Israel Fernández-Cadenas1, Maite Mendióroz2, Dolors Giralt2, Cristina Nafria2, Elena Garcia2, Caty Carrera2, Cristina Gallego-Fabrega2, Sophie Domingues-Montanari2, Pilar Delgado2, Marc Ribó2, Mar Castellanos2, Sergi Martínez2, Marimar Freijo2, Jordi Jiménez-Conde2, Marta Rubiera2, José Alvarez-Sabín2, Carlos A Molina2, Maria Angels Font2, Marta Grau Olivares2, Ernest Palomeras2, Natalia Perez de la Ossa2, Maite Martinez-Zabaleta2, Jaime Masjuan2, Francisco Moniche2, David Canovas2, Carlos Piñana2, Francisco Purroy2, Dolores Cocho2, Inma Navas2, Carlos Tejero2, Nuria Aymerich2, Natalia Cullell2, Elena Muiño2, Joaquín Serena2, Francisco Rubio2, Antoni Davalos2, Jaume Roquer2, Juan Francisco Arenillas2, Joan Martí-Fábregas2, Keith Keene2, Wei-Min Chen2, Bradford Worrall2, Michele Sale2, Adrià Arboix2, Jerzy Krupinski2, Joan Montaner2. 1. From the Stroke Pharmacogenomics and Genetics, Fundacio Docència i Recerca MutuaTerrassa, Spain (I.F.-C., E.G., C.G.-F., N.C., E.M.); Neurovascular Research Laboratory and Neurovascular Unit, Neurology and Medicine Departments-Universitat Autònoma de Barcelona (I.F.-C., M.M., D.G., C.N., C.C., S.D.-M., P.D., J.M.) and Neurology Department (M.Ribó, M.Rubiera, J.A.-S., C.A.M.), Vall d'Hebron Hospital, Barcelona, Spain; Neuroepigenetics Research Group, Navarrabiomed, Pamplona, Spain (M.M.); Department of Neurology, Hospital Universitari Dr Josep Trueta, Institut d'Investigació Biomèdica de Girona, Spain (M.C., J.S.); Department of Neurology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain (S.M., J.M.-F.); Department of Neurology, Hospital de Basurto, Bilbao, Spain (M.F.); Department of Neurology, Hospital del Mar and Centre de Regulació Genòmica, Universitat Pompeu Fabra, Barcelona, Spain (J.J.-C., J.R.); Department of Neurology, Hospital de Bellvitge, Hospitalet del Llobregat, Spain (M.A.F., F.R.); Department of Neurology, Hospital Universitari Sagrat Cor, Barcelona, Spain (M.G.O., A.A.); Department of Neurology, Hospital de Mataró, Spain (E.P.); Department of Neurology, Hospital Universitari Germans Trias i Pujol, Badalona, Spain (N.P.d.l.O., A.D.); Department of Neurology, Hospital Donostia, San Sebastián, Spain (M.M.-Z.); Department of Neurology, Hospital Ramón y Cajal, Madrid, Spain (J.M.); Department of Neurology, Hospital Universitario Virgen del Rocío, Sevilla, Spain (F.M.); Department of Neurology, Corporació Sanitària Parc Taulí, Sabadell, Spain (D.C.); Department of Neurology, Hospital Universitario Virgen de las Nieves, Granada, Spain (C.P.); Department of Neurology, Hospital Universitario Arnau De Vilanova, Lleida, Spain (F.P.); Department of Neurology, Hospital de Granollers, Spain (D.C.); Department of Neurology, Hospital Mútua de Terrassa, Spain (I.N., J.K.); Department of Neurology, Hospital Clinico Universitario Lozano Blesa, Zaragoza, Spain (C.T.); Department of Neurology, Hospital De Navarra, Pamplona, Spain (N.A.); Department of Neurology, Hospital Clínico Universitario de Valladolid, Spain (J.F.A.); Department of Biology, Center for Health Disparities, East Carolina University, Greenville, North Carolina (K.K.); Department of Public Health Sciences, Center for Public Health Genomics (W.-M.C.); Departments of Neurology (B.W.), Public Health Sciences (B.W., M.S.), and Biochemistry and Molecular Genetics (M.S.), and Center for Public Health Genomics (M.S.), University of Virginia, Charlottesville. israelcadenas@yahoo.es. 2. From the Stroke Pharmacogenomics and Genetics, Fundacio Docència i Recerca MutuaTerrassa, Spain (I.F.-C., E.G., C.G.-F., N.C., E.M.); Neurovascular Research Laboratory and Neurovascular Unit, Neurology and Medicine Departments-Universitat Autònoma de Barcelona (I.F.-C., M.M., D.G., C.N., C.C., S.D.-M., P.D., J.M.) and Neurology Department (M.Ribó, M.Rubiera, J.A.-S., C.A.M.), Vall d'Hebron Hospital, Barcelona, Spain; Neuroepigenetics Research Group, Navarrabiomed, Pamplona, Spain (M.M.); Department of Neurology, Hospital Universitari Dr Josep Trueta, Institut d'Investigació Biomèdica de Girona, Spain (M.C., J.S.); Department of Neurology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain (S.M., J.M.-F.); Department of Neurology, Hospital de Basurto, Bilbao, Spain (M.F.); Department of Neurology, Hospital del Mar and Centre de Regulació Genòmica, Universitat Pompeu Fabra, Barcelona, Spain (J.J.-C., J.R.); Department of Neurology, Hospital de Bellvitge, Hospitalet del Llobregat, Spain (M.A.F., F.R.); Department of Neurology, Hospital Universitari Sagrat Cor, Barcelona, Spain (M.G.O., A.A.); Department of Neurology, Hospital de Mataró, Spain (E.P.); Department of Neurology, Hospital Universitari Germans Trias i Pujol, Badalona, Spain (N.P.d.l.O., A.D.); Department of Neurology, Hospital Donostia, San Sebastián, Spain (M.M.