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Association of Polygenic Susceptibility to Hyperlipidemia With Cholesterol Control and Recurrent Stroke in Ischemic
Kane Wu1, Shufan Huo1, Cyprien A Rivier1
1Department of Neurology, Yale School of Medicine, New Haven, CT.
Insights
High polygenic susceptibility to hyperlipidemia (PSH) increases the risk of uncontrolled cholesterol and recurrent vascular events in stroke survivors. This genetic factor impacts lipid management and post-stroke outcomes.
Area of Science:
- Genetics
- Cardiovascular Medicine
- Neurology
Background:
- Common genetic variations influence stroke risk.
- Polygenic susceptibility to hypertension and diabetes worsens outcomes for ischemic stroke survivors.
- The impact of polygenic susceptibility to hyperlipidemia (PSH) on cholesterol control in stroke survivors is unknown.
Purpose of the Study:
- To investigate the association between PSH and cholesterol control in ischemic stroke survivors.
- To determine if PSH is linked to uncontrolled hyperlipidemia and resistant hyperlipidemia.
- To assess the impact of PSH on recurrent stroke and acute coronary events.
Main Methods:
- Genetic association study using data from the Vitamin Intervention Stroke Prevention (VISP) study.
- Polygenic risk score developed using 38 LDL-c genetic variants to define PSH categories (low, intermediate, high).
- Multivariable regression analyses tested associations with uncontrolled/resistant hyperlipidemia and clinical outcomes, replicated in the UK Biobank.
Main Results:
- Higher PSH was associated with a 66% increased risk of uncontrolled hyperlipidemia (LDL-c >100 mg/dL).
- Higher PSH correlated with twice the risk of recurrent stroke and an 87% higher risk of acute coronary events.
- Findings were replicated in a UK Biobank cohort, showing increased risk for uncontrolled and resistant hyperlipidemia.
Conclusions:
- Elevated PSH is linked to poorer lipid control and increased risk of recurrent vascular events in acute ischemic stroke survivors.
- Findings support evaluating polygenic profiles for failed risk factor control in stroke survivors.
- This research contributes to developing precision medicine tools for post-stroke management.
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.
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