Diversity in genetic risk of recurrent stroke: a genome-wide association study meta-analysis

IntroductionStroke is a leading cause of death and disability worldwide. Recurrent strokes are seven times more lethal than initial ones, with 54% leading to long-term disability. Substantial recurrent stroke risk disparities exist among ancestral groups. Notably, Africans face double the risk and higher fatality rates compared to Europeans. Although genetic studies, particularly GWAS, hold promise for uncovering biological insights into recurrent stroke, they remain underexplored. Our study addresses this gap through meta-analyses of recurrent stroke GWAS, considering specific ancestral groups and a combined approach.MethodsWe utilized four independent study cohorts for African, European, and Combined ancestry recurrent stroke GWAS with genotyping, imputation, and strict quality control. We harmonized recurrent stroke phenotype and effect allele estimates across cohorts. The logistic regression GWAS model was adjusted for age, sex, and principal components. We assessed how well genetic risk of stroke informs recurrent stroke risk using Receiver Operating Characteristic (ROC) curve analysis with the GIGASTROKE Consortium's polygenic risk scores (PRS).ResultsHarmonization included 4,420 participants (818 African ancestry and 3,602 European ancestry) with a recurrent stroke rate of 16.8% [median age 66.9 (59.1, 73.6) years; 56.2% male]. We failed to find genome-wide significant variants (p < 5e−8). However, we found 18 distinct suggestive (p < 5e−6) genetic loci with high biological relevance consistent across African and European ancestries, including PPARGC1B, CCDC3, OPRL1, and MYH11 genes. These genes affect vascular stenosis through constriction and dilation. We also observed an association with SDK1 gene, which has been previous linked with hypertension in Nigerian and Japanese populations). ROC analysis showed poor performance of the ischemic stroke PRS in discriminating recurrent stroke status (area under the curve = 0.48).DiscussionOur study revealed genetic associations with recurrent stroke not previously associated with incident ischemic stroke. We found suggestive associations in genes previously linked with hypertension. We also determined that knowing the genetic risk of incident stroke does currently not inform recurrent stroke risk. We urgently need more studies to understand better the overlap or lack thereof between incident and recurrent stroke biology

Distinct Regulatory Functions of Gbx2 and FGF Signaling in Midbrain-Hindbrain Lineage Restriction Border Formation and Stability

The prospective midbrain-hindbrain border (MHB) in the developing vertebrate brain is demarcated at the end of gastrulation by the common expression border of Gbx2 and Otx2, two homeobox genes. Researchers have shown that a compartment boundary exists at the MHB, but the precise timing and mechanism of its formation are still unclear. By genetic inducible fate-mapping in a Gbx2CreER knock-in mouse line, we demonstrate that descendants of Gbx2+ cells as early as embryonic day (E) 7.5 do not cross the MHB. Gbx2 is required to specify hindbrain fate. In its absence, hindbrain lineage cells abnormally populate the midbrain. In chimaeric embryos that mimic the nascent brain, Gbx2+ and Otx2+ cells segregate from each other, suggesting that the differential expression of these two genes leads to cell sorting, which initiates MHB formation. Fgf8, the midbrain-hindbrain organiser gene, is required to maintain the lineage-restriction boundary after E7.5. In our studies, even partial deletion of Fgf8 impairs lineage separation. Activation of FGF pathways has a cell-autonomous effect on cell sorting in midbrain progenitor cells. Our findings suggest that Fgf8-activated FGF signalling induces distinct cell surface properties or cell-cell communication, which is an important step in restricting cell movement across the MHB. Overall, our work highlights the distinct temporal and spatial requirements for Gbx2 and Fgf8 in establishing a lineage restriction border at the MHB and reveals a new role for Fgf8 in maintaining the MHB lineage border.

Table_1_Predictors of stroke literacy among African Americans in the “buckle of the stroke belt”.docx

BackgroundStroke is associated with racial disparities in morbidity and mortality and stroke outcomes. Stroke literacy is a significant predictor of on-time arrival to the emergency room for acute stroke treatment. In this study, we examined sociodemographic and socioeconomic factors that predict key aspects of stroke literacy: knowledge of stroke signs/symptoms and intent to call 911 in the event of a stroke.MethodsWe analyzed archived data from a survey of African American adults over 18 years residing in the “buckle of the stroke belt.” Participants were ranked into 2 categories: low or no and moderate to adequate stroke knowledge. Then we performed univariate and multivariable analyses to determine the independent predictors of (1) knowledge of stroke signs and symptoms and (1) intent to call 911.ResultsParticipants aged 18–39 years (OR = 0.46, 95% CI: 0.27– 0.80) were more likely to correctly recognize stroke signs and symptoms compared to those who are 65 years and above. Those age 40–64 years were also more likely to recognize stroke signs and symptoms compared to those who are 65 years and above. On the other hand, those with less than high school (OR = 2.83, 95% CI: 2.03–3.96) or complete high school education (OR = 1.95, 95% CI: 1.28–2.96) were less likely to recognize stroke signs and symptoms. Males were less likely (OR = 0.65, 95% CI: 0.64–0.66) to report that they would call 911 in the event of a stroke. While respondents aged 40–64 years (OR = 1.87, 95% CI: 1.14–3.09) and those with moderate to adequate knowledge of stroke (OR = 1.39, 95% CI: 1.18–1.65) were more likely to call 911 in the event of a stroke. Socioeconomic status was generally associated with stroke literacy.ConclusionAmong resident of the “buckle of the stroke belt,” we observed that age, sex, and educational level are among the key predictors of knowledge of stroke signs and symptoms and intent to call 911 in the event of a stroke. Stroke literacy and educational programs needs to incorporate these key sociodemographic aspects as a strategy for improving literacy and reduce stroke-related disability and health disparities.</p

2024 AHA/ASA Performance and Quality Measures for Spontaneous Intracerebral Hemorrhage: A Report From the American Heart Association/American Stroke Association

The American Heart Association/American Stroke Association released a revised spontaneous intracerebral hemorrhage guideline in 2022. A working group of stroke experts reviewed this guideline and identified a subset of recommendations that were deemed suitable for creating performance measures. These 15 performance measures encompass a wide spectrum of intracerebral hemorrhage patient care, from prehospital to posthospital settings, highlighting the importance of timely interventions. The measures also include 5 quality measures and address potential challenges in data collection, with the aim of future improvements