Genetically-Determined Low-density Lipoprotein in Ischemic Stroke Survivors.

Background And Objectives: Polygenic susceptibility to hypertension and diabetes negatively impacts the clinical trajectory of ischemic stroke survivors. We hypothesize that polygenic susceptibility to hyperlipidemia (PSH) negatively impacts 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 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.

Results: 1,567 ischemic stroke survivors (mean age 68 years, 35% female) enrolled in VISP were included in the study. Stroke survivors with higher versus low PSH had 66% higher risk of uncontrolled hyperlipidemia (OR 1.66, 95%CI 1.17-2.36), 83% higher risk of resistant hyperlipidemia (1.83, 95%CI 1.00-3.37), twice the risk of recurrent stroke (HR 2.03, 95%CI 1.14-3.61) and 80% higher risk of acute coronary events (HR 1.81, 95%CI 1.18-2.78). The association between high PSH and higher risk of uncontrolled and resistant hyperlipidemia were replicated in 1,634 stroke survivors (mean age 61, 32% female sex) enrolled in the UK Biobank (OR 2.34, 95%CI 1.68-3.28 and OR 2.33, 95%CI 1.61-3.38, respectively).

Discussion: Among acute ischemic stroke survivors, higher PSH is associated with worse lipid control and higher risk of recurrent vascular events. Combined with existing evidence on the role of adverse genetic profiles in blood pressure and blood control in this population, our findings support the comprehensive evaluation of polygenic profiles as a cause of failed risk factor control in stroke survivors.