PATJ Low Frequency Variants Are Associated With Worse Ischemic Stroke Functional Outcome

Marina Mola-Caminal, From the Department of Neurology, Neurovascular Research Group, Hospital del Mar Medical Research Institute, Universitat Autònoma de Barcelona/DCEXS-Universitat Pompeu Fabra (M.M.-C., C.S.-T., E.G.-S., A.R.-C., A.O., E.C.-G., R.M.V.-H., J.R., J.J.-C.).
Caty Carrera, Neurovascular Research Laboratory, Vall d'Hebron Institute of Research (C.C., M.H.-G., M.S., P.D., A.B., T.G.-B., M.M., J.M., I.F.-C.), Universitat Autònoma de Barcelona.
Carolina Soriano-Tárraga, From the Department of Neurology, Neurovascular Research Group, Hospital del Mar Medical Research Institute, Universitat Autònoma de Barcelona/DCEXS-Universitat Pompeu Fabra (M.M.-C., C.S.-T., E.G.-S., A.R.-C., A.O., E.C.-G., R.M.V.-H., J.R., J.J.-C.).
Eva Giralt-Steinhauer, From the Department of Neurology, Neurovascular Research Group, Hospital del Mar Medical Research Institute, Universitat Autònoma de Barcelona/DCEXS-Universitat Pompeu Fabra (M.M.-C., C.S.-T., E.G.-S., A.R.-C., A.O., E.C.-G., R.M.V.-H., J.R., J.J.-C.).
Rosa M. Díaz-Navarro, Department of Neurology (R.M.D.-N., S.T., C.J.), Son Espases University Hospital, Institut d'Investigació Sanitària de Les Illes Balears, Palma de Mallorca.
Sílvia Tur, Department of Neurology (R.M.D.-N., S.T., C.J.), Son Espases University Hospital, Institut d'Investigació Sanitària de Les Illes Balears, Palma de Mallorca.
Carmen Jiménez, Department of Neurology (R.M.D.-N., S.T., C.J.), Son Espases University Hospital, Institut d'Investigació Sanitària de Les Illes Balears, Palma de Mallorca.
Aina Medina-Dols, Research Unit (A.M.-D., C.V.-B.), Son Espases University Hospital, Institut d'Investigació Sanitària de Les Illes Balears, Palma de Mallorca.
Natàlia Cullell, Stroke Pharmacogenomics and Genetics Group, Fundació Docència i Recerca Mútua Terrassa (N.C., N.P.T.-A., E.M., I.F.-C.).
Nuria P. Torres-Aguila, Stroke Pharmacogenomics and Genetics Group, Fundació Docència i Recerca Mútua Terrassa (N.C., N.P.T.-A., E.M., I.F.-C.).
Elena Muiño, Stroke Pharmacogenomics and Genetics Group, Fundació Docència i Recerca Mútua Terrassa (N.C., N.P.T.-A., E.M., I.F.-C.).
Ana Rodríguez-Campello, From the Department of Neurology, Neurovascular Research Group, Hospital del Mar Medical Research Institute, Universitat Autònoma de Barcelona/DCEXS-Universitat Pompeu Fabra (M.M.-C., C.S.-T., E.G.-S., A.R.-C., A.O., E.C.-G., R.M.V.-H., J.R., J.J.-C.).
Angel Ois, From the Department of Neurology, Neurovascular Research Group, Hospital del Mar Medical Research Institute, Universitat Autònoma de Barcelona/DCEXS-Universitat Pompeu Fabra (M.M.-C., C.S.-T., E.G.-S., A.R.-C., A.O., E.C.-G., R.M.V.-H., J.R., J.J.-C.).
Elisa Cuadrado-Godia, From the Department of Neurology, Neurovascular Research Group, Hospital del Mar Medical Research Institute, Universitat Autònoma de Barcelona/DCEXS-Universitat Pompeu Fabra (M.M.-C., C.S.-T., E.G.-S., A.R.-C., A.O., E.C.-G., R.M.V.-H., J.R., J.J.-C.).
Rosa M. Vivanco-Hidalgo, From the Department of Neurology, Neurovascular Research Group, Hospital del Mar Medical Research Institute, Universitat Autònoma de Barcelona/DCEXS-Universitat Pompeu Fabra (M.M.-C., C.S.-T., E.G.-S., A.R.-C., A.O., E.C.-G., R.M.V.-H., J.R., J.J.-C.).
Mar Hernandez-Guillamon, Neurovascular Research Laboratory, Vall d'Hebron Institute of Research (C.C., M.H.-G., M.S., P.D., A.B., T.G.-B., M.M., J.M., I.F.-C.), Universitat Autònoma de Barcelona.
Montse Solé, Neurovascular Research Laboratory, Vall d'Hebron Institute of Research (C.C., M.H.-G., M.S., P.D., A.B., T.G.-B., M.M., J.M., I.F.-C.), Universitat Autònoma de Barcelona.
Pilar Delgado, Neurovascular Research Laboratory, Vall d'Hebron Institute of Research (C.C., M.H.-G., M.S., P.D., A.B., T.G.-B., M.M., J.M., I.F.-C.), Universitat Autònoma de Barcelona.
Alejandro Bustamante, Neurovascular Research Laboratory, Vall d'Hebron Institute of Research (C.C., M.H.-G., M.S., P.D., A.B., T.G.-B., M.M., J.M., I.F.-C.), Universitat Autònoma de Barcelona.
Teresa García-Berrocoso, Neurovascular Research Laboratory, Vall d'Hebron Institute of Research (C.C., M.H.-G., M.S., P.D., A.B., T.G.-B., M.M., J.M., I.F.-C.), Universitat Autònoma de Barcelona.
Maite Mendióroz, Neurovascular Research Laboratory, Vall d'Hebron Institute of Research (C.C., M.H.-G., M.S., P.D., A.B., T.G.-B., M.M., J.M., I.F.-C.), Universitat Autònoma de Barcelona.
Mar Castellanos, Neurology Service, A Coruña University Hospital and Biomedical Research Institute, La Coruña (M.C.).
Joaquín Serena, Department of Neurology, Doctor Josep Trueta University Hospital, Girona Institute of Biomedical Investigation (J.S.).
Joan Martí-Fàbregas, Stroke Unit, Department of Neurology, Hospital de la Santa Creu i Sant Pau, Barcelona (J.M.-F.S.).
Tomás Segura, Department of Neurology (T.S.), Complejo Hospitalario Universitario de Albacete.
Gemma Serrano-Heras, Research Unit (G.S.-H.), Complejo Hospitalario Universitario de Albacete.
Victor Obach, Department of Neurology, Hospital Clínic i Provincial de Barcelona (V.O.).
Marc Ribó, Stroke Unit, Department of Neurology, Hospital Universitari Vall d'Hebron, Barcelona (M.R., C.A.M., J.A.-S.).
Carlos A. Molina, Stroke Unit, Department of Neurology, Hospital Universitari Vall d'Hebron, Barcelona (M.R., C.A.M., J.A.-S.).
José Alvarez-Sabín, Stroke Unit, Department of Neurology, Hospital Universitari Vall d'Hebron, Barcelona (M.R., C.A.M., J.A.-S.).
Ernest Palomeras, Department of Neurology, Hospital de Mataró (E.P.).

