AU - Jiménez-Conde, Jordi
AU - Roquer, Jaume
AU - Tur, Silvia
AU - Obach, Victor
AU - Arenillas, Juan F.
AU - Segura, Tomas
AU - Serrano-Heras, Gemma
AU - Marti-Fabregas, Joan
AU - Freijo-Guerrero, Marimar
AU - Moniche, Francisco
AU - Castellanos, Maria del Mar
AU - Morrison, Alanna C.
AU - Spanish Stroke Genetic Consortium
AU - Smith, Nicholas L.
AU - de Vries, Paul S.
AU - Fernández-Cadenas, Israel
AU - Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium
AU - Sabater-Lleal, Maria
AU - Dehghan, Abbas
AU - Heath, Adam S.
AU - Reiner, Alex P.
AU - Johnson, Andrew
AU - Richmond, Anne
AU - Peters, Annette
AU - van Hylckama Vlieg, Astrid
AU - McKnight, Barbara
AU - Psaty, Bruce M.
AU - Hayward, Caroline
AU - Ward-Caviness, Cavin
AU - O'Donnell, Christopher
AU - Chasman, Daniel
AU - Strachan, David P.
AU - Tregouet, David A.
AU - Mook-Kanamori, Dennis
AU - Gill, Dipender
AU - Asselbergs, Folkert W.
AU - Rosendaal, Frits R.
N1 - Publisher Copyright: © 2023 The Authors
PY - 2024/4
Y1 - 2024/4
N2 - 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.
AB - 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.
KW - fibrinogen
KW - hemorrhagic transformation
KW - hemostatic factors
KW - r-tPA treatment
KW - von Willebrand factor
UR - http://www.scopus.com/inward/record.url?scp=85183554315&partnerID=8YFLogxK
U2 - 10.1016/j.jtha.2023.11.027
DO - 10.1016/j.jtha.2023.11.027
M3 - Article
C2 - 38103737
SN - 1538-7933
VL - 22
SP - 936
EP - 950
JO - Journal of thrombosis and haemostasis
JF - Journal of thrombosis and haemostasis
IS - 4
ER -