1. A predictive clinical-genetic model of tissue plasminogen activator response in acute ischemic stroke
- Author
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Israel Fernandez-Cadenas, Patricia Fernández‐Álvarez, Pilar Delgado, Adoración Quiroga, Alberto del Río-Espínola, Victor Obach, Agustín Ruiz, Elisa Cuadrado-Godia, Pilar Chacón, Joan Martí-Fàbregas, Joan Montaner, Dolors Giralt, Jordi Jiménez-Conde, Natacha Turck, Mari Mar Freijo, Sergi Martínez, Mar Castellanos, Maite Mendioroz, Jaume Roquer, Manuel Quintana, Maria Gutiérrez‐Agulló, Jean-Charles Sanchez, Sophie Domingues-Montanari, and Marc Ribó
- Subjects
Male ,Time Factors ,030204 cardiovascular system & hematology ,Tissue plasminogen activator ,Intracranial Hemorrhages/etiology/genetics ,Tissue Plasminogen Activator/therapeutic use ,Cohort Studies ,0302 clinical medicine ,Alpha-Macroglobulins/genetics/metabolism ,Acute ischemic stroke ,Mortality rate ,Factor XII/genetics/metabolism ,Polymorphism, Single Nucleotide/genetics ,3. Good health ,Stroke ,Neurology ,Tissue Plasminogen Activator ,Factor XII ,Cardiology ,Spain/epidemiology ,Female ,Intracranial Hemorrhages ,medicine.drug ,medicine.medical_specialty ,Genotype ,Polymorphism, Single Nucleotide ,03 medical and health sciences ,Predictive Value of Tests ,Internal medicine ,Genetic variation ,medicine ,Clinical genetic ,Humans ,alpha-Macroglobulins ,ddc:576 ,Genetic Association Studies ,Retrospective Studies ,Models, Genetic ,business.industry ,Stroke/drug therapy/genetics/mortality ,Surgery ,ROC Curve ,Pharmacogenetics ,Spain ,Case-Control Studies ,Ischemic stroke ,Neurology (clinical) ,business ,Tomography, X-Ray Computed ,030217 neurology & neurosurgery - Abstract
Objective: Wide interindividual variability exists in response to tissue plasminogen activator (t-PA) treatment in the acute phase of ischemic stroke. We aimed to find genetic variations associated with hemorrhagic transformation (HT) and mortality rates after t-PA. We then generated a clinicalgenetic model for predicting t-PA response. Methods: Our prospective study used SNPlex to genotype 140 single nucleotide polymorphisms (SNPs) from 97 candidate genes in 3 patient cohorts. The cohorts included 1,172 patients who were treated with t-PA; 20.9% of them developed HT as evaluated by systematic brain computed tomography scan, and 10.6% died. A predictive model was generated by logistic regression (LR). Functional studies included real time quantitative polymerase chain reaction, nephelometry, and Western blot for alpha-2-macroglobulin (A2M) and activated partial thromboplastin time measurement for coagulation factor XII (FXII). Results: Replication analysis revealed that the SNP rs669 (Val1000Ile) in A2M was associated with HT, and rs1801020 (-4C>T) of F12 was associated with in-hospital death. The rs669 SNP withstood Bonferroni correction for HT (p < 3.57E-4). LR-based scores predicted HT occurrence (p = 9.13E-15) and in-hospital mortality (p = 8.7E-9) and were validated in an independent cohort. Val1000Ile modified A2M serum levels at baseline and after t-PA infusion, but not mRNA expression or protein structure; -4C>T affected FXII activity both prior to and after t-PA treatment. Interpretation: Two functional polymorphisms were consistently associated with t-PA safety. Our validated LR-based score predicts t-PA safety in the Spanish population. ANN NEUROL 2012;72:716729
- Published
- 2012
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