Document Type

Article

Abstract

RATIONALE: Ischemic stroke is among the leading causes of adult disability. Part of the variability in functional outcome after stroke has been attributed to genetic factors but no locus has been consistently associated with stroke outcome. OBJECTIVE: Our aim was to identify genetic loci influencing the recovery process using accurate phenotyping to produce the largest GWAS (genome-wide association study) in ischemic stroke recovery to date. METHODS AND RESULTS: A 12-cohort, 2-phase (discovery-replication and joint) meta-analysis of GWAS included anterior-territory and previously independent ischemic stroke cases. Functional outcome was recorded using 3-month modified Rankin Scale. Analyses were adjusted for confounders such as discharge National Institutes of Health Stroke Scale. A gene-based burden test was performed. The discovery phase (n=1225) was followed by open (n=2482) and stringent joint-analyses (n=1791). Those cohorts with modified Rankin Scale recorded at time points other than 3-month or incomplete data on previous functional status were excluded in the stringent analyses. Novel variants in PATJ (Pals1-associated tight junction) gene were associated with worse functional outcome at 3-month after stroke. The top variant was rs76221407 (G allele, β=0.40, P=1.70×10). CONCLUSIONS: Our results identify a set of common variants in PATJ gene associated with 3-month functional outcome at genome-wide significance level. Future studies should examine the role of PATJ in stroke recovery and consider stringent phenotyping to enrich the information captured to unveil additional stroke outcome loci.

Medical Subject Headings

Brain Ischemia (diagnosis, genetics, physiopathology, rehabilitation); Disability Evaluation; Gene Frequency; Genetic Predisposition to Disease; Genome-Wide Association Study; Humans; Phenotype; Polymorphism, Single Nucleotide; Recovery of Function; Risk Factors; Stroke (diagnosis, genetics, physiopathology, therapy); Stroke Rehabilitation; Tight Junction Proteins (genetics); Treatment Outcome

Publication Date

1-4-2019

Publication Title

Circulation research

E-ISSN

1524-4571

Volume

124

Issue

1

First Page

114

Last Page

120

PubMed ID

30582445

Digital Object Identifier (DOI)

10.1161/CIRCRESAHA.118.313533

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