These authors contributed equally to the work.
A predictive clinical–genetic model of tissue plasminogen activator response in acute ischemic stroke†
Article first published online: 27 DEC 2012
Copyright © 2012 American Neurological Association
Annals of Neurology
Volume 72, Issue 5, pages 716–729, November 2012
How to Cite
del Río-Espínola, A., Fernández-Cadenas, I., Giralt, D., Quiroga, A., Gutiérrez-Agulló, M., Quintana, M., Fernández-Álvarez, P., Domingues-Montanari, S., Mendióroz, M., Delgado, P., Turck, N., Ruíz, A., Ribó, M., Castellanos, M., Obach, V., Martínez, S., Freijo, M. M., Jiménez-Conde, J., Cuadrado-Godia, E., Roquer, J., Chacón, P., Martí-Fábregas, J., Sánchez, J. C., the GRECOS Investigators and Montaner, J. (2012), A predictive clinical–genetic model of tissue plasminogen activator response in acute ischemic stroke. Ann Neurol., 72: 716–729. doi: 10.1002/ana.23664
See the Appendix on page 13.
- Issue published online: 27 DEC 2012
- Article first published online: 27 DEC 2012
- Accepted manuscript online: 9 JUN 2012 10:49AM EST
- Manuscript Accepted: 1 JUN 2012
- Manuscript Revised: 29 MAY 2012
- Manuscript Received: 27 DEC 2011
- Neurovascular Research Laboratory receives grants
- Spanish Stroke Research Network. Grant Number: RENEVAS, RD06/0026/0010
- European Stroke Network. Grant Number: EUSTROKE 7FP Health F2-08-202213
- Spanish government. Grant Number: FIS PJ060586
- Ramón Areces Foundation. Grant Number: 2006
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 clinical–genetic model for predicting t-PA response.
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).
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.
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;72:716–729