Date of Award

January 2026

Document Type

Thesis

Degree Name

Medical Doctor (MD)

Department

Medicine

First Advisor

Guido J. Falcone

Abstract

BACKGROUND/SCIENTIFIC PREMISECommon genetic variation significantly influences the risk of stroke, and prior research has indicated that polygenic susceptibility to hypertension and diabetes negatively impacts the clinical trajectory of ischemic stroke survivors. Higher circulating low-density-lipoprotein cholesterol (LDL-c) levels are associated with greater ischemic stroke events but with reduced risk of spontaneous, non-traumatic intracranial hemorrhage (ICH). RESEARCH AIMS We aim to investigate the relationship between genetically modeled LDL-c risk and outcomes in ischemic stroke survivors. We also aim to investigate the role of genetic LDL-c levels in ICH risk in individuals anticoagulated for atrial fibrillation. HYPOTHESIS OR QUESTION We hypothesize that polygenic susceptibility to hyperlipidemia (PSH) negatively impacts cholesterol control in ischemic stroke survivors. We further hypothesize that genetic predisposition to low LDL-c associates with higher ICH risk in patients treated with apixaban. METHODS/APPROACH We conducted a genetic association study using data from the Vitamin Intervention Stroke Prevention (VISP) study, a clinical trial that enrolled survivors of ischemic stroke. PSH was modeled through a polygenic risk score built with 38 independent genetic risk variants for LDL-c that was divided into <20, 20-80, and >80 percentile categories labeled as low, intermediate, and high PSH. We used multivariable linear, logistic, and Cox regression, as appropriate, to test whether high PSH was associated with risk of uncontrolled hyperlipidemia (LDL-c > 100mg/dl), resistant hyperlipidemia (LDL-c > 100mg/dl despite statin treatment), and clinical outcomes. We replicated our findings in a cohort of ischemic stroke survivors enrolled in the UK Biobank. To investigate the relationship between genetic LDL-c levels and ICH risk for individuals on apixaban anticoagulation, we conducted a genetic association study within the ongoing All of Us Research Program. Inclusion criteria were >50 years old, atrial fibrillation history, apixaban anticoagulation, and no prior ischemic stroke or ICH. Genetic susceptibility to elevated LDL-c was modeled through a validated polygenic risk score based on 441 known genetic variants, likewise divided into low, intermediate, and high LDL-c genetic percentiles. The outcome was incident ICH after apixaban initiation. RESULTS 1,567 ischemic stroke survivors (mean age 68 years, 35% female) enrolled in VISP were included in the study. Stroke survivors with high versus low PSH had 66% higher risk of uncontrolled hyperlipidemia (OR 1.66, 95%CI 1.17-2.35), 80% higher risk of resistant hyperlipidemia (1.80, 95%CI 0.99-3.29), twice the risk of recurrent stroke (HR 2.12, 95%CI 1.19-3.78), and 87% higher risk of acute coronary events (HR 1.87, 95%CI 1.21-2.87). The association between high PSH and higher risk of uncontrolled and resistant hyperlipidemia were replicated in 1,634 stroke survivors (mean age 61 years, 32% female) enrolled in the UK Biobank (OR 2.34, 95%CI 1.67-3.27 and OR 2.33, 95%CI 1.61-3.37, respectively). For the ICH analysis, 2,549 participants were included (mean age 71 years, 1,140 [44.7%] female, 2,090 [82%] European ancestry) from the All of Us study. Over five years of follow-up, 38 participants sustained an ICH. Compared to patients with low polygenic risk (<20 events), those with moderate (24 events [1.6%]) and high polygenic risk (<20 events) for elevated LDL-c had fewer incident ICH (p=0.033). Multivariable Cox regressions adjusting for demographics confirmed this association: participants with high polygenic risk had 82% lower risk of ICH compared to those with low polygenic risk (HR:0.18, 95%CI:0.04-0.82, p=0.026), persisting in sensitivity analysis including measured LDL-c levels and statin use. STATEMENT OF SCIENTIFIC IMPACT Among acute ischemic stroke survivors, higher PSH is associated with worse lipid control and higher risk of recurrent vascular events. Our findings support the comprehensive evaluation of polygenic profiles as a component of risk factor control in stroke survivors and its role in developing precision medicine tools for post-stroke clinical management. Conversely, higher polygenic risk for increased LDL-c is associated with lower risk of ICH in patients with atrial fibrillation on apixaban. These results parallel ongoing clinical trial investigations including the Statin Use in Intracerebral Hemorrhage Patients (SATURN) trial. A better understanding of genetic risks for ICH in patients on anticoagulation will help guide clinical practice for tailored risk management.

Comments

This thesis is restricted to Yale network users only. This thesis is permanently embargoed from public release.

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