Dataset Information

Multi-ancestry genetic study in 5,876 patients identifies an association between excitotoxic genes and early outcomes after acute ischemic stroke.

ABSTRACT: During the first hours after stroke onset neurological deficits can be highly unstable: some patients rapidly improve, while others deteriorate. This early neurological instability has a major impact on long-term outcome. Here, we aimed to determine the genetic architecture of early neurological instability measured by the difference between NIH stroke scale (NIHSS) within six hours of stroke onset and NIHSS at 24h (ΔNIHSS). A total of 5,876 individuals from seven countries (Spain, Finland, Poland, United States, Costa Rica, Mexico and Korea) were studied using a multi-ancestry meta-analyses. We found that 8.7% of ΔNIHSS variance was explained by common genetic variations, and also that early neurological instability has a different genetic architecture than that of stroke risk. Seven loci (2p25.1, 2q31.2, 2q33.3, 4q34.3, 5q33.2, 6q26 and 7p21.1) were genome-wide significant and explained 2.1% of the variability suggesting that additional variants influence early change in neurological deficits. We used functional genomics and bioinformatic annotation to identify the genes driving the association from each loci. eQTL mapping and SMR indicate that ADAM23 (log Bayes Factor (LBF)=6.34) was driving the association for 2q33.3. Gene based analyses suggested that GRIA1 (LBF=5.26), which is predominantly expressed in brain, is the gene driving the association for the 5q33.2 locus. These analyses also nominated PARK2 (LBF=5.30) and ABCB5 (LBF=5.70) for the 6q26 and 7p21.1 loci. Human brain single nuclei RNA-seq indicates that the gene expression of ADAM23 and GRIA1 is enriched in neurons. ADAM23 , a pre-synaptic protein, and GRIA1 , a protein subunit of the AMPA receptor, are part of a synaptic protein complex that modulates neuronal excitability. These data provides the first evidence in humans that excitotoxicity may contribute to early neurological instability after acute ischemic stroke.

Research into context

Evidence before this study: No previous genome-wide association studies have investigated the genetic architecture of early outcomes after ischemic stroke.Added Value of this study: This is the first study that investigated genetic influences on early outcomes after ischemic stroke using a genome-wide approach, revealing seven genome-wide significant loci. A unique aspect of this genetic study is the inclusion of all of the major ethnicities by recruiting from participants throughout the world. Most genetic studies to date have been limited to populations of European ancestry.Implications of all available evidence: The findings provide the first evidence that genes implicating excitotoxicity contribute to human acute ischemic stroke, and demonstrates proof of principle that GWAS of acute ischemic stroke patients can reveal mechanisms involved in ischemic brain injury.

SUBMITTER: Ibanez L

PROVIDER: S-EPMC7654887 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Multi-ancestry genetic study in 5,876 patients identifies an association between excitotoxic genes and early outcomes after acute ischemic stroke.

Ibanez Laura L Heitsch Laura L Carrera Caty C Farias Fabiana H G FHG Dhar Rajat R Budde John J Bergmann Kristy K Bradley Joseph J Harari Oscar O Phuah Chia-Ling CL Lemmens Robin R Souza Alessandro A Viana Oliveira AAVO Moniche Francisco F Cabezas-Juan Antonio A Arenillas Juan Francisco JF Krupinksi Jerzy J Cullell Natalia N Torres-Aguila Nuria N Muiño Elena E Cárcel-Márquez Jara J Marti-Fabregas Joan J Delgado-Mederos Raquel R Marin-Bueno Rebeca R Hornick Alejandro A Vives-Bauza Cristofol C Navarro Rosa Diaz RD Tur Silvia S Jimenez Carmen C Obach Victor V Segura Tomas T Serrano-Heras Gemma G Chung Jong-Won JW Roquer Jaume J Soriano-Tarraga Carol C Giralt-Steinhauer Eva E Mola-Caminal Marina M Pera Joanna J Lapicka-Bodzioch Katarzyna K Derbisz Justyna J Davalos Antoni A Lopez-Cancio Elena E Muñoz Lucia L Tatlisumak Turgut T Molina Carlos C Ribo Marc M Bustamante Alejandro A Sobrino Tomas T Castillo-Sanchez Jose J Campos Francisco F Rodriguez-Castro Emilio E Arias-Rivas Susana S Rodríguez-Yáñez Manuel M Herbosa Christina C Ford Andria L AL Arauz Antonio A Lopes-Cendes Iscia I Lowenkopf Theodore T Barboza Miguel A MA Amini Hajar H Stamova Boryana B Ander Bradley P BP Sharp Frank R FR Kim Gyeong Moon GM Bang Oh Young OY Jimenez-Conde Jordi J Slowik Agnieszka A Stribian Daniel D Tsai Ellen A EA Burkly Linda C LC Montaner Joan J Fernandez-Cadenas Israel I Lee Jin-Moo JM Cruchaga Carlos C

medRxiv : the preprint server for health sciences 20201103

During the first hours after stroke onset neurological deficits can be highly unstable: some patients rapidly improve, while others deteriorate. This early neurological instability has a major impact on long-term outcome. Here, we aimed to determine the genetic architecture of early neurological instability measured by the difference between NIH stroke scale (NIHSS) within six hours of stroke onset and NIHSS at 24h (ΔNIHSS). A total of 5,876 individuals from seven countries (Spain, Finland, Pola ...[more]

