TY - JOUR
T1 - Genetic Imbalance Is Associated With Functional Outcome After Ischemic Stroke
AU - Pfeiffer, Dorothea
AU - Chen, Bowang
AU - Schlicht, Kristina
AU - Ginsbach, Philip
AU - Abboud, Sherine
AU - Bersano, Anna
AU - Bevan, Steve
AU - Brandt, Tobias
AU - Caso, Valeria
AU - Debette, Stéphanie
AU - Erhart, Philipp
AU - Freitag-Wolf, Sandra
AU - Giacalone, Giacomo
AU - Grau, Armin J.
AU - Hayani, Eyad
AU - Jern, Christina
AU - Jiménez-Conde, Jordi
AU - Kloss, Manja
AU - Krawczak, Michael
AU - Lee, Jin Moo
AU - Lemmens, Robin
AU - Leys, Didier
AU - Lichy, Christoph
AU - Maguire, Jane M.
AU - Martin, Juan J.
AU - Metso, Antti J.
AU - Metso, Tiina M.
AU - Mitchell, Braxton D.
AU - Pezzini, Alessandro
AU - Rosand, Jonathan
AU - Rost, Natalia S.
AU - Stenman, Martin
AU - Tatlisumak, Turgut
AU - Thijs, Vincent
AU - Touzé, Emmanuel
AU - Traenka, Christopher
AU - Werner, Inge
AU - Woo, Daniel
AU - Del Zotto, Elisabetta
AU - Engelter, Stefan T.
AU - Kittner, Steven J.
AU - Cole, John W.
AU - Grond-Ginsbach, Caspar
AU - Lyrer, Philippe A.
AU - Lindgren, Arne
PY - 2019/2/1
Y1 - 2019/2/1
N2 - 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.
AB - 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.
KW - DNA copy number variations
KW - genetics
KW - polymorphism, single nucleotide
KW - prognosis
KW - stroke
KW - Gene Duplication
KW - Severity of Illness Index
KW - Chromosomes, Human/genetics
KW - Follow-Up Studies
KW - Humans
KW - Middle Aged
KW - Brain Ischemia/genetics
KW - Genotype
KW - Gene Dosage
KW - Recovery of Function
KW - Adult
KW - Aged
KW - Polymorphism, Single Nucleotide
UR - http://www.mendeley.com/research/genetic-imbalance-associated-functional-outcome-after-ischemic-stroke
U2 - 10.1161/STROKEAHA.118.021856
DO - 10.1161/STROKEAHA.118.021856
M3 - Article
C2 - 30661490
SN - 1524-4628
VL - 50
SP - 298
EP - 304
JO - Stroke
JF - Stroke
ER -
