Polygenic Risk Scores Augment Stroke Subtyping

Li, Jiang; Chaudhary, Durgesh; Khan, Ayesha; Griessenauer, Christoph J.; Carey, David J.; Zand, Ramin; Abedi, Vida

doi:10.1212/nxg.0000000000000560

Cited by 19 publications

(28 citation statements)

References 43 publications

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“…The polygenic contribution to early-onset was much higher than to late-onset in the same disease (241). Our retrospective study from the sensitivity analysis alternatively confirmed this disproportional increased PRS burden for ischemic stroke using younger cases vs. three tiers of older controls (from 59, 69 to 79) (243). Gene sets analyses highlighted the association of PRS with Gene Ontology terms (vascular endothelial growth factor, amyloid precursor protein, and atherosclerosis).…”

Section: Genetic Predisposition To Cardiovascular Disease and Strokesupporting

confidence: 65%

Stroke in SARS-CoV-2 Infection: A Pictorial Overview of the Pathoetiology

Neshin

Shahjouei

Koza

et al. 2021

Front. Cardiovasc. Med.

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Since the early days of the pandemic, there have been several reports of cerebrovascular complications during the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Numerous studies proposed a role for SARS-CoV-2 in igniting stroke. In this review, we focused on the pathoetiology of stroke among the infected patients. We pictured the results of the SARS-CoV-2 invasion to the central nervous system (CNS) via neuronal and hematogenous routes, in addition to viral infection in peripheral tissues with extensive crosstalk with the CNS. SARS-CoV-2 infection results in pro-inflammatory cytokine and chemokine release and activation of the immune system, COVID-19-associated coagulopathy, endotheliitis and vasculitis, hypoxia, imbalance in the renin-angiotensin system, and cardiovascular complications that all may lead to the incidence of stroke. Critically ill patients, those with pre-existing comorbidities and patients taking certain medications, such as drugs with elevated risk for arrhythmia or thrombophilia, are more susceptible to a stroke after SARS-CoV-2 infection. By providing a pictorial narrative review, we illustrated these associations in detail to broaden the scope of our understanding of stroke in SARS-CoV-2-infected patients. We also discussed the role of antiplatelets and anticoagulants for stroke prevention and the need for a personalized approach among patients with SARS-CoV-2 infection.

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Section: Genetic Predisposition To Cardiovascular Disease and Strokesupporting

confidence: 65%

Stroke in SARS-CoV-2 Infection: A Pictorial Overview of the Pathoetiology

Neshin

Shahjouei

Koza

et al. 2021

Front. Cardiovasc. Med.

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“…Our findings also demonstrate that TMAO is a powerful metabolite that plays an essential role in the association between microbiome and stroke and may serve as an actionable target. As there is new evidence that polygenic risk scores can be used to augment stroke subtypes (7), microbiome composition can also be an additional layer of information that can be used to better inform care providers when planning individualized care paths for their patients to improve outcome. Taken together, the gut microbiome plays an important role in stroke and can transform how stroke and its subtypes are diagnosed and treated.…”

Section: Discussion and Future Prospectivesmentioning

confidence: 99%

“…Ischemic stroke is classified into subtypes using the Trial of ORG 10172 in Acute Stroke Treatment (TOAST) classification, including large artery atherosclerosis, cardioembolic, small vessel occlusion, other determined cause, or undetermined cause (6). There is also evidence that polygenic risk scores can augment stroke subtyping (7).…”

Section: Introductionmentioning

confidence: 99%

At the Intersection of Gut Microbiome and Stroke: A Systematic Review of the Literature

Sharma

Shahjouei

et al. 2021

Front. Neurol.

