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PATJ Low Frequency Variants Are Associated With Worse Ischemic Stroke Functional Outcome.

ABSTRACT: RATIONALE:Ischemic stroke is among the leading causes of adult disability. Part of the variability in functional outcome after stroke has been attributed to genetic factors but no locus has been consistently associated with stroke outcome. OBJECTIVE:Our aim was to identify genetic loci influencing the recovery process using accurate phenotyping to produce the largest GWAS (genome-wide association study) in ischemic stroke recovery to date. METHODS AND RESULTS:A 12-cohort, 2-phase (discovery-replication and joint) meta-analysis of GWAS included anterior-territory and previously independent ischemic stroke cases. Functional outcome was recorded using 3-month modified Rankin Scale. Analyses were adjusted for confounders such as discharge National Institutes of Health Stroke Scale. A gene-based burden test was performed. The discovery phase (n=1225) was followed by open (n=2482) and stringent joint-analyses (n=1791). Those cohorts with modified Rankin Scale recorded at time points other than 3-month or incomplete data on previous functional status were excluded in the stringent analyses. Novel variants in PATJ (Pals1-associated tight junction) gene were associated with worse functional outcome at 3-month after stroke. The top variant was rs76221407 (G allele, ?=0.40, P=1.70×10-9). CONCLUSIONS:Our results identify a set of common variants in PATJ gene associated with 3-month functional outcome at genome-wide significance level. Future studies should examine the role of PATJ in stroke recovery and consider stringent phenotyping to enrich the information captured to unveil additional stroke outcome loci.

SUBMITTER: Mola-Caminal M

PROVIDER: S-EPMC6501820 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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PATJ Low Frequency Variants Are Associated With Worse Ischemic Stroke Functional Outcome.

Mola-Caminal Marina M Carrera Caty C Soriano-Tárraga Carolina C Giralt-Steinhauer Eva E Díaz-Navarro Rosa M RM Tur Sílvia S Jiménez Carmen C Medina-Dols Aina A Cullell Natàlia N Torres-Aguila Nuria P NP Muiño Elena E Rodríguez-Campello Ana A Ois Angel A Cuadrado-Godia Elisa E Vivanco-Hidalgo Rosa M RM Hernandez-Guillamon Mar M Solé Montse M Delgado Pilar P Bustamante Alejandro A García-Berrocoso Teresa T Mendióroz Maite M Castellanos Mar M Serena Joaquín J Martí-Fàbregas Joan J Segura Tomás T Serrano-Heras Gemma G Obach Victor V Ribó Marc M Molina Carlos A CA Alvarez-Sabín José J Palomeras Ernest E Freijo Mar M Font Maria A MA Rosand Jonathan J Rost Natalia S NS Gallego-Fabrega Cristina C Lee Jin-Moo JM Heitsch Laura L Ibanez Laura L Cruchaga Carlos C Phuah Chia-Ling CL Lemmens Robin R Thijs Vincent V Lindgren Arne A Maguire Jane J Rannikmae Kristiina K Sudlow Catherine L CL Jern Christina C Stanne Tara M TM Lorentzen Erik E Muñoz-Narbona Lucía L Dávalos Antonio A López-Cancio Elena E Worrall Bradford B BB Woo Daniel D Kittner Steven J SJ Mitchell Braxton D BD Montaner Joan J Roquer Jaume J Krupinski Jurek J Estivill Xavier X Rabionet Raquel R Vives-Bauzá Cristòfol C Fernández-Cadenas Israel I Jiménez-Conde Jordi J

Circulation research 20190101 1

<h4>Rationale</h4>Ischemic stroke is among the leading causes of adult disability. Part of the variability in functional outcome after stroke has been attributed to genetic factors but no locus has been consistently associated with stroke outcome.<h4>Objective</h4>Our aim was to identify genetic loci influencing the recovery process using accurate phenotyping to produce the largest GWAS (genome-wide association study) in ischemic stroke recovery to date.<h4>Methods and results</h4>A 12-cohort, 2 ...[more]

PMID: 30582445

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Project description: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.

