Braxton (United States)

Objective: The goal of this study was to test whether the strength of association of stroke-associated genetic variants differs by age of stroke onset. Background: In the MEGASTROKE GWAS study, 55 variants were robustly associated with ischemic stroke in predominantly older populations. Yet limited research has been carried out to date to understand how these genetic associations are modified by age, which could provide clues to the underlying biological mechanisms of these associations. Methods: Analyses were based on 16,000 stroke cases of European ancestry identified from the Stroke Genetics Network (SiGN) and Early Onset Ischemic Stroke Consortium and 24,838 stroke-free controls. We tested if the associations of each variant with stroke differed by age using two complementary approaches. First, we used a case-control logistic regression model testing for the associations of stroke with variant, age, and a variant*age interaction term and second, we used a case-only approach, testing for an association of variant with age of stroke onset. All analyses were adjusted for sex and population structure. Results: We identified six variants whose associations were significantly modified by age (p ≤ 0.001) by either analysis; 5 variants by the case-control analysis and 4 variants by the case-only analysis. Among these were 2 variants at the ABO locus that have been previously shown to be more strongly associated with early compared to late onset stroke, tagging blood groups A and O, respectively, and a variant in WNT2B that has previously been associated with early, but not late, onset ischemic stroke in a small case-control study. Conclusions: Six out of 55 variants previously associated with ischemic stroke in large GWAS studies show differential effects by age, with the stroke risk allele more strongly associated with early onset stroke for 5 variants or more strongly associated with older onset stroke (1 variant). Future work is needed to understand the reasons for this age dependency. Disclosures: None. Study Supported By: R01NS100178, R01NS105150, R01NS114045

Introduction: While chronic alcohol (EtOH) abuse has long been considered a risk factor for several cardiovascular disorders including ischemic stroke, the relationship between intracerebral hemorrhage (ICH) and EtOH abuse is less known. Objective: To characterize ICH patients with EtOH abuse and examine the effects of EtOH abuse on in-hospital outcomes over 20 years. Methods: A query of the 2000-2019 National Inpatient Sample was performed for patients admitted with ICH (ICD9 431, 432.9, ICD-10 I61, I62.9). Demographics, comorbidities, and outcomes were identified. Univariate analysis with t-tests or chi-square performed as appropriate. A 1:1 nearest neighbor propensity score matched cohort was generated. Variables with standardized mean differences >0.1 used in multivariate regression to generate adjusted odds ratios (AOR)/β-coefficients for EtOH abuse on outcomes. Significance set at an alpha level of <0.001. All analysis performed in R version 4.1.3. Results: In total, 2,000,868 patients with ICH were identified; 106,987 (5.3%) abused EtOH. EtOH abuse patients had higher Elixhauser Comorbidity Score (12.95 ± 10.51 vs. 10.28 ± 8.98; p<0.001) and a non-significantly lower NIH Stroke Score (11.0 ± 8.69 vs. 11.34 ± 9.53; p >0.001). Patients with EtOH abuse were more likely to be male, younger, smokers, on Medicaid, be in the 0-25% percentile median income bracket, and have atrial fibrillation, hyperlipidemia, diabetes, and seizures (all p<0.001). Patients with EtOH abuse had less in-hospital mortality, more discharge home or short term hospital, longer hospital stays and more hospital charges (all p<0.001), but after propensity matching and regression analysis these differences were no longer significant. Conclusion: This 20 year nationally representative propensity matched analysis of patients with ICH demonstrates that concomitant EtOH does not significantly worsen in-hospital outcomes despite a higher association of other comorbidities.

