GRECOS Project (Genotyping Recurrence Risk of Stroke): The Use of Genetics to Predict the Vascular Recurrence After Stroke

Israel Fernández-Cadenas; Maite Mendióroz; Dolors Giralt; Cristina Nafria; Elena Garcia; Caty Carrera; Cristina Gallego-Fabrega; Sophie Domingues-Montanari; Pilar Delgado; Marc Ribó; Mar Castellanos; Sergi Martínez; Marimar Freijo; Jordi Jiménez-Conde; Marta Rubiera; José Alvarez-Sabín; Carlos A Molina; Maria Angels Font; Marta Grau Olivares; Ernest Palomeras; Natalia Perez de la Ossa; Maite Martinez-Zabaleta; Jaime Masjuan; Francisco Moniche; David Canovas; Carlos Piñana; Francisco Purroy; Dolores Cocho; Inma Navas; Carlos Tejero; Nuria Aymerich; Natalia Cullell; Elena Muiño; Joaquín Serena; Francisco Rubio; Antoni Davalos; Jaume Roquer; Juan Francisco Arenillas; Joan Martí-Fábregas; Keith Keene; Wei-Min Chen; Bradford Worrall; Michele Sale; Adrià Arboix; Jerzy Krupinski; Joan Montaner; GRECOS Study Group

doi:10.1161/STROKEAHA.116.014322

GRECOS Project (Genotyping Recurrence Risk of Stroke): The Use of Genetics to Predict the Vascular Recurrence After Stroke

Stroke. 2017 May;48(5):1147-1153. doi: 10.1161/STROKEAHA.116.014322. Epub 2017 Apr 14.

Authors

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; GRECOS Study Group

Affiliations

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.

Keywords: genetics; ischemic attack, transient; recurrence; risk factors; stroke.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Aged
Brain Ischemia / diagnosis
Brain Ischemia / genetics*
Cardiovascular Diseases / diagnosis
Cardiovascular Diseases / genetics*
Cohort Studies
Female
Genotype
Humans
Ischemic Attack, Transient / diagnosis
Ischemic Attack, Transient / genetics
Male
North America
Polymorphism, Single Nucleotide
Prognosis
Recurrence
Risk
Scotland
Spain
Stroke / diagnosis
Stroke / genetics*

Abstract

Publication types

MeSH terms

Grants and funding