Please use this identifier to cite or link to this item: https://ahro.austin.org.au/austinjspui/handle/1/20234
Title: Genetic Imbalance Is Associated With Functional Outcome After Ischemic Stroke.
Austin Authors: Pfeiffer, Dorothea;Chen, Bowang;Schlicht, Kristina;Ginsbach, Philip;Abboud, Sherine;Bersano, Anna;Bevan, Steve;Brandt, Tobias;Caso, Valeria;Debette, Stéphanie;Erhart, Philipp;Freitag-Wolf, Sandra;Giacalone, Giacomo;Grau, Armin J;Hayani, Eyad;Jern, Christina;Jiménez-Conde, Jordi;Kloss, Manja;Krawczak, Michael;Lee, Jin-Moo;Lemmens, Robin;Leys, Didier;Lichy, Christoph;Maguire, Jane M;Martin, Juan J;Metso, Antti J;Metso, Tiina M;Mitchell, Braxton D;Pezzini, Alessandro;Rosand, Jonathan;Rost, Natalia S;Stenman, Martin;Tatlisumak, Turgut;Thijs, Vincent N ;Touzé, Emmanuel;Traenka, Christopher;Werner, Inge;Woo, Daniel;Del Zotto, Elisabetta;Engelter, Stefan T;Kittner, Steven J;Cole, John W;Grond-Ginsbach, Caspar;Lyrer, Philippe A;Lindgren, Arne
Affiliation: Department of Neurology, Heidelberg University Hospital, Germany
and Department of Neurology University of Maryland School of Medicine, Baltimore
Department of Biology, Southern University of Science and Technology, Shenzhen, China
Inserm, Bordeaux Population Health Research Center, UMR 1219, University of Bordeaux, France
Department of Neurology, Bordeaux University Hospital, France
The Sahlgrenska Academy, University of Gothenburg, Sweden
Sahlgrenska University Hospital, Sweden
Department of Neurosciences, Experimental Neurology, and Leuven Brain Institute, KU Leuven, University of Leuven, Belgium
VIB, Center for Brain & Disease Research, Laboratory of Neurobiology, Leuven, Belgium
Department of Neurology, University Hospitals Leuven, Belgium
Faculty of Health, University of Technology Sydney, Australia
Hunter Medical Research Institute, Priority Research Centre for Stroke and Traumatic Brain Injury, University of Newcastle, Australia
Division of Endocrinology, Diabetes and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore
Geriatrics Research and Education Clinical Center, Baltimore Veterans Administration Medical Center, Baltimore, MD
Department of Clinical Sciences Lund, Neurology, Lund University, Sweden
Department of Neurology and Rehabilitation Medicine, Skåne University Hospital, Lund, Sweden
Department of Neurology, Helsinki University Central Hospital, Finland
Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Sweden
Department of Neurology, Sahlgrenska University Hospital, Gothenburg, Sweden
Stroke Division, Florey Institute of Neuroscience and Mental Health, University of Melbourne, Heidelberg, Victoria, Australia
Department of Neurology, Austin Health, Heidelberg, Victoria, Australia
Paris Descartes University, INSERM UMR S894, Department of Neurology, Sainte-Anne Hospital, Paris, France
Normandie Université, Université Caen-Normandie, Inserm U1237, CHU Côte de Nacre, Service de Neurologie, Caen, France
Department of Neurology and Stroke Center, University Hospital Basel, Switzerland
Neurorehabilitation Unit, University of Basel, Switzerland
University Center for Medicine of Aging, Felix Platter Hospital, Basel, Switzerland
Department of Neurology, Veterans Affairs Medical Center, Baltimore, MD
Institute of Medical Informatics and Statistics, Kiel University, University Hospital Schleswig-Holstein Campus Kiel, Germany
School of Informatics, University of Edinburgh, United Kingdom
Laboratory of Experimental Neurology, Université Libre de Bruxelles, Brussels, Belgium
Cerebrovascular Unit IRCCS Foundation C. Besta Neurological Institute, Milan, Italy
School of Life Science, University of Lincoln, United Kingdom
Suva/Swiss National Accident Insurance Fund, Lucerne, Switzerland
Stroke Unit, Perugia University Hospital, Italy
Department of Vascular and Endovascular Surgery, University Hospital Heidelberg, Germany
Institute of Medical Informatics and Statistics, Kiel University, University Hospital Schleswig-Holstein Campus Kiel, Germany
