Journal
STROKE
Volume 50, Issue 2, Pages 298-304Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/STROKEAHA.118.021856
Keywords
DNA copy number variations; genetics; polymorphism, single nucleotide; prognosis; stroke
Categories
Funding
- Inserm, Lille 2 University, Institut Pasteur de Lille and Lille University Hospital
- Contrat de Projet Etat-Region 2007 Region Nord-Pas-de-Calais
- Centre National de Genotypage
- Emil Aaltonen Foundation
- Paavo Ilmari Ahvenainen Foundation
- Helsinki University Central Hospital Research Fund
- Academy of Finland
- Helsinki University Medical Foundation
- Paivikki and Sakari Sohlberg Foundation
- Aarne Koskelo Foundation
- Maire Taponen Foundation
- Aarne and Aili Turunen Foundation
- Lilly Foundation
- Alfred Kordelin Foundation
- Finnish Medical Foundation
- Biomedicum Helsinki Foundation
- Maud Kuistila Foundation
- Orion-Farmos Research Foundation
- Finnish Brain Foundation
- Projet Hospitalier de Recherche Clinique Regional
- Fondation de France
- Genopole de Lille
- Kathe-Zingg-Schwichtenberg-Fonds of the Swiss Academy of Medical Sciences
- Swiss National Science Foundation [33CM30-124119, 33CM30-140340/1]
- Swiss Heart Foundation
- University of Basel
- Fonds voor Wetenschappelijk Onderzoek (FWO) Vlaanderen (Research Foundation-Flanders) - US National Institute of Neurological Disorders and Stroke, National Institutes of Health [U01 NS069208, pp 159-170]
- National Institutes of Health (NIH) [R01-NS100178, R01-NS105150]
- US Department of Veterans Affairs
- American Heart Association (AHA) Cardiovascular Genome-Phenome Study (Grant15GPSPG23770000) [Grant17IBDG33700328]
- Swedish Research Council [K2014-64X-14605-12-5]
- Swedish state and Region Vastra Gotaland [ALFGBG-429981]
- Swedish Heart and Lung Foundation
- Swedish Stroke Association - Region Skane, Lund University
- Freemasons Lodge of Instruction Eos Lund
- Skane University Hospital
- Foundation of FarsAMP
- Frostaone of Sparbanken Skane's ownership Foundations
- Swedish Stroke Association - German Research Foundation (DFG) through the Cluster of Excellence [306]
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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.
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