-Z.); Department of Neurology, Hospital Ramón y Cajal, Madrid, Spain (J.M.); Department of Neurology, Hospital Universitario Virgen del Rocío, Sevilla, Spain (F.M.); Department of Neurology, Corporació Sanitària Parc Taulí, Sabadell, Spain (D.C.); Department of Neurology, Hospital Universitario Virgen de las Nieves, Granada, Spain (C.P.); Department of Neurology, Hospital Universitario Arnau De Vilanova, Lleida, Spain (F.P.); Department of Neurology, Hospital de Granollers, Spain (D.C.); Department of Neurology, Hospital Mútua de Terrassa, Spain (I.N., J.K.); Department of Neurology, Hospital Clinico Universitario Lozano Blesa, Zaragoza, Spain (C.T.); Department of Neurology, Hospital De Navarra, Pamplona, Spain (N.A.); Department of Neurology, Hospital Clínico Universitario de Valladolid, Spain (J.F.A.); Department of Biology, Center for Health Disparities, East Carolina University, Greenville, North Carolina (K.K.); Department of Public Health Sciences, Center for Public Health Genomics (W.-M.C.); Departments of Neurology (B.W.), Public Health Sciences (B.W., M.S.), and Biochemistry and Molecular Genetics (M.S.), and Center for Public Health Genomics (M.S.), University of Virginia, Charlottesville.
Abstract
BACKGROUND AND PURPOSE: Vascular recurrence occurs in 11% of patients during the first year after ischemic stroke (IS) or transient ischemic attack. Clinical scores do not predict the whole vascular recurrence risk; therefore, we aimed to find genetic variants associated with recurrence that might improve the clinical predictive models in IS. METHODS: We analyzed 256 polymorphisms from 115 candidate genes in 3 patient cohorts comprising 4482 IS or transient ischemic attack patients. The discovery cohort was prospectively recruited and included 1494 patients, 6.2% of them developed a new IS during the first year of follow-up. Replication analysis was performed in 2988 patients using SNPlex or HumanOmni1-Quad technology. We generated a predictive model using Cox regression (GRECOS score [Genotyping Reurrence Risk of Stroke]) and generated risk groups using a classification tree method. RESULTS: The analyses revealed that rs1800801 in the MGP gene (hazard ratio, 1.33; P=9×10-03), a gene related to artery calcification, was associated with new IS during the first year of follow-up. This polymorphism was replicated in a Spanish cohort (n=1.305); however, it was not significantly associated in a North American cohort (n=1.683). The GRECOS score predicted new IS (P=3.2×10-09) and could classify patients, from low risk of stroke recurrence (1.9%) to high risk (12.6%). Moreover, the addition of genetic risk factors to the GRECOS score improves the prediction compared with previous Stroke Prognosis Instrument-II score (P=0.03). CONCLUSIONS: The use of genetics could be useful to estimate vascular recurrence risk after IS. Genetic variability in the MGP gene was associated with vascular recurrence in the Spanish population.
BACKGROUND AND PURPOSE: Vascular recurrence occurs in 11% of patients during the first year after ischemic stroke (IS) or transient ischemic attack. Clinical scores do not predict the whole vascular recurrence risk; therefore, we aimed to find genetic variants associated with recurrence that might improve the clinical predictive models in IS. METHODS: We analyzed 256 polymorphisms from 115 candidate genes in 3 patient cohorts comprising 4482 IS or transient ischemic attack patients. The discovery cohort was prospectively recruited and included 1494 patients, 6.2% of them developed a new IS during the first year of follow-up. Replication analysis was performed in 2988 patients using SNPlex or HumanOmni1-Quad technology. We generated a predictive model using Cox regression (GRECOS score [Genotyping Reurrence Risk of Stroke]) and generated risk groups using a classification tree method. RESULTS: The analyses revealed that rs1800801 in the MGP gene (hazard ratio, 1.33; P=9×10-03), a gene related to artery calcification, was associated with new IS during the first year of follow-up. This polymorphism was replicated in a Spanish cohort (n=1.305); however, it was not significantly associated in a North American cohort (n=1.683). The GRECOS score predicted new IS (P=3.2×10-09) and could classify patients, from low risk of stroke recurrence (1.9%) to high risk (12.6%). Moreover, the addition of genetic risk factors to the GRECOS score improves the prediction compared with previous Stroke Prognosis Instrument-II score (P=0.03). CONCLUSIONS: The use of genetics could be useful to estimate vascular recurrence risk after IS. Genetic variability in the MGP gene was associated with vascular recurrence in the Spanish population.
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