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Genetic Imbalance Is Associated With Functional Outcome After Ischemic Stroke

Journal article
Authors D. Pfeiffer
B. Chen
K. Schlicht
P. Ginsbach
S. Abboud
A. Bersano
S. Bevan
T. Brandt
V. Caso
S. Debette
P. Erhart
S. Freitag-Wolf
G. Giacalone
A. J. Grau
E. Hayani
Christina Jern
J. Jimenez-Conde
M. Kloss
M. Krawczak
J. M. Lee
R. Lemmens
D. Leys
C. Lichy
J. M. Maguire
J. J. Martin
A. J. Metso
T. M. Metso
B. D. Mitchell
A. Pezzini
J. Rosand
N. S. Rost
M. Stenman
Turgut Tatlisumak
V. Thijs
E. Touze
C. Traenka
I. Werner
D. Woo
E. Del Zotto
S. T. Engelter
S. J. Kittner
J. W. Cole
C. Grond-Ginsbach
P. A. Lyrer
A. Lindgren
Published in Stroke
Volume 50
Issue 2
Pages 298-304
ISSN 0039-2499
Publication year 2019
Published at Institute of Neuroscience and Physiology
Pages 298-304
Language en
Links dx.doi.org/10.1161/strokeaha.118.02...
Keywords DNA copy number variations, genetics, polymorphism, single nucleotide, prognosis, stroke, copy-number variation, genome-wide, ohnologs, risk
Subject categories Neurosciences

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.

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