PMID: 33173895

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Project description:ObjectiveTo investigate the difference in early edema, quantified by net water uptake (NWU) based on computed tomography (CT) between ischemic core and penumbra and to explore predictors of NWU and test its predictive power for clinical outcome.MethodsRetrospective analysis was conducted on patients admitted to Ningbo First Hospital with anterior circulation stroke and multi-modal CT. In 154 included patients, NWU of the ischemic core and penumbra were calculated and compared by Mann-Whitney U test. Correlations between NWU and variables including age, infarct time (time from symptom onset to imaging), volume of ischemic core, collateral status, and National Institutes of Health Stroke Scale (NIHSS) scores were investigated by Spearman's correlation analyses. Clinical outcome was defined using the modified Rankin Scale (mRS) at 90 days. Logistic regression and receiver operating characteristic analyses were performed to test the predictive value of NWU. Summary statistics are presented as median (interquartile range), mean (standard deviation) or estimates (95% confidence interval).ResultsThe NWU within the ischemic core [6.1% (2.9-9.2%)] was significantly higher than that of the penumbra [1.8% (-0.8-4.0%)]. The only significant predictor of NWU within the ischemic core was infarct time (p = 0.004). The NWU within the ischemic core [odds ratio = 1.23 (1.10-1.39)], the volume of ischemic core [1.04, (1.02-1.06)], age [1.09 (1.01-1.17)], and admission NHISS score [1.05 (1.01-1.09)] were associated with the outcome of patients adjusted for sex and treatment. The predictive power for the outcome of the model was significantly higher when NWU was included (area under the curve 0.875 vs. 0.813, p < 0.05 by Delong test).ConclusionsEarly edema quantified by NWU is relatively limited in the ischemic core and develops in a time-dependent manner. NWU estimates within the ischemic core may help to predict clinical outcomes of patients with acute ischemic stroke.

Project description:Plasma total homocysteine (tHcy) is a risk factor for ischemic stroke (IS) but its relationship with IS outcome is uncertain. Moreover, previous studies underrepresented older IS patients, although risk of both hyperhomocysteinemia and IS increases with age. We investigated whether, in elderly patients with acute IS, tHcy measured on admission to the Stroke Unit (SU) is an independent predictor of SU discharge outcomes.Data are for 644 consecutive patients aged 80.3 ± 8.7 years, admitted to an Italian SU with diagnosis of acute IS. Plasma tHcy was measured on SU admission. Investigated outcomes included mortality during SU stay and poor functional status (modified Rankin Scale score ≥3) at SU discharge for survivors. The association of plasma tHcy with the study outcomes was assessed using Odds Ratios (OR) and their corresponding 95% confidence intervals (95%CI) from logistic regression models adjusted for demographics, pre-stroke features, IS severity, and laboratory data on SU admission (serum C-reactive protein, serum albumin, and renal function).Median plasma tHcy was 16.7 μmol/L (interquartile range, 13.0-23.3 μmol/L). Outcome incidence was 5.3% for mortality and 49.7% for poor functional status. Plasma tHcy was unrelated to mortality in both univariate and multivariable-adjusted analyses. Conversely, plasma tHcy was associated with poor functional status of survivors in univariate analyses (P = 0.014). Multivariable-adjusted analyses showed that, compared to normal homocysteinemia (tHcy <16 μmol/L), risk of being discharged with poor functional status significantly increased for moderate (tHcy ≥30 mol/L) but not mild (16.0-29.9 μmol/L) hyperhomocysteinemia.In elderly patients with acute IS, high admission plasma tHcy is unrelated to mortality during SU stay but is an independent predictor of poor functional status at SU discharge in survivors. The association, however, is limited to patients with moderate hyperhomocysteinemia.

Project description:BackgroundSeveral prognostic scores have been proposed to predict functional outcomes after an acute ischemic stroke (AIS). Most of these scores are based on structured information and have been used to develop prediction models via the logistic regression method. With the increased use of electronic health records and the progress in computational power, data-driven predictive modeling by using machine learning techniques is gaining popularity in clinical decision-making.ObjectiveWe aimed to investigate whether machine learning models created by using unstructured text could improve the prediction of functional outcomes at an early stage after AIS.MethodsWe identified all consecutive patients who were hospitalized for the first time for AIS from October 2007 to December 2019 by using a hospital stroke registry. The study population was randomly split into a training (n=2885) and test set (n=962). Free text in histories of present illness and computed tomography reports was transformed into input variables via natural language processing. Models were trained by using the extreme gradient boosting technique to predict a poor functional outcome at 90 days poststroke. Model performance on the test set was evaluated by using the area under the receiver operating characteristic curve (AUC).ResultsThe AUCs of text-only models ranged from 0.768 to 0.807 and were comparable to that of the model using National Institutes of Health Stroke Scale (NIHSS) scores (0.811). Models using both patient age and text achieved AUCs of 0.823 and 0.825, which were similar to those of the model containing age and NIHSS scores (0.841); the model containing preadmission comorbidities, level of consciousness, age, and neurological deficit (PLAN) scores (0.837); and the model containing Acute Stroke Registry and Analysis of Lausanne (ASTRAL) scores (0.840). Adding variables from clinical text improved the predictive performance of the model containing age and NIHSS scores, the model containing PLAN scores, and the model containing ASTRAL scores (the AUC increased from 0.841 to 0.861, from 0.837 to 0.856, and from 0.840 to 0.860, respectively).ConclusionsUnstructured clinical text can be used to improve the performance of existing models for predicting poststroke functional outcomes. However, considering the different terminologies that are used across health systems, each individual health system may consider using the proposed methods to develop and validate its own models.

Dataset Information

Multi-ancestry genetic study in 5,876 patients identifies an association between excitotoxic genes and early outcomes after acute ischemic stroke.

Research into context

Publications

Multi-ancestry genetic study in 5,876 patients identifies an association between excitotoxic genes and early outcomes after acute ischemic stroke.

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