Identification of genetic risk factors associated with ischaemic stroke in young Mexican patients

Abstract

Background: Numerous polymorphisms in candidate genes coding for haemostatic system proteins have been proposed as risk factors for thrombosis. Methods: We performed a case-control study of consecutive ischaemic stroke survivors aged ≤45 years, treated at our neurology department from 2006 to 2014. Polymerase chain reaction–restriction fragment length polymorphism identified the following polymorphisms: Thr325Ile and Ala147Thr in TAFI, 4 G/5 G in PAI-1, PLA1/A2 in platelet glycoprotein IIb/IIIa, Glu298Asp in eNOS, and C677 T in 5,10-MTHFR. A multivariate logistic regression analysis was performed to evaluate the independent risk of stroke. Results: 204 cases and 204 age- and sex-matched controls were included in the study. Clinical and genetic variables associated with ischaemic stroke were hypertension (P = .03), tobacco use (P = .02), and the polymorphisms Glu298Asp (genotype: P = .001, allele frequency: P = .001) and C677 T (genotype: P = .01); the Ala147Thr, Thr325IIe, 4 G/5 G, and PLA1/A2 mutations were not associated with ischaemic stroke. The 298Asp (P = .03) and T (P = .01) alleles, hypertension (P = .03), tobacco use (P = .01) and family history of stroke (P = .04) were identified as independent risk factors. Conclusion: The polymorphisms Glu298Asp and C677T, affecting the eNOS and 5,10-MTHFR enzymes, respectively, and smoking, hypertension, and family history of stroke were associated with ischaemic stroke in young Mexican patients; this was not the case for the Thr325Ile, Ala147Thr, 4 G/5 G, and PLA1/A2 polymorphisms of the genes coding for fibrinolytic proteins and platelet receptors. Resumen: Introducción: Diversos polimorfismos en genes candidatos que codifican proteínas del sistema hemostático se han propuesto como factores de riesgo para el desarrollo de trombosis. Métodos: Casos y controles, sobrevivientes de enfermedad vascular cerebral (EVC) isquémico idiopático ≤ 45 años de edad del servicio de Neurología incluidos de manera consecutiva del 2006 al 2014. Por PCR-RFLP se identificaron los polimorfismos: Thr325Ile y Ala147Thr del gen de TAFI, 4 G/5 G del gen de PAI-1, PLA1/A2 del gen de la glicoproteína plaquetaria IIb/IIIa, Glu298Asp del gen de eNOS, y C677 T del gen de la 5,10 MTHFR. Se realizó un análisis multivariado de regresión logística para calcular el riesgo independiente de EVC. Resultados: 204 casos y 204 controles pareados por edad y sexo. Se asoció al polimorfismo Glu298Asp (genotipo p=0.001 y frecuencia alélica p=0.001), C677 T (genotipo p=0.01), hipertensión (p=0.03) y tabaquismo (p=0.02) con la presencia de EVC isquémico, no así para los polimorfismos Ala147Thr, Thr325IIe, 4 G/5 G, y PLA1/A2. Se identificó como factor de riesgo independiente al alelo 298Asp (p = 0.03), T (p = 0.01), hipertensión (p = 0.03), tabaquismo (p = 0.01) y AHFEAT (p = 0.04). Conclusiones: Los polimorfismos Glu298Asp y C677 T de los genes que codifican a la enzima eNOS y 5,10 MTHFR, tabaquismo, hipertensión y AHFEAT, se asociaron a la presencia de EVC isquémico en jóvenes mexicanos, no así el Thr325Ile, Ala147Thr, 4 G/5 G, PLA1/A2 en genes que codifican proteínas del sistema de fibrinólisis y receptores plaquetarios.

Keywords

• TAFI
• PAI-1
• GP IIb/IIIa
• eNOS
• 5,10 MTHFR
• EVC.