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

作者：del Rio Espinola Alberto; Fernandez Cadenas Israel; Giralt Dolors; Quiroga Adoracion; Gutierrez Agullo Maria; Quintana Manuel; Fernandez Alvarez Patricia; Domingues Montanari Sophie; Mendioroz Maite; Delgado Pilar; Turck Natacha; Ruiz Agustin; Ribo Marc; Castellanos Mar; Obach Victor; Martinez Sergi; Mar Freijo Mari; Jimenez Conde Jordi; Cuadrado Godia Elisa; Roquer Jaume; Chacon Pilar; Marti Fabregas Joan; Sanchez Jean Charles; Montaner Joan^*

来源：Annals of Neurology, 2012, 72(5): 716-729.

DOI：10.1002/ana.23664

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%26gt;T) of F12 was associated with in-hospital death. The rs669 SNP withstood Bonferroni correction for HT (p %26lt; 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%26gt;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

• 出版日期2012-11