Department of Neurology, San Raffaele University Hospital, Milan, Italy
Department of Neurology, Klinikum Ludwigshafen, Germany
IMIM-Parc de Salut Mar, Universitat Autonoma de Barcelona, Spain
Institute of Medical Informatics and Statistics, Kiel University, University Hospital Schleswig-Holstein Campus Kiel, Germany
Department of Neurology, Washington University School of Medicine, St Louis, MO, USA
Department of Neurology, University of Lille, France
Department of Neurology, Klinikum Memmingen, Germany
Department of Neurology, Sanatorio Allende, Cordoba, Argentina
Department of Neurology, Helsinki University Central Hospital, Finland
Department of Clinical and Experimental Sciences, Neurology Clinic, University of Brescia, Italy
Center for Genomic Medicine, Massachusetts General Hospital, Boston
Department of Neurology, Massachusetts General Hospital, Boston
Department of Neurology and Stroke Center, University Hospital Basel, Switzerland
Department of Neurology, Heidelberg University Hospital, Germany
Department of Neurology and Rehabilitation Medicine, University of Cincinnati, OH
Department of Clinical and Experimental Sciences, Neurology Clinic, University of Brescia, Italy
Department of Neurology, Heidelberg University Hospital, Germany
Department of Neurology and Stroke Center, University Hospital Basel, Switzerland
Issue Date: Feb-2019
Publication information: Stroke 2019; 50(2): 298-304
Abstract: Background and Purpose- We sought to explore the effect of genetic imbalance on functional outcome after ischemic stroke (IS). Methods- Copy number variation was identified in high-density single-nucleotide polymorphism microarray data of IS patients from the CADISP (Cervical Artery Dissection and Ischemic Stroke Patients) and SiGN (Stroke Genetics Network)/GISCOME (Genetics of Ischaemic Stroke Functional Outcome) networks. Genetic imbalance, defined as total number of protein-coding genes affected by copy number variations in an individual, was compared between patients with favorable (modified Rankin Scale score of 0-2) and unfavorable (modified Rankin Scale score of ≥3) outcome after 3 months. Subgroup analyses were confined to patients with imbalance affecting ohnologs-a class of dose-sensitive genes, or to those with imbalance not affecting ohnologs. The association of imbalance with outcome was analyzed by logistic regression analysis, adjusted for age, sex, stroke subtype, stroke severity, and ancestry. Results- The study sample comprised 816 CADISP patients (age 44.2±10.3 years) and 2498 SiGN/GISCOME patients (age 67.7±14.2 years). Outcome was unfavorable in 122 CADISP and 889 SiGN/GISCOME patients. Multivariate logistic regression analysis revealed that increased genetic imbalance was associated with less favorable outcome in both samples (CADISP: P=0.0007; odds ratio=0.89; 95% CI, 0.82-0.95 and SiGN/GISCOME: P=0.0036; odds ratio=0.94; 95% CI, 0.91-0.98). The association was independent of age, sex, stroke severity on admission, stroke subtype, and ancestry. On subgroup analysis, imbalance affecting ohnologs was associated with outcome (CADISP: odds ratio=0.88; 95% CI, 0.80-0.95 and SiGN/GISCOME: odds ratio=0.93; 95% CI, 0.89-0.98) whereas imbalance without ohnologs lacked such an association. Conclusions- Increased genetic imbalance was associated with poorer functional outcome after IS in both study populations. Subgroup analysis revealed that this association was driven by presence of ohnologs in the respective copy number variations, suggesting a causal role of the deleterious effects of genetic imbalance.
URI: http://ahro.austin.org.au/austinjspui/handle/1/20234
DOI: 10.1161/STROKEAHA.118.021856
ORCID: 0000-0002-6614-8417
PubMed URL: 30661490
Type: Journal Article
Subjects: DNA copy number variations
genetics
polymorphism, single nucleotide
prognosis
Stroke
Appears in Collections:Journal articles

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