Project description:Currently, few studies are reported on the composition of microbiota in stroke patients and the association with stroke prognosis. This study investigated the differing microbiota composition in stroke patients and confirmed the association of microbiota composition with poor functional outcome. Between January of 2018 and December of 2019, 198 patients with acute cerebral infarction were included in this study. For the case-control study, age and sex-matched normal healthy subjects (n = 200) were included when receiving their health screening examinations. We isolated bacterial extracellular membrane vesicles and extracted DNA from blood samples. Taxonomic assignments were performed by using the sequence reads of 16S rRNA genes following blood microbiota analysis. Statistical analysis was conducted appropriately by using Statistical Analysis System software. The mean age of the stroke patients were 63.7 ± 12.5 years, and the male sex was 58.5%. Of the total enrolled patients, poor functional outcome (modified Rankin Score ≥ 3) was noted in 19.7%. The principal component analysis of microbiota composition revealed significant differences between healthy control subjects and stroke patients. At the genus level, Aerococcaceae(f), ZB2(c), TM7-1(c), and Flavobacterium were significantly increased in stroke patients compared to the healthy controls, whereas Mucispirillum, rc4-4, Akkermansia, Clostridiales(o), Lactobacillus, and Stenotrophomonas were decreased considerably. For the functional outcome after ischemic stroke, Anaerococcus, Blautia, Dialister, Aerococcaceae(f), Propionibacterium, Microbacteriaceae(f), and Rothia were enriched in the group with good outcomes, whereas Ruminococcaceae(f) and Prevotella were enriched in the group with poor outcome. There was apparent dysbiosis of blood microbiota in patients with acute ischemic stroke compared to healthy people. Ruminococcaceae(f) and Prevotella were elevated in stroke patients with poor functional outcome.

Project description:BackgroundMixed data exist regarding the association between hyperglycemia and functional outcome after acute ischemic stroke when accounting for the impact of leptomeningeal collateral flow. We sought to determine whether collateral status modifies the association between treatment group and functional outcome in a subset of patients with large vessel occlusion enrolled in the Stroke Hyperglycemia Insulin Network Effort (SHINE) trial.MethodsIn this post-hoc analysis, we analyzed patients enrolled into the SHINE trial with anterior circulation large vessel occlusion who underwent imaging with CT angiography prior to glucose control treatment group assignment. The primary analysis assessed the degree to which collateral status modified the effect between treatment group and functional outcome as defined by the 90-day modified Rankin Scale score. Logistic regression was used to model the data, with adjustments made for thrombectomy status, age, post-perfusion thrombolysis in cerebral infarction (TICI) score, tissue plasminogen activator (tPA) use, and baseline National Institutes of Health Stroke Scale (NIHSS) score. Five SHINE trial centers contributed data for this analysis. Statistical significance was defined as a p-value < 0.05.ResultsAmong the 1151 patients in the SHINE trial, 57 with angiographic data were included in this sub-analysis, of whom 19 had poor collaterals and 38 had good collaterals. While collateral status had no effect (p = 0.855) on the association between glucose control treatment group and functional outcome, patients with good collaterals were more likely to have a favorable functional outcome (p = 0.001, OR 5.02; 95% CI 1.37-16.0).ConclusionsIn a post-hoc analysis using a subset of patients with angiographic data enrolled in the SHINE trial, collateral status did not modify the association between glucose control treatment group and functional outcome. However, consistent with prior studies, there was a significant association between good collateral status and favorable outcome in patients with large vessel occlusion stroke.Trial registrationClinicalTrials.gov Identifier is NCT01369069. Registration date is June 8, 2011.

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PATJ Low Frequency Variants Are Associated With Worse Ischemic Stroke Functional Outcome.

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PATJ Low Frequency Variants Are Associated With Worse Ischemic Stroke Functional Outcome.

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