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

被引:37
作者
del Rio-Espinola, Alberto [1 ,2 ,3 ]
Fernandez-Cadenas, Israel [1 ,2 ,3 ]
Giralt, Dolors [1 ,2 ,3 ]
Quiroga, Adoracion [13 ]
Gutierrez-Agullo, Maria [14 ]
Quintana, Manuel [15 ]
Fernandez-Alvarez, Patricia [13 ]
Domingues-Montanari, Sophie [1 ,2 ,3 ]
Mendioroz, Maite [1 ,2 ,3 ]
Delgado, Pilar [1 ,2 ,3 ]
Turck, Natacha [4 ]
Ruiz, Agustin [5 ]
Ribo, Marc [15 ]
Castellanos, Mar [6 ]
Obach, Victor [7 ,8 ]
Martinez, Sergi [9 ]
Mar Freijo, Mari [10 ]
Jimenez-Conde, Jordi [11 ,12 ]
Cuadrado-Godia, Elisa [11 ,12 ]
Roquer, Jaume [11 ,12 ]
Chacon, Pilar [14 ]
Marti-Fabregas, Joan [9 ]
Sanchez, Jean Charles [4 ]
Montaner, Joan [1 ,2 ,3 ]
机构
[1] Autonomous Univ Barcelona, Neurovasc Res Lab, Barcelona, Spain
[2] Autonomous Univ Barcelona, Dept Neurol, Neurovasc Unit, Barcelona, Spain
[3] Autonomous Univ Barcelona, Dept Med, Barcelona, Spain
[4] Med Univ Ctr, Dept Struct Biol & Bioinformat, Biomed Prote Res Grp, Geneva, Switzerland
[5] Neocodex, Dept Struct Genom, Seville, Spain
[6] Dr Josep Trueta Univ Hosp, Girona Inst Biomed Invest, Dept Neurol, Girona, Spain
[7] Univ Barcelona, Stroke Unit, Dept Neurol Sci, Hosp Clin, Barcelona, Spain
[8] Univ Barcelona, August Pi & Sunyer Inst Biomed Invest, Barcelona, Spain
[9] Santa Creu & St Pau Hosp, Dept Neurol, Barcelona, Spain
[10] Basurto Hosp, Dept Neurol, Bilbao, Spain
[11] Hosp Mar, Dept Neurol, Barcelona, Spain
[12] Pompeu Fabra Univ, Ctr Genom Regulat, Barcelona, Spain
[13] Vall dHebron Hosp, Expt Cardiol Res Lab, Barcelona, Spain
[14] Vall dHebron Hosp, Dept Biochem, Lipids Unit, Barcelona, Spain
[15] Vall dHebron Hosp, Dept Neurol, Barcelona, Spain
关键词
PREGNANCY ZONE PROTEIN; FACTOR-XII GENE; HEMORRHAGIC TRANSFORMATION; THROMBOLYTIC THERAPY; T-PA; COAGULATION; ANGIOEDEMA; RISK; POLYMORPHISM; ALPHA(2)-MACROGLOBULIN;
D O I
10.1002/ana.23664
中图分类号
R74 [神经病学与精神病学];
学科分类号
摘要
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>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;72:716729
引用
收藏
页码:716 / 729
页数:14
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