作者
Cristina Gallego-Fábrega,Gerard Temprano‐Sagrera,Jara Cárcel‐Márquez,Elena Muiño,Natàlia Cullell,Miquel Lledós,Laia Llucià‐Carol,Jesús M. Martín‐Campos,Tomás Sobrino,José Castillo,Mónica Millán,Lucía Muñoz-Narbona,Elena López‐Cancio,Marc Ribó,José Álvarez-Sabín,Jordi Jiménez‐Conde,Jaume Roquer,Sílvia Tur,Vı́ctor Obach,Juan F. Arenillas,Tomás Segura,Gemma Serrano‐Heras,Joan Martí‐Fàbregas,M M Freijo-Guerrero,Francisco Moniche,Mar Castellanos,Alanna C. Morrison,Nicholas L. Smith,Paul S. de Vries,Israel Fernández-Cadenas,Maria Sabater‐Lleal
摘要
Background Thrombolytic recombinant tissue-plasminogen activator (r-tPA) treatment is the only pharmacological intervention available in the ischemic stroke acute phase. This treatment is associated with an increased risk of intracerebral hemorrhages, known as hemorrhagic transformations (HT), which worsen patient’s prognosis. Objectives To investigate the association between genetically-determined natural hemostatic factors’ levels, with increased risk of HT after r-tPA treatment. Patients/Methods Using genome-wide association studies data on risk of HT after r-tPA treatment, and from seven hemostatic factors (VII, VIII, von-Willebrand factor [VWF], XI, fibrinogen, plasminogen activator inhibitor-1 [PAI-1], and tissue plasminogen activator [tPA]), we performed local and global genetic correlations estimation multi-trait analyses and colocalization, and two-sample Mendelian Randomization (MR) analyses between hemostatic factors and HT. Results Local correlations identified a genomic region on chromosome 16 with shared covariance: fibrinogen-HT, p-value=2.45×10-11. Multi-trait analysis between fibrinogen-HT revealed 3 loci that simultaneously regulate circulating levels of fibrinogen and risk of HT: rs56026866 (PLXND1), p-value=8.80×10-10, rs1421067 (CHD9), p-value=1.81×10-14, and rs34780449, near ROBO1 gene, p-value=1.64×10-08. Multi-trait analysis between VWF-HT showed a novel common association regulating VWF and risk of HT after r-tPA at rs10942300 (ZNF366), p-value=1.81×10-14. MR analysis did not find significant causal associations, although a nominal association was observed for FXI-HT (inverse variance weighted estimate [SE], 0.07[-0.29–0.00]; OR 0.87[0.75–1.00], raw-p-value=0.05). Conclusions 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 are needed.