CD40-1C>T polymorphism (rs1883832) is associated with brain vessel reocclusion after fibrinolysis in ischemic stroke.
OBJECTIVE
To find genetic predictors of reocclusion after successful fibrinolytic therapy during the acute phase of ischemic stroke.


METHODS
This was a case-case prospective study analyzing 236 polymorphisms in a cohort of 222 patients treated with tissue plasminogen activator, from which 16 patients suffered a reocclusion event (7.2%). A predictive scale was generated using independent polymorphisms with a dominant/recessive model and tandem occlusion, weighted by their beta-coefficients in logistic regression.


RESULTS
Using a dominant/recessive model, the rs1800801 SNP from the MGP gene (odds ratio [OR]: 15.25; 95% CI: 2.23-104.46; adjusted p = 0.006) and the rs1883832 SNP from CD40 gene (OR: 0.077; 95% CI: 0.009-0.66; adjusted p = 0.019) were independently associated with reocclusion after logistic regression adjustment by clinical predictors. In an additive model, only the rs1883832 SNP (OR: 4.43; 95% CI: 1.62-12.15; adjusted p = 0.004) was related to reocclusion occurrence. The predictive model that was generated stratified the reocclusion risk from less than 1% to more than 70%. Reocclusions were associated with neurological worsening at 24 h (patients with reocclusion: 26.7%, versus patients without reocclusion: 4.9%; p = 0.002), as it was seen for MGP -7A>G (AA: 17.2% vs AG+GG: 4.5%; p = 0.027), but not for CD40 1C>T (CC: 4.5% vs CT+TT: 7.7%; p = 0.565). There was an association between CD40 -1C>T genotype and CD40 transcriptional activity in peripheral blood mononuclear cells (median expression values TT: 65.75%, CT: 70.80%, CC: 96.00%; p = 0.023). However, CD40 soluble fraction was not a useful biomarker of reocclusion status.


CONCLUSIONS
An association was found between MGP -7A>G and CD40 -1C>T polymorphisms, and reocclusion risk. The predictive scale that was generated permits the stratification of patients by their reocclusion risk with higher accuracy than clinical parameters alone.
del Río-Espínola
Alberto
A
Neurovascular Research Laboratory, Institut de Recerca, Hospital Vall d'Hebron, Pg Vall d'Hebron 119-129, 08035, Barcelona, Spain.
Fernández-Cadenas
Israel
I
Rubiera
Marta
M
Quintana
Manuel
M
Domingues-Montanari
Sophie
S
Mendióroz
Maite
M
Fernández-Morales
Jessica
J
Giralt
Dolors
D
Molina
Carlos A
CA
Alvarez-Sabín
José
J
Montaner
Joan
J
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D015415:Biomarkers / Q000097:blood; D001921:Brain / Q000098:blood supply / Q000187:drug effects / Q000378:metabolism; D002545:Brain Ischemia / Q000150:complications / Q000000981:diagnostic imaging / Q000453:epidemiology / Q000235:genetics*; D002135:Calcium-Binding Proteins / Q000235:genetics; D002339:Carotid Arteries / Q000000981:diagnostic imaging; D016326:Extracellular Matrix Proteins / Q000235:genetics; D005260:Female; D005343:Fibrinolytic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D006801:Humans; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011237:Predictive Value of Tests; D011446:Prospective Studies; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012306:Risk; D020521:Stroke / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000453:epidemiology / Q000209:etiology / Q000235:genetics*; D048008:TNF Receptor-Associated Factor 3 / Q000097:blood / Q000235:genetics*; D010959:Tissue Plasminogen Activator / Q000008:administration & dosage / Q000627:therapeutic use*; D016896:Treatment Outcome; D018608:Ultrasonography, Doppler; D000097568:Matrix Gla Protein
D015415:Biomarkers; D002135:Calcium-Binding Proteins; D016326:Extracellular Matrix Proteins; D005343:Fibrinolytic Agents; D048008:TNF Receptor-Associated Factor 3; D010959:Tissue Plasminogen Activator; D000097568:Matrix Gla Protein; C090656:TRAF3 protein, human