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    Genetic Predisposition to Mosaic Chromosomal Loss Is Associated With Functional Outcome After Ischemic Stroke

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    Author
    Johansson, Malin
    Pedersen, Annie
    Cole, John W
    Lagging, Cecilia
    Lindgren, Arne
    Maguire, Jane M
    Rost, Natalia S
    Söderholm, Martin
    Worrall, Bradford B
    Stanne, Tara M
    Jern, Christina
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    Date
    2021-11-12
    Journal
    Neurology. Genetics
    Publisher
    Wolters Kluwer Health
    Type
    Article
    
    Metadata
    Show full item record
    See at
    https://doi.org/10.1212/NXG.0000000000000634
    http://www.ncbi.nlm.nih.gov/pmc/articles/pmc8589264/
    Abstract
    Background and objectives: To test the hypothesis that a predisposition to acquired genetic alterations is associated with ischemic stroke outcome by investigating the association between a polygenic risk score (PRS) for mosaic loss of chromosome Y (mLOY) and outcome in a large international data set. Methods: We used data from the genome-wide association study performed within the Genetics of Ischemic Stroke Functional Outcome network, which included 6,165 patients (3,497 men and 2,668 women) with acute ischemic stroke of mainly European ancestry. We assessed a weighted PRS for mLOY and examined possible associations with the modified Rankin Scale (mRS) score 3 months poststroke in logistic regression models. We investigated the whole study sample as well as men and women separately. Results: Increasing PRS for mLOY was associated with poor functional outcome (mRS score >2) with an odds ratio (OR) of 1.11 (95% confidence interval [CI] 1.03-1.19) per 1 SD increase in the PRS after adjustment for age, sex, ancestry, stroke severity (NIH Stroke Scale), smoking, and diabetes mellitus. In sex-stratified analyses, we found a statistically significant association in women (adjusted OR 1.20, 95% CI 1.08-1.33). In men, the association was in the same direction (adjusted OR 1.04, 95% CI 0.95-1.14), and we observed no significant genotype-sex interaction. Discussion: In this exploratory study, we found associations between genetic variants predisposing to mLOY and stroke outcome. The significant association in women suggests underlying mechanisms related to genomic instability that operate in both sexes. These findings need replication and mechanistic exploration.
    Rights/Terms
    Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.
    Keyword
    Clonal Hematopoiesis
    Ischemic Stroke--genetics
    Sex Factors
    Identifier to cite or link to this item
    http://hdl.handle.net/10713/17185
    ae974a485f413a2113503eed53cd6c53
    10.1212/NXG.0000000000000634
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