Association of Polygenic Susceptibility to Hyperlipidemia With Cholesterol Control and Recurrent Stroke in Ischemic Stroke Survivors.

Background And Objectives: Common genetic variation significantly influences the risk of stroke, and previous research has indicated that polygenic susceptibility to hypertension and diabetes negatively affects the clinical trajectory of ischemic stroke survivors. We hypothesize that polygenic susceptibility to hyperlipidemia (PSH) negatively affects cholesterol control in this same population.

Methods: 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 using a polygenic risk score built with 38 independent genetic risk variants for low-density lipoprotein cholesterol (LDL-c), which was divided into <20, 20-80, and >80 percentile categories labeled as low, intermediate, and high PSH, respectively. We used multivariable linear, logistic, and Cox regression, as appropriate, to test whether high PSH was associated with risk of uncontrolled hyperlipidemia (HLD) (LDL-c >100 mg/dL), resistant HLD (LDL-c >100 mg/dL despite statin treatment), and clinical outcomes. We replicated our findings in a cohort of ischemic stroke survivors enrolled in the UK Biobank.

Results: A total of 1,567 ischemic stroke survivors (mean age 68 years, 35% female) enrolled in VISP were included in the study. Stroke survivors with higher vs low PSH had 66% higher risk of uncontrolled HLD (OR 1.66, 95% CI 1.17-2.35), 80% higher risk of resistant HLD (1.80, 95% CI 0.99-3.29), twice the risk of recurrent stroke (hazard ratio [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 HLD was replicated in 1,634 stroke survivors (mean age 61, 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).

Discussion: Among acute ischemic stroke survivors, higher PSH is associated with worse lipid control and higher risk of recurrent vascular events. Our findings, combined with existing evidence on the role of adverse genetic profiles in blood pressure and glycemic control in this population, support the comprehensive evaluation of polygenic profiles as a cause of failed risk factor control in stroke survivors and its role in developing precision medicine tools for post-stroke clinical management.