Koohi Fatemeh, Harshfield Eric L, Gill Dipender, Ge Wenjing, Burgess Stephen, Markus Hugh S
Stroke Research Group, Department of Clinical Neurosciences, University of Cambridge, Cambridge, CB2 0QQ, UK.
Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, W12 0BZ, UK.
Brain. 2024 Dec 11. doi: 10.1093/brain/awae399.
Cerebral small vessel disease (cSVD) causes lacunar stroke (LS), intracerebral haemorrhage, and is the most common pathology underlying vascular dementia. However, there are few trials examining whether treating conventional cardiovascular risk factors reduce stroke risk in cSVD, as opposed to stroke as a whole. We used Mendelian randomization techniques to investigate which risk factors are causally related to cSVD and to evaluate whether specific drugs may be beneficial in cSVD prevention. We identified genetic proxies for blood pressure traits, lipids, glycaemic markers, anthropometry measures, smoking, alcohol consumption, and physical activity from large-scale genome-wide association studies of European ancestry. We also selected genetic variants as proxies for drug target perturbation in hypertension, dyslipidaemia, hyperglycaemia, and obesity. Mendelian randomization was performed to assess their associations with LS from the GIGASTROKE Consortium (n = 6811) and in a sensitivity analysis in a cohort of patients with MRI-confirmed LS (n = 3306). We also investigated associations with three neuroimaging features of cSVD, namely, white matter hyperintensities (n = 55 291), fractional anisotropy (n = 36 460), and mean diffusivity (n = 36 012). Genetic predisposition to higher systolic and diastolic blood pressure was associated with LS and cSVD imaging markers. Genetically predicted liability to diabetes, obesity, smoking, higher triglyceride levels, and the ratio of triglycerides to high density lipoprotein (HDL) also showed detrimental associations with LS risk, while genetic predisposition to higher HDL concentrations and moderate-to-vigorous physical activity showed protective associations. Genetically proxied blood pressure-lowering through calcium channel blockers (CCBs) was associated with cSVD imaging markers, while genetically proxied HDL-raising through Cholesteryl Ester Transfer Protein (CETP) inhibitors, triglyceride-lowering through lipoprotein lipase (LPL), and weight-lowering through gastric inhibitory polypeptide receptor (GIPR) were associated with lower risk of LS. Our findings highlight the importance of some conventional cardiovascular risk factors, including blood pressure and BMI, in cSVD, but not other e.g. LDL. The findings further demonstrate the potential beneficial effects of CCBs on cSVD imaging markers and CETP inhibitors, LPL enhancement, and GIPR obesity-targeted drugs on LS. They provide useful information for initiating future clinical trials examining secondary prevention strategies in cSVD.
脑小血管病（cSVD）可导致腔隙性卒中（LS）、脑出血，并且是血管性痴呆最常见的潜在病理原因。然而，与整体卒中相比，很少有试验研究治疗传统心血管危险因素是否能降低cSVD的卒中风险。我们使用孟德尔随机化技术来研究哪些危险因素与cSVD存在因果关系，并评估特定药物在预防cSVD方面是否有益。我们从欧洲血统的大规模全基因组关联研究中确定了血压性状、血脂、血糖标志物、人体测量指标、吸烟、饮酒和身体活动的遗传代理变量。我们还选择了基因变异作为高血压、血脂异常、高血糖和肥胖中药物靶点扰动的代理变量。进行孟德尔随机化以评估它们与GIGASTROKE联盟（n = 6811）中LS的关联，并在一组MRI确诊的LS患者（n = 3306）中进行敏感性分析。我们还研究了与cSVD的三个神经影像学特征的关联，即白质高信号（n = 55291）、分数各向异性（n = 36460）和平均扩散率（n = 36012）。收缩压和舒张压升高的遗传易感性与LS和cSVD影像学标志物相关。遗传预测的糖尿病、肥胖、吸烟、较高甘油三酯水平以及甘油三酯与高密度脂蛋白（HDL）的比率的易感性也与LS风险呈有害关联，而较高HDL浓度和中度至剧烈身体活动的遗传易感性则呈保护关联。通过钙通道阻滞剂（CCB）进行遗传代理的血压降低与cSVD影像学标志物相关，而通过胆固醇酯转移蛋白（CETP）抑制剂进行遗传代理的HDL升高、通过脂蛋白脂肪酶（LPL）进行甘油三酯降低以及通过胃抑制多肽受体（GIPR）进行体重降低与较低的LS风险相关。我们的研究结果强调了一些传统心血管危险因素，包括血压和BMI，在cSVD中的重要性，但不包括其他因素，例如低密度脂蛋白（LDL）。研究结果进一步证明了CCB对cSVD影像学标志物以及CETP抑制剂、LPL增强和针对肥胖的GIPR药物对LS的潜在有益作用。它们为启动未来研究cSVD二级预防策略的临床试验提供了有用信息。