Introduction: Severity of leukoaraiosis detected on T2 MRI scans as white matter hyperintensities (WMH) is associated with infarct growth and poor poststroke outcomes in patients with acute ischemic stroke (AIS). Traditional vascular risk factors (VRF) such as age, hypertension (HTN), type 2 diabetes mellitus (T2D), and cigarette smoking are linked to WMH in large population-based studies, yet casual inferences for WMH in AIS patients are limited. We sought to examine the VRFs for evidence of causal relationships with WMH burden in AIS patients using mendelian randomization principles and polygenic risk score (PRS) methods. Method: We examined FLAIR MRIs obtained within 48 hours of AIS onset in 4,362 European Caucasian patients from the MRI-GENetics Interface Exploration (MRI-GENIE) study. WMH volume (WMHv) was measured using a fully automated deep-learning trained algorithm. We considered 13 VRFs: blood pressure (HTN, SBP, DBP, Pulse Pressure), lipid (total cholesterol, HDL, LDL, TG), BMI, T2D, atrial fibrillation, alcohol use and smoking. For each factor, we calculated a weighted PRS for each individual based on the most recent GWAS with various GWAS p-value cutoff. We then used linear regression to estimate associations between each PRS and log transformed WMHv, controlling for age, gender and principal components of genetic ancestries. Strata-specific estimates were combined using inverse-variance weighting based meta-analysis. Results: PRS of both SBP and DBP were positively and robustly associated with WMHv in the meta-analysis (p value of the association ranging from <0.001 to 0.046 for various SNP selection strategies (GWAS p-value cutoff ranging from p<1E-5 to p<1E-8)), unlike the PRS of other risk factors, although stratum-specific significance was achieved for some factors. Conclusion: Using mendelian randomization, our results lend further evidence that high blood pressure is a causal risk factor for WMH in AIS patients. This result is consistent with previous epidemiological studies of leukoaraiosis in stroke-free populations, and it supports universal control of HTN as common contributor to WMH burden and the overall brain health.

Introduction: While oral contraceptive (OC) use is generally safe, women at higher risk for vascular disease are advised to use alternative forms of contraception. Smoking, a prothrombotic factor, is a contraindication for OC use in women over age 35. ABO blood group, specifically the non-O blood types, has also been associated with thrombosis risk. We therefore hypothesized that the effects of smoking and OC use on stroke risk would be accentuated in women with non-O blood groups. Methods: Using data from the Genetics of Early Onset Stroke Study, we used 3 polymorphisms within the ABO locus to classify blood group type in women under age 50, including 347 cases and 383 controls. Logistic regression was used to assess the stroke risk of current OC use, defined as use within 30 days, adjusted for other risk factors, and stratified by O and non-O blood group type. Results: Of the 347 women with early-onset stroke, 45% had African ancestry, 51% had European ancestry, and 4% had other ancestry. The median age was 42 years. After adjusting for race, age, hypertension, diabetes, migraines and aura, and smoking status, the odds ratio (OR) for stroke for smoking alone and OC use alone were 3.0 (95% CI 2.1-4.2) and 3.7 (95% CI 1.7-8.4), respectively in this population. Blood group (O vs non-O) did not appreciably alter the magnitude of these associations. However, the joint risk of smoking and OC use was substantially higher in women with blood group non-O (OR = 9.5, 95% CI 3.2-34.9) vs in women with blood group O (OR=4.9, 95% CI 0.4-110.2). Conclusions: Our findings are consistent with the possibility that non-O type blood group confers an increased risk of early onset stroke among OC users who smoke. Further studies are needed to confirm or refute this possibility and to determine whether non-O blood type should be considered in assessing the risk of OC use.

