A predictive clinical-genetic model of tissue plasminogen activator response in acute ischemic stroke

Del Río-Espínola, Alberto; Fernández-Cadenas, Israel; Giralt, Dolors; Quiroga, Adoración; Gutiérrez-Agulló, María; Quintana, Manuel; Fernández-Álvarez, Patricia; Domingues-Montanari, Sophie; Mendióroz, Maite; Delgado, Pilar; Turck, Natacha; Ruiz Laza, Agustín; Ribó, Marc; Castellanos, María del Mar; Obach, Victor; Martínez, Sergi; Freijo Guerrero, María del Mar; Jiménez-Conde, Jordi; Cuadrado-Godia, Elisa; Roquer, Jaume; Chacón, Pilar; Martí-Fábregas, Joan; Sánchez, Jean Charles; Montaner, Joan

doi:10.1002/ana.23664

Title

A predictive clinical-genetic model of tissue plasminogen activator response in acute ischemic stroke

Date

2012-06-09

Citation

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 MM, Jiménez-Conde J, Cuadrado-Godia E, Roquer J, Chacón P, Martí-Fábregas J, Sánchez JC; GRECOS Investigators; Montaner J. A predictive clinical-genetic model of tissue plasminogen activator response in acute ischemic stroke. Ann Neurol. 2012 Nov;72(5):716-29.

Abstract

[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 clinical-genetic 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.