Wu Kane, Huo Shufan, Rivier Cyprien A, Torres-Lopez Victor M, Sharma Richa, de Havenon Adam, Worrall Bradford, Sheth Kevin N, Falcone Guido J
medRxiv. 2025 Feb 27:2025.02.26.25322908. doi: 10.1101/2025.02.26.25322908.
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.
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.
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).
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.
高血压和糖尿病的多基因易感性对缺血性脑卒中幸存者的临床病程产生负面影响。我们假设高脂血症的多基因易感性（PSH）对同一人群的胆固醇控制有负面影响。
我们利用维生素干预卒中预防（VISP）研究的数据进行了一项基因关联研究，VISP是一项纳入缺血性脑卒中幸存者的临床试验。PSH通过一个多基因风险评分来建模，该评分由38个独立的低密度脂蛋白胆固醇（LDL-c）基因风险变异构建而成，并分为<20、20 - 80和>80百分位数类别，分别标记为低、中、高PSH。我们酌情使用多变量线性、逻辑和Cox回归来测试高PSH是否与血脂控制不佳（LDL-c > 100mg/dl）风险、难治性高脂血症（尽管接受他汀类药物治疗但LDL-c > 100mg/dl）风险及临床结局相关。我们在英国生物银行纳入的一组缺血性脑卒中幸存者中重复了我们的研究结果。
VISP研究中纳入了1567名缺血性脑卒中幸存者（平均年龄68岁，35%为女性）。与低PSH的脑卒中幸存者相比，高PSH的幸存者血脂控制不佳风险高66%（比值比[OR] 1.66，95%置信区间[CI] 1.17 - 2.36），难治性高脂血症风险高83%（1.83，95%CI 1.00 - 3.37），复发性卒中风险高两倍（风险比[HR] 2.03，95%CI 1.14 - 3.61），急性冠脉事件风险高80%（HR 1.81，95%CI 1.18 - 2.78）。在英国生物银行纳入并参与研究的1634名脑卒中幸存者（平均年龄61岁，32%为女性）中重复了高PSH与血脂控制不佳和难治性高脂血症高风险之间的关联（OR分别为2.34，95%CI 1.68 - 3.28和OR 2.33，95%CI 1.61 - 3.38）。
在急性缺血性脑卒中幸存者中，较高的PSH与较差的血脂控制及复发性血管事件的较高风险相关。结合关于不良基因谱在该人群血压和血糖控制中作用的现有证据，我们的研究结果支持将多基因谱作为脑卒中幸存者危险因素控制失败的一个原因进行综合评估。