Introduction: Even though neuroinflammation is increasingly recognized as an essential contributor to ischemic brain injury, the exact underlying mechanisms remain unclear. Higher expression of the vascular cell adhesion molecule 1 (VCAM-1) increases leukocyte-brain endothelium interaction and has been associated with larger infarct size following acute ischemic stroke (AIS). The activation of the TGF-β signaling pathways can down-regulate VCAM-1 expression and ameliorate deleterious tissue outcome during neuroinflammation. Hypothesis: We sought to investigate whether genetic variation in the TGF-beta pathway and adhesion molecule genes is associated with acute stroke lesion size. Methods: We completed genome-wide association (GWA) testing and diffusion-weighted imaging lesion volume (DWIv) analysis in a discovery cohort of 532 AIS patients of European ancestry enrolled within 48 hours of symptom onset. An independent European ancestry cohort of 724 AIS patients with GWA data and automated DWIv served as replication cohort. GWA testing per SNP was performed using linear regression modeling of natural log-transformed DWIv adjusted for age, sex and relevant principal components. We selected 42 inflammatory genes in the TGF-beta pathway for a gene-based analysis using VEGAS (Versatile Gene-based -Association Study) software. A pre-specified discovery phase Bonferroni-corrected threshold was set at p<0.001. In the replication phase, 14 SNPs overlapping were tested at the Bonferroni-corrected p-value threshold of p<0.004. Results: Of all genes in the TGF-beta pathway, VCAM1 (p=0.0006) was significantly associated with DWIv in the discovery AIS cohort (age: 66 ± 14.9 years, sex: 63.4% male, DWIv: 2.2cm 3 (IQR: 0.6-11.7cm 3 )). A single SNP within the VCAM1 gene boundaries (rs3176876 (BETA=0.2341, p=0.003)) was significantly associated with DWIv in the replication AIS cohort (age: 65 ± 14.1 years, sex: 68.6% male, DWIv: 4cm 3 (IQR: 1.3-17.2cm 3 )). Conclusion: The genetic variant rs3176876 in the VCAM1 gene is associated with larger infarct lesion size measured on brain MRI of AIS patients. These findings suggest genetic contribution to the pro-inflammatory mechanisms in acute cerebral ischemia and warrant further investigation.

Background and Purpose: Current use of oral contraceptives (OCs) has been associated with increased risk of ischemic stroke. We sought to determine whether elevated stroke risk in women using OCs was restricted to women with other concurrent high risk conditions (risk modifiers), whether patients with these conditions recalled being advised not to use or to stop using OCs, and whether this advice resulted in behavioral change. Methods: 59 hospitals in the Baltimore-Washington area participated in a population based case-control study of stroke in young women ages 15 to 49 (228 cases/348 controls). Data on OC use was gathered through standardized interview. Potential risk modifiers to OC use included hypertension, smoking, headache, chest pain or heart attack, and blood clots in the legs or lungs. Results: Overall the unadjusted odds ratio for OC use and stroke was 1.5 (95% CI: 1.0-2.3). Participants who had one or more potential risk modifiers to OC use while using OCs had an OR of 2.4 (95% CI: 1.3-4.3), while participants without any of these conditions had an OR of 1.1 (95% CI: 0.6-1.9). The most common conditions cited were smoking and headache. Thirty-eight women with ≥1 high risk conditions recalled being advised not to start OCs; however 9 (24%) of these women were taking OCs at the time of stroke or interview. There were 93 women with ≥1 high risk conditions who recalled being told to discontinue OCs, of whom 14 (15%) were still taking OCs at the time of stroke or interview. Conclusions: Our data are consistent with prior studies suggesting that increased the risk of stroke associated with OC use is restricted primarily to women with concurrent high risk conditions, such as headache or smoking. Improved physician and patient education about the medical conditions associated with higher stroke risk among OC users and a better understanding of the dynamics of the physician-patient encounter could further reduce risk.

A community atlas is an effective method of promoting student‐centered, learning oriented instruction. It provides an integrated framework for teaching thematic interdisciplinary material and promotes collaborative work by students, whose efforts can be shared amongst themselves and with the community. This paper describes community atlas projects from three West Virginia middle schools, in which 320 students and five teachers participated. Younger and less structured students responded with more enthusiasm to the open‐ended nature of the assignment. Self‐disciplined students produced effective web pages combining images, maps, and non‐spatial information such as demographic tables and local perceptions. Although this project was a collaboration between a university and local middle schools, sufficient resources are available for teachers to implement community atlases without specialized assistance.