title: A predictive clinical-genetic model of tissue plasminogen activator response in acute ischemic stroke.
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.
  
  
  CONCLUSIONS
  Two functional polymorphisms were consistently associated with t-PA safety. Our validated LR-based score predicts t-PA safety in the Spanish population.
authors.affiliation: Neurovascular Research Laboratory and Neurovascular Unit, Departments of Neurology and Medicine Departments, Autonomous University of Barcelona, Passeig Vall d'Hebron 119-129, Barcelona, Spain.
authors.forename: Alberto
authors.initials: A
authors.lastname: del Río-Espínola
authors.forename: Israel
authors.initials: I
authors.lastname: Fernández-Cadenas
authors.forename: Dolors
authors.initials: D
authors.lastname: Giralt
authors.forename: Adoracion
authors.initials: A
authors.lastname: Quiroga
authors.forename: Maria
authors.initials: M
authors.lastname: Gutiérrez-Agulló
authors.forename: Manuel
authors.initials: M
authors.lastname: Quintana
authors.forename: Patricia
authors.initials: P
authors.lastname: Fernández-Álvarez
authors.forename: Sophie
authors.initials: S
authors.lastname: Domingues-Montanari
authors.forename: Maite
authors.initials: M
authors.lastname: Mendióroz
authors.forename: Pilar
authors.initials: P
authors.lastname: Delgado
authors.forename: Natacha
authors.initials: N
authors.lastname: Turck
authors.forename: Agustin
authors.initials: A
authors.lastname: Ruíz
authors.forename: Marc
authors.initials: M
authors.lastname: Ribó
authors.forename: Mar
authors.initials: M
authors.lastname: Castellanos
authors.forename: Victor
authors.initials: V
authors.lastname: Obach
authors.forename: Sergi
authors.initials: S
authors.lastname: Martínez
authors.forename: Mari Mar
authors.initials: MM
authors.lastname: Freijo
authors.forename: Jordi
authors.initials: J
authors.lastname: Jiménez-Conde
authors.forename: Elisa
authors.initials: E
authors.lastname: Cuadrado-Godia
authors.forename: Jaume
authors.initials: J
authors.lastname: Roquer
authors.forename: Pilar
authors.initials: P
authors.lastname: Chacón
authors.forename: Joan
authors.initials: J
authors.lastname: Martí-Fábregas
authors.forename: Jean Charles
authors.initials: JC
authors.lastname: Sánchez
authors.forename: Joan
authors.initials: J
authors.lastname: Montaner
mesh_terms: D016022:Case-Control Studies; D015331:Cohort Studies; D005174:Factor XII / Q000235:genetics / Q000378:metabolism; D005260:Female; D056726:Genetic Association Studies; D005838:Genotype; D006801:Humans; D020300:Intracranial Hemorrhages / Q000209:etiology / Q000235:genetics; D008297:Male; D008957:Models, Genetic; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011237:Predictive Value of Tests; D012372:ROC Curve; D012189:Retrospective Studies; D013030:Spain / Q000453:epidemiology; D020521:Stroke / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality; D013997:Time Factors; D010959:Tissue Plasminogen Activator / Q000627:therapeutic use*; D014057:Tomography, X-Ray Computed; D000511:alpha-Macroglobulins / Q000235:genetics / Q000378:metabolism
chemical_list: D000511:alpha-Macroglobulins; D005174:Factor XII; D010959:Tissue Plasminogen Activator