RESUMEN
BACKGROUND: The biologic agents causing leukoaraiosis are unknown. Our aim was to study the genetic basis of leukoaraiosis. METHODS: We analyzed 212 single nucleotide polymorphisms (SNPs) in 142 patients with ischaemic stroke, generating a total of 30,104 genotypes. Seventy-nine subjects (55.6%) presented leukoaraiosis measured by the Fazekas scale and 69 (48.6%) by ARWMC scale. We analyzed the presence of synergic associations between SNPs using the hfcc software. Finally, functional studies were performed in 56 subjects. The Ingenuity Pathways software (ipa) was used to examine the role of the identified genes. RESULTS: Six SNPs were associated with leukoaraiosis using both measuring scales. After logistic regression adjusted for leukoaraiosis risk factors, the rs2252070 of MMP13 (OR = 4.9, 95%CI: 1.34-17.9, P = 0.016), rs662 of PON1 (OR = 0.37, 95%CI: 0.15-0.87, P = 0.024) and rs1800779 of NOS3 (OR = 3.9, 95%CI: 1.38-11.38, P = 0.01) were independently associated with leukoaraiosis under a dominant/recessive model and the rs2290608 of IL5RA (OR = 0.46, 95%CI: 0.25-0.85, P = 0.013) and rs669 of A2M (OR = 2.5, 95%CI: 1.36-4.83, P = 0.004) under an additive model. Computational analysis showed a synergic association of rs10497212-AA of ITGB6 and rs2290608-GG of IL5RA with leukoaraiosis using both scales. (i) ARWMC (P = 1.3 × 10(-4) ) and (ii) Fazekas (P = 4.5 × 10(-5) ). Functional studies showed that the rs669 SNP was associated with plasma levels of A2M (P = 0.012) and A2M levels with leukoaraiosis in Fazekas scale (P = 0.02). ipa analysis revealed that the genes associated with leukoaraiosis were involved in blood-brain barrier (BBB) homeostasis. CONCLUSIONS: Amongst patients with ischaemic stroke, several genes associated with BBB homeostasis could be involved with a higher risk of leukoaraiosis.
Asunto(s)
Barrera Hematoencefálica/fisiopatología , Isquemia Encefálica/genética , Predisposición Genética a la Enfermedad/genética , Homeostasis/genética , Leucoaraiosis/genética , Accidente Cerebrovascular/genética , Adulto , Anciano , Anciano de 80 o más Años , Isquemia Encefálica/metabolismo , Isquemia Encefálica/fisiopatología , Femenino , Regulación de la Expresión Génica , Humanos , Subunidad alfa del Receptor de Interleucina-5/biosíntesis , Subunidad alfa del Receptor de Interleucina-5/genética , Leucoaraiosis/metabolismo , Leucoaraiosis/fisiopatología , Masculino , Persona de Mediana Edad , Factores de Riesgo , Accidente Cerebrovascular/metabolismo , Accidente Cerebrovascular/fisiopatologíaRESUMEN
BACKGROUND: The angiotensin-converting enzyme 1 (ACE1) gene has been extensively studied in stroke, yet generating conflicting results. The goal of our study was thus to clarify the influence of the ACE1 on the risk of suffering an ischaemic stroke (IS). METHODS: We genotyped the rs4341 (in linkage disequilibrium with the I/D polymorphism) of the ACE1 gene in 531 patients with IS and 549 healthy controls, and the rs1799752 (I/D polymorphism) in a subset of 68 patients with IS and 27 controls. We also performed functional studies by measuring serum ACE protein levels and enzymatic activity in 27 controls, 68 patients with IS at baseline and 35 patients with IS 24 h after onset of stroke symptoms. RESULTS: There was no association of the ACE1 variant with IS, although it affected ACE protein levels (P = 0.001). Indeed, patients with IS showed lower ACE levels than controls in the acute phase (115.9 } 38.9 vs. 174.1 } 56.1 ng/ml, P < 0.001), but not in the chronic phase (168.2 } 51.2, P = 0.673), and ACE protein levels did not differ between IS etiologies. Similar results were found for ACE activity. CONCLUSIONS: The D allele of the ACE1 I/D and ACE protein levels was not associated with a higher risk of IS in Spanish individuals.
Asunto(s)
Ácido Aspártico/genética , Isoleucina/genética , Desequilibrio de Ligamiento/genética , Peptidil-Dipeptidasa A/genética , Polimorfismo Genético , Accidente Cerebrovascular/genética , Anciano , Anciano de 80 o más Años , Femenino , Frecuencia de los Genes , Estudio de Asociación del Genoma Completo , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Peptidil-Dipeptidasa A/metabolismo , España/epidemiologíaRESUMEN
BACKGROUND: Despite t-PA proven benefits related to vessel reopening, up to 13% of stroke patients suffer reocclusions after t-PA. We aimed to analyze whether a functional polymorphism in a fibrinolysis inhibitor gene [plasminogen activator inhibitor-1 (PAI-1)] might be associated with reocclusion rates after stroke thrombolytic therapy. METHODS: 165 patients with ischemic stroke who received t-PA < 3 h were studied. Reocclusion and recanalization was diagnosed by transcranial Doppler. PAI-1 4G/5G polymorphism determination was performed by sequencing. PAI-1 mRNA was studied by real-time PCR analysis. National institutes of health stroke scale (NIHSS) was serially measured since patients arrival to assess the neurological outcome, and modified ranking scale (mRS) at 3rd month was used to evaluate functional outcome following stroke. RESULTS: PAI-1 4G/4G patients had higher reocclusion rates (4G/4G = 12.5% versus other genotypes = 2.7%, p = 0.025). . In a logistic regression, the 4G/4G genotype was the only factor associated with reocclusion (OR = 15.16 95%, CI = 1.4-163.4, p = 0.025). 4G/4G genotype was also associated with poor functional outcome at 3rd month (4G/4G = 4 versus others genotypes = 3, p = 0.017) and with mRNA levels at 12 h post stroke symptoms onset (4G/4G patients = 2.01% versus other genotypes = 0.68%, p = 0.034). CONCLUSIONS: PAI-1 4G/4G genotype is associated with reocclusion rates and poor functional outcome among stroke patients treated with t-PA.
Asunto(s)
Predisposición Genética a la Enfermedad , Inhibidor 1 de Activador Plasminogénico/genética , Polimorfismo Genético/genética , Terapia Trombolítica/efectos adversos , Trombosis/inducido químicamente , Trombosis/genética , Anciano , Anciano de 80 o más Años , Distribución de Chi-Cuadrado , Femenino , Frecuencia de los Genes , Humanos , Masculino , Inhibidor 1 de Activador Plasminogénico/metabolismo , ARN Mensajero/genética , Estadísticas no Paramétricas , Accidente Cerebrovascular/tratamiento farmacológico , Accidente Cerebrovascular/genética , Trombosis/diagnóstico por imagen , Factores de Tiempo , Ultrasonografía Doppler Transcraneal/métodosRESUMEN
An accurate understanding of the mechanisms underlying an individual's response to rt-PA treatment is critical to improve stroke patients' management. We thus reviewed the literature in order to identify biochemical and genetic factors that have been associated with safety and efficacy of rt-PA administration after stroke.