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Background: Ischemic and hemorrhagic stroke are associated with a high rate of long-term disability and death. Recent investigations focus efforts to better understand how alterations in gut microbiota composition influence clinical outcomes. A key metabolite, trimethylamine N-oxide (TMAO), is linked to multiple inflammatory, vascular, and oxidative pathways. The current biochemical underpinnings of microbial effects on stroke remain largely understudied. The goal of our study is to explore the current literature to explain the interactions between the human gut microbiome and stroke progression, recovery, and outcome. We also provide a descriptive review of TMAO.Methods: A systematic literature search of published articles between January 1, 1990, and March 22, 2020, was performed on the PubMed database to identify studies addressing the role of the microbiome and TMAO in the pathogenesis and recovery of acute stroke. Our initial investigation focused on human subject studies and was further expanded to include animal studies. Relevant articles were included, regardless of study design. The analysis included reviewers classifying and presenting selected articles by study design and sample size in a chart format.Results: A total of 222 titles and abstracts were screened. A review of the 68 original human subject articles resulted in the inclusion of 24 studies in this review. To provide further insight into TMAO as a key player, an additional 40 articles were also reviewed and included. Our findings highlighted that alterations in richness and abundance of gut microbes and increased plasma TMAO play an important role in vascular events and outcomes. Our analysis revealed that restoration of a healthy gut, through targeted TMAO-reducing therapies, could provide alternative secondary prevention for at-risk patients.Discussion: Biochemical interactions between the gut microbiome and inflammation, resulting in metabolic derangements, can affect stroke progression and outcomes. Clinical evidence supports the importance of TMAO in modulating underlying stroke risk factors. Lack of standardization and distinct differences in sample sizes among studies are major limitations.

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“…Genome-wide association studies (GWAS) on IS and its etiologic subtypes have been conducted for a decade, and more stroke risk loci have been identified 3 . Polygenic risk scores (PRSs) based on the effect sizes estimated from the meta/mega-analyses of GWAS, led by the MEGASTROKE consortium, have proven informative for IS risk stratification 4 and augmenting subtyping 5 . The short-term or long-term outcomes have become “The Next Big Thing” in the focus of stroke genetics with a great demand for the development of neuroprotective agents 6 .…”

Section: Introductionmentioning

confidence: 99%

“…Through a regularized regression model to integrate multiple sets of GWAS summary statistics on stroke and its modifiable clinical risk factors, a metaGRS has been developed to determine its independent predictability for IS 16 . Our previous study has identified several pathway-specific PRSs that are significantly associated with IS or IS subtypes 5 . This study is aimed to evaluate whether we can prioritize mortality-related PRSs from these candidates through a regularized regression and further demonstrate their independent predictability in an integrated mortality prediction model.…”

Section: Introductionmentioning

confidence: 99%

Predicting mortality among ischemic stroke patients using pathways-derived polygenic risk scores

Chaudhary

Griessenauer

et al. 2022

Sci Rep

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We aim to determine whether ischemic stroke(IS)-related PRSs are also associated with and further predict 3-year all-cause mortality. 1756 IS patients with European ancestry were randomly split into training (n = 1226) and testing (n = 530) groups with 3-year post-event observations. Univariate Cox proportional hazards regression model (CoxPH) was used for primary screening of individual prognostic PRSs. Only the significantly associated PRSs and clinical risk factors with the same direction for a causal relationship with IS were used to construct a multivariate CoxPH. Feature selection was conducted by the LASSO method. After feature selection, a prediction model with 11 disease-associated pathway-specific PRSs outperformed the base model, as demonstrated by a higher concordance index (0.751, 95%CI [0.693–0.809] versus 0.729, 95%CI [0.676–0.782]) in the testing sample. A PRS derived from endothelial cell apoptosis showed independent predictability in the multivariate CoxPH (Hazard Ratio = 1.193 [1.027–1.385], p = 0.021). These PRSs fine-tuned the model by better stratifying high, intermediate, and low-risk groups. Several pathway-specific PRSs were associated with clinical risk factors in an age-dependent manner and further confirmed some known etiologies of IS and all-cause mortality. In conclusion, Pathway-specific PRSs for IS are associated with all-cause mortality, and the integrated multivariate risk model provides prognostic value in this context.

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Polygenic Risk Scores Augment Stroke Subtyping

Cited by 19 publications

References 43 publications

Stroke in SARS-CoV-2 Infection: A Pictorial Overview of the Pathoetiology

Stroke in SARS-CoV-2 Infection: A Pictorial Overview of the Pathoetiology

At the Intersection of Gut Microbiome and Stroke: A Systematic Review of the Literature

Predicting mortality among ischemic stroke patients using pathways-derived polygenic risk scores

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