Introduction: Aneurysm rupture is associated with high mortality and morbidity, including both intracranial aneurysms (IA) and abdominal aortic aneurysms (AAA). Despite potential preemptive treatment in those identified prior to IA or AAA rupture, the evidence for whom to screen remains limited. IA and AAA share both environmental and genetic risk, and prior cost-effectiveness models suggest the potential efficacy of screening in these high-risk individuals. We hypothesized that reciprocal screening in those presenting with IA for AAA would yield positive results. Methods: The BAAS study sought to establish the co-prevalence of IA and AAA. In this arm of BAAS, we recruited patients presenting with IA and screened them for AAA using abdominal ultrasound (aU/S) at two sites: Mayo Clinic and the University of Virginia (UVA). All participants underwent a detailed interview to collect demographic, radiographic, and clinical data. At UVA, participants also received genetic counseling. Results: At Mayo Clinic, we enrolled and screened 81 consecutive patients with aSAH (3 patients with known AAA were excluded) with 3 (3.7%) positive aU/S for AAA. At UVA, we recruited 195 consecutive patients presenting with ruptured or unruptured IA and completed screening aU/S in 178 (93%). Only one (0.6%) had an AAA. Conclusion: The lower positive screening at UVA (0.6%) which enrolled both ruptured and unruptured IA compared to the 3.7% positive results at Mayo suggests that future efforts to identify who with IA might benefit from AAA screening should focus on those with aneurysmal subarachnoid hemorrhage (aSAH).
Introduction: Abdominal aortic aneurysm (AAA) rupture has a mortality rate of 64% and intracranial aneurysm (IA) rupture has a mortality rate of 50%. Despite the high mortality rates, early detection and treatment of these vascular lesions prior to rupture can prevent devastating clinical outcomes, underscoring the need to identify high-risk populations for screening. Current evidence demonstrates shared genetic and environmental risk factors for both AAA and IA. Methods: The BAAS study sought to establish the co-prevalence of AAA and IA. In one arm of BAAS, we recruited patients presenting with AAA and screened them for IA. All participants underwent a detailed interview to collect demographic, radiographic, and clinical data and also had genetic counseling. Results: Of the 126 individuals with an AAA enrolled, 65% (82/126) completed the MRA. Difficulty with logistics of obtaining the research MRA with long distance travel to clinic was the principal reason for failure to obtain MRA. We identified 20.7% (17/82) with one or more IA, including 21 aneurysms found during systematic screening. IA ranged in size from 1.5-14 mm (height) x 1.4-7 mm (width) and varied in location. 9.5% (2/21) had a maximum diameter of 7 mm or more. One participant with a positive MRA underwent early coil embolization with the remainder undergoing continued clinical surveillance. Of the 15 individuals completing the genetic counseling screening, two underwent recommended clinical genetic testing, revealing one negative screen and one variant of unknown significance in the MYH11 gene. Conclusion: Consistent with our prior cost effectiveness models, these prospective data support the clinical utility of routine screening for IA in patients presenting with AAA.
Introduction: The pathogenesis of spontaneous cervical artery dissection (sCeAD), a common cause of stroke in young adults, is poorly understood. The majority of published data in sCeAD derive from populations of European ancestry, including a recent genome-wide study identifying an association with the rs9349379 polymorphism of the PHACTR1 gene. Little is known about sCeAD in individuals of African ancestry despite robust epidemiological data showing increased risk of stroke at younger ages, partially explained by higher prevalence of traditional vascular risk factors. We hypothesize that people of African ancestry with sCeAD have different epidemiology and clinical profiles compared to those of European ancestry, and a different genetic architecture related to rs9349379 of the PHACTR1 gene. Methods: We searched a single-center database of sCeAD (n=278) to identify individuals of African and European ancestry. We compared differential prevalence of sCeAD versus all young stroke (≤ 60) between patients of African and European ancestry at our center. We characterized clinical profiles, confirmed by electronic medical record review. Data include descriptive statistics reported as medians or percentages as appropriate. We also used the publicly available HapMap Project to obtain allele frequencies of rs9349379 in different ancestral populations. Results: Conclusion: Individuals of African Ancestry account for a relatively smaller proportion of sCeAD cases compared to the proportion of all young stroke cases. Despite similar ages at time of event, individuals of African ancestry suffering sCeAD have higher prevalence of vascular risk factors compared to individuals of European Ancestry. Reviewing HapMap data demonstrates striking differences in allele frequencies for rs9349379 in the PHACTR1 gene between ancestral populations. Further prospective research is needed to clarify these associations and disparities in the pathogenesis of sCeAD.
Introduction: Recent success identifying genetic variation in ischemic stroke (IS) has yet to translate into actionable targets or pathways. Weighted Gene Co-Expression Network Analysis (WGCNA) uses an unsupervised approach to cluster genes into modules based on co-expression profiles. Modules likely contain biologically related genes. The correlation between a gene’s expression and the module’s overall expression pattern (eigengene) defines connectivity. Genes with high connectivity may inform and supplement genome-wide association studies (GWAS). Methods: Gene Expression in Carotid Artery GSE43292 (GEO) resource contains publically available Affymetrix Human GeneChip Gene 1.0 ST data from 34 carotid atherosclerotic plaques and paired normal carotid tissue from the same individual. WGCNA resulted in 16 co-expression modules tested against the atherosclerosis phenotype. Significant modules had strong correlation between module eigengene and atherosclerosis. We took the top genes from significantly associated modules and looked them up in two existing IS genetic datasets: Stroke Genetic Network (SiGN) (17,000 IS cases & 32,000 controls) and METASTROKE (10,307 cases & 19,326 controls). We conducted a secondary GWAS informed by WGCNA for only known functional variants in METASTROKE with replication in SiGN. Results: Five of 16 modules showed evidence of association with two standouts (“Turquoise” and “Brown”) both enriched for genes associated with vascular disease related traits (carotid IMT, coronary artery disease, etc.) and contain genes associated with IS, especially large artery atherosclerotic stroke (including HDAC9). We took the top 20 genes from these modules, not currently known to associate with IS, and looking them up in SiGN and METASTROKE, we found association with variants in three genomic regions (SLC7A7, ATXN2/SH2B3, ALDH2). The informed GWAS approach identified ADAMTSL3 as a potential novel translational target. Conclusion: Leveraging expression data in a convergent genomics approach holds promise to supplement on-going GWAS and accelerate identification of potential translational targets. Gene ontology analyses of genes from the top modules are underway.
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