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Genetic Imbalance Is Associated With Functional Outcome After Ischemic Stroke

Pfeiffer, Dorothea; Chen, Bowang; Schlicht, Kristina; Ginsbach, Philip; Abboud, Sherine; Bersano, Anna; Bevan, Steve; Brandt, Tobias; Caso, Valeria and Debette, Stéphanie, et al. (2019) In Stroke 50(2). p.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... (More)

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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publication status
published
subject
keywords
DNA copy number variations, genetics, polymorphism, single nucleotide, prognosis, stroke
in
Stroke
volume
50
issue
2
pages
7 pages
publisher
American Heart Association
external identifiers
  • scopus:85060656883
ISSN
1524-4628
DOI
10.1161/STROKEAHA.118.021856
language
English
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yes
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6883f323-7ec1-4fed-855c-6bad162c346f
date added to LUP
2019-02-05 08:42:11
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2019-03-05 04:31:35
@article{6883f323-7ec1-4fed-855c-6bad162c346f,
  abstract     = {<p>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.</p>},
  author       = {Pfeiffer, Dorothea and Chen, Bowang and Schlicht, Kristina and Ginsbach, Philip and Abboud, Sherine and Bersano, Anna and Bevan, Steve and Brandt, Tobias and Caso, Valeria and Debette, Stéphanie and Erhart, Philipp and Freitag-Wolf, Sandra and Giacalone, Giacomo and Grau, Armin J. and Hayani, Eyad and Jern, Christina and Jiménez-Conde, Jordi and Kloss, Manja and Krawczak, Michael and Lee, Jin Moo and Lemmens, Robin and Leys, Didier and Lichy, Christoph and Maguire, Jane M. and Martin, Juan J. and Metso, Antti J. and Metso, Tiina M. and Mitchell, Braxton D. and Pezzini, Alessandro and Rosand, Jonathan and Rost, Natalia S. and Stenman, Martin and Tatlisumak, Turgut and Thijs, Vincent and Touzé, Emmanuel and Traenka, Christopher and Werner, Inge and Woo, Daniel and Del Zotto, Elisabetta and Engelter, Stefan T. and Kittner, Steven J. and Cole, John W. and Grond-Ginsbach, Caspar and Lyrer, Philippe A. and Lindgren, Arne},
  issn         = {1524-4628},
  keyword      = {DNA copy number variations,genetics,polymorphism, single nucleotide,prognosis,stroke},
  language     = {eng},
  number       = {2},
  pages        = {298--304},
  publisher    = {American Heart Association},
  series       = {Stroke},
  title        = {Genetic Imbalance Is Associated With Functional Outcome After Ischemic Stroke},
  url          = {http://dx.doi.org/10.1161/STROKEAHA.118.021856},
  volume       = {50},
  year         = {2019},
}