Nguyen, Kevin2025-03-052025-03-052024https://archive.hshsl.umaryland.edu/handle/10713/23163University of Maryland, Baltimore, School of Medicine. Ph.D. 2024.Background: Ischemic stroke (IS) is the leading cause of disability and the 4th leading cause of death in the US. It is a multifactorial disease with genetic and environmental components that influences an individual’s risk of stroke. Thanks to increased awareness of stroke risk factors as well as advancement in intervention and treatment, there has been a substantial fall in stroke incidence and improvement in patient outcome in high-income countries. However, numerous studies have highlighted a divergent temporal trend among young adults; stroke incidence rate among young adults has steadily risen thus far in the 21st century. In tandem to this concerning trend, young adults are experiencing a higher prevalence of conventional stroke risk factors due to sedentary lifestyle and other behavioral changes. Objective The goals of this study were to compare and contrast the impact of conventional and novel risk factors on early (EOS, onset 18-59 years) and late (LOS, onset > 60 years) onset stroke. This study has two specific aims: 1) To demonstrate and compare causal associations of five modifiable stroke risk factors (blood pressure, body mass index, type 2 diabetes, hyperlipidemia, and smoking) within EOS and LOS. 2) To assess causality between higher genetic predisposition of inflammation to risk of stroke and identify potential differential effects in EOS and LOS. Methods: Two-sample MR design was employed to assess the causal relationships between various exposures (previously observed stroke risk factors) and outcome (stroke onset). From publicly available genome-wide association studies’ (GWAS) summary results, genetic variants were identified to be used as instrumental variables to proxy levels of the stroke risk factors. Variant-Stroke Onset associations were derived from GWAS performed on the Early Onset Stroke Consortium (n = 40492) and the Stroke Genetics Network (n = 34396). Causal estimates were calculated respectively in the two groups and then odds ratios between EOS and LOS, as well as stratified by TOAST subtypes. Results: Results from this study suggest that some genetically determined levels of risk factors play a causal role in the increased risk of EOS and LOS. While conventional risk factors do not impact stroke subtypes uniquely, there may be a differential effect attributed to inflammatory biomarkers in EOS and LOS subtypes.en-USInflammationIschemic StrokeMendelian Randomization AnalysisRisk Factorsdissertation2025-01-13Mitchell, Braxton DKittner, Steven J