Genetic imbalance is associated with functional outcome after ischemic stroke

• Verfasst von: Pfeiffer, Dorothea [VerfasserIn]
• Verfasst von: Brandt, Tobias [VerfasserIn]
• Verfasst von: Kloss, Manja [VerfasserIn]
• Verfasst von: Grond-Ginsbach, Caspar [VerfasserIn]
• Titel: Genetic imbalance is associated with functional outcome after ischemic stroke
• Verf.angabe: Dorothea Pfeiffer, Bowang Chen, Kristina Schlicht, Philip Ginsbach, Sherine Abboud, Anna Bersano, Steve Bevan, Tobias Brandt, Valeria Caso, Stéphanie Debette, Philipp Erhart, Sandra Freitag-Wolf, Giacomo Giacalone, Armin J. Grau, Eyad Hayani, Christina Jern, Jordi Jiménez-Conde, Manja Kloss, Michael Krawczak, Jin-Moo Lee, Robin Lemmens, Didier Leys, Christoph Lichy, Jane M. Maguire, Juan J. Martin, Antti J. Metso, Tiina M. Metso, Braxton D. Mitchell, Alessandro Pezzini, Jonathan Rosand, Natalia S. Rost, Martin Stenman, Turgut Tatlisumak, Vincent Thijs, Emmanuel Touzé, Christopher Traenka, Inge Werner, Daniel Woo, Elisabetta Del Zotto, Stefan T. Engelter, Steven J. Kittner, John W. Cole, Caspar Grond-Ginsbach, Philippe A. Lyrer, Arne Lindgren, and on behalf of CADISP; GISCOME; SiGN studies; and ISGC
• E-Jahr: 2019
• Jahr: 21 Jan 2019
• Umfang: 7 S.
• Teil: volume:50
• Teil: year:2019
• Teil: number:2
• Teil: pages:298-304
• Teil: extent:7
• Fussnoten: Gesehen am 04.12.2019
• Titel Quelle: Enthalten in: Stroke
• Ort Quelle: New York, NY : Association, 1970
• Jahr Quelle: 2019
• Band/Heft Quelle: 50(2019), 2, Seite 298-304
• ISSN Quelle: 1524-4628
• DOI: doi:10.1161/STROKEAHA.118.021856
• Datenträger: Online-Ressource
• Sprache: eng
• K10plus-PPN: 1684204909

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.