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A predictive clinical–genetic model of tissue plasminogen activator response in acute ischemic stroke
Author(s) -
del RíoEspínola Alberto,
FernándezCadenas Israel,
Giralt Dolors,
Quiroga Adoracion,
GutiérrezAgulló Maria,
Quintana Manuel,
FernándezÁlvarez Patricia,
DominguesMontanari Sophie,
Mendióroz Maite,
Delgado Pilar,
Turck Natacha,
Ruíz Agustin,
Ribó Marc,
Castellanos Mar,
Obach Victor,
Martínez Sergi,
Freijo Mari Mar,
JiménezConde Jordi,
CuadradoGodia Elisa,
Roquer Jaume,
Chacón Pilar,
MartíFábregas Joan,
Sánchez Jean Charles,
Montaner Joan
Publication year - 2012
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.23664
Subject(s) - single nucleotide polymorphism , medicine , partial thromboplastin time , gastroenterology , snp , tissue plasminogen activator , genotype , cardiology , coagulation , biology , genetics , gene
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. ANN NEUROL 2012;72:716–729