A multitrait genetic study of hemostatic factors and hemorrhagic transformation after stroke treatment
Por:
Gallego-Fabrega C., Temprano-Sagrera G., Cárcel-Márquez J., Muiño E., Cullell N., Lledós M., Llucià-Carol L., Martin-Campos J.M., Sobrino T., Castillo J., Millán M., Muñoz-Narbona L., López-Cancio E., Ribó M., Alvarez-Sabin J., Jiménez-Conde J., Roquer J., Tur S., Obach V., Arenillas J.F., Segura T., Serrano-Heras G., Marti-Fabregas J., Freijo-Guerrero M., Moniche F., Castellanos M.D.M., Morrison A.C., Smith N.L., de Vries P.S., Fernández-Cadenas I., Sabater-Lleal M., Dehghan A., Heath A.S., Reiner A.P., Johnson A., Richmond A., Peters A., van Hylckama Vlieg A., McKnight B., Psaty B.M., Hayward C., Ward-Caviness C., O'Donnell C., Chasman D., Strachan D.P., Tregouet D.A., Mook-Kanamori D., Gill D., Thibord F., Asselbergs F.W., Leebeek F.W.G., Rosendaal F.R., Davies G., Homuth G., Temprano G., Campbell H., Taylor H.A., Bressler J., Huffman J.E., Rotter J.I., Yao J., Wilson J.F., Bis J.C., Hahn J.M., Desch K.C., Wiggins K.L., Díez-Ahijado L., Raffield L.M., Bielak L.F., Yanek L.R., Kleber M.E., Mueller M., Kavousi M., Mangino M., Conomos M.P., Liu M., Brown M.R., Jhun M.-A., Chen M.-H., de Maat M.P.M., Pankratz N., Peyser P.A., Elliot P., Wei P., Wild P.S., Morange P.E., van der Harst P., Yang Q., Marioni R., Li R., Damrauer S.M., Cox S.R., Trompet S., Felix S.B., Völker U., Tang W., Koenig W., Jukema J.W., Guo X.
Publicada:
1 abr 2024
Ahead of Print:
15 dic 2023
Resumen:
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 identi fied a genomic region on chromosome 16 with shared covariance: fibrinogen -HT, P = 2.45 x 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 x 10 -10 ; rs1421067 ( CHD9 ), P = 1.81 x 10 -14 ; and rs34780449, near ROBO1 gene, P = 1.64 x 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 x 10 -14 . Mendelian randomization analysis did not find signi ficant 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 identi fied 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.
Filiaciones:
Gallego-Fabrega C.:
Stroke Pharmacogenomics and Genetics Group, Institut de Recerca Sant Pau (IR SANT PAU), Barcelona, Spain
Temprano-Sagrera G.:
Genomics of Complex Disease Group, Institut de Recerca Sant Pau (IR SANT PAU), Barcelona, Spain
Cárcel-Márquez J.:
Stroke Pharmacogenomics and Genetics Group, Institut de Recerca Sant Pau (IR SANT PAU), Barcelona, Spain
Muiño E.:
Stroke Pharmacogenomics and Genetics Group, Institut de Recerca Sant Pau (IR SANT PAU), Barcelona, Spain
Cullell N.:
Stroke Pharmacogenomics and Genetics Group, Institut de Recerca Sant Pau (IR SANT PAU), Barcelona, Spain
Neurology Unit, Hospital Universitari MútuaTerrassa, Terrassa, Spain
Lledós M.:
Stroke Pharmacogenomics and Genetics Group, Institut de Recerca Sant Pau (IR SANT PAU), Barcelona, Spain
Llucià-Carol L.:
Stroke Pharmacogenomics and Genetics Group, Institut de Recerca Sant Pau (IR SANT PAU), Barcelona, Spain
Martin-Campos J.M.:
Stroke Pharmacogenomics and Genetics Group, Institut de Recerca Sant Pau (IR SANT PAU), Barcelona, Spain
Sobrino T.:
Clinical Neurosciences Research Laboratories, Health Research Institute of Santiago de Compostela (IDIS), Santiago de Compostela, Spain
Castillo J.:
Department of Neurology, Hospital Clínico Universitario de Santiago (CHUS), Santiago de Compostela, Spain
Millán M.:
Department of Neuroscience, Hospital Universitario Hermanos Trias y Pujol (HUGTP), Badalona, Spain
Muñoz-Narbona L.:
Department of Neuroscience, Hospital Universitario Hermanos Trias y Pujol (HUGTP), Badalona, Spain
López-Cancio E.:
Stroke Unit, Neurology Department, Hospital Universitario Central de Asturias (HUCA), Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Oviedo, Spain
Ribó M.:
Stroke Unit, Hospital Universitario Valle de Hebrón (HUVH), Barcelona, Spain
Alvarez-Sabin J.:
Department of Neurology, Hospital Universitario Valle de Hebrón (HUVH), Universitat Autònoma de Barcelona (UAB), Barcelona, Spain
Jiménez-Conde J.:
Department of Neurology, Neurovascular Research Group, Instituto de investigaciones médicas Hospital del Mar (IMIM) Hospital del Mar, Barcelona, Spain
Roquer J.:
Department of Neurology, Neurovascular Research Group, Instituto de investigaciones médicas Hospital del Mar (IMIM) Hospital del Mar, Barcelona, Spain
Tur S.:
Department of Neurology, Hospital Universitario Son Espases (HUSE), Mallorca, Spain
Obach V.:
Department of Neurology, Hospital Clínic i Provincial de Barcelona, Barcelona, Spain
Arenillas J.F.:
Department of Neurology, Hospital Clínico Universitario, University of Valladolid, Valladolid, Spain
Segura T.:
Department of Neurology, Complejo Hospitalario Universitario de Albacete (CHUA), Universidad de Castilla-La Mancha (UCLM), Albacete, Spain
Serrano-Heras G.:
Research Unit, Complejo Hospital Universitario de Albacete (CHUA), Albacete, Spain
Marti-Fabregas J.:
Department of Neurology, Hospital de la Santa Creu i Sant Pau, IIB-Sant Pau, Barcelona, Spain
Freijo-Guerrero M.:
Neurovascular Unit, Biocruces Bizkaia Health Research Institute, Bilbao, Spain
Moniche F.:
Department of Neurology, Hospital Universitario Virgen del Rocio, Instituto de Biomedicina de Sevilla (IBIS), Seville, Spain
Castellanos M.D.M.:
Department of Neurology, Hospital Universitario de A Coruña (CHUAC), Biomedical Research Institute, A Coruña, Spain
Morrison A.C.:
Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, the University of Texas Health Science Center at Houston, Houston, TX, United States
Smith N.L.:
Department of Epidemiology, University of Washington, Seattle, WA, United States
Kaiser Permanente Washington Health Research Institute, Kaiser Permanente Washington, Seattle, WA, United States
Department of Veterans Affairs Office of Research and Development, Seattle Epidemiologic Research and Information Center, Seattle, WA, United States
de Vries P.S.:
Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, the University of Texas Health Science Center at Houston, Houston, TX, United States
Fernández-Cadenas I.:
Stroke Pharmacogenomics and Genetics Group, Institut de Recerca Sant Pau (IR SANT PAU), Barcelona, Spain
Sabater-Lleal M.:
Genomics of Complex Disease Group, Institut de Recerca Sant Pau (IR SANT PAU), Barcelona, Spain
Cardiovascular Medicine Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden
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