Blood lipids are causally involved in the pathogenesis of atherosclerosis, but their role in cerebral small vessel disease remains largely elusive. Here, we explored associations of genetic determinants of blood lipid levels, lipoprotein particle components, and targets for lipid-modifying drugs with small vessel disease phenotypes. We selected genetic instruments for blood levels of high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglycerides, for cholesterol and triglycerides components of size-defined lipoprotein particles, and for lipid-modifying drug targets based on published genome-wide association studies (up to 617 303 individuals). Applying two-sample Mendelian randomization approaches we investigated associations with ischaemic and haemorrhagic manifestations of small vessel disease [small vessel stroke: 11 710 cases, 287 067 controls; white matter hyperintensities (WMH): 10 597 individuals; intracerebral haemorrhage: 1545 cases, 1481 controls]. We applied the inverse-variance weighted method and multivariable Mendelian randomization as our main analytical approaches. Genetic predisposition to higher HDL-C levels was associated with lower risk of small vessel stroke [odds ratio (OR) per standard deviation = 0.85, 95% confidence interval (CI) = 0.78-0.92] and lower WMH volume (β = -0.07, 95% CI = -0.12 to -0.02), which in multivariable Mendelian randomization remained stable after adjustments for LDL-C and triglycerides. In analyses of lipoprotein particle components by size, we found these effects to be specific for cholesterol concentration in medium-sized high-density lipoprotein, and not large or extra-large high-density lipoprotein particles. Association estimates for intracerebral haemorrhage were negatively correlated with those for small vessel stroke and WMH volume across all lipid traits and lipoprotein particle components. HDL-C raising genetic variants in the gene locus of the target of CETP inhibitors were associated with lower risk of small vessel stroke (OR: 0.82, 95% CI = 0.75-0.89) and lower WMH volume (β = -0.08, 95% CI = -0.13 to -0.02), but a higher risk of intracerebral haemorrhage (OR: 1.64, 95% CI = 1.26-2.13). Genetic predisposition to higher HDL-C, specifically to cholesterol in medium-sized high-density lipoprotein particles, is associated with both a lower risk of small vessel stroke and lower WMH volume. These analyses indicate that HDL-C raising strategies could be considered for the prevention of ischaemic small vessel disease but the net benefit of such an approach would need to be tested in a randomized controlled trial.

中文翻译：

---

血脂和脑小血管疾病的遗传决定因素：高密度脂蛋白胆固醇的作用。

血脂与动脉粥样硬化的发病机理有因果关系，但它们在脑小血管疾病中的作用仍然难以捉摸。在这里，我们探讨了血脂水平，脂蛋白颗粒成分和具有小血管疾病表型的脂质修饰药物靶标的遗传决定因素之间的联系。我们为高密度脂蛋白胆固醇（HDL-C），低密度脂蛋白胆固醇（LDL-C）和甘油三酸酯的血液水平，确定大小的脂蛋白颗粒的胆固醇和甘油三酸酯成分以及脂质修饰选择了遗传仪器基于已发表的全基因组关联研究（最多617 303个个体）的药物靶标。应用孟德尔随机抽样的两样本方法，我们调查了与小血管疾病的缺血性和出血性表现的相关性[小血管卒中：11710例，287067例对照；白质高血压（WMH）：10 597个人；脑出血：1545例，1481例对照]。我们应用逆方差加权方法和多变量孟德尔随机化作为我们的主要分析方法。较高的HDL-C水平的遗传易感性与较低的小血管卒中风险[每标准偏差的比值比（OR）= 0.85、95％置信区间（CI）= 0.78-0.92]和WMH量较低（β= -0.07）相关，95％CI = -0.12至-0.02），在调整LDL-C和甘油三酸酯后，在多变量孟德尔随机中保持稳定。在按大小分析脂蛋白颗粒成分时，我们发现这些作用对中型高密度脂蛋白中的胆固醇浓度具有特异性，而不是大或超大的高密度脂蛋白颗粒中的胆固醇浓度。脑出血的关联估计值与所有脂质性状和脂蛋白颗粒成分中小血管搏动和WMH量的估计值呈负相关。CETP抑制剂靶基因位点中升高HDL-C的遗传变异与小血管卒中风险较低（OR：0.82，95％CI = 0.75-0.89）和WMH量较低（β= -0.08，95％ CI = -0.13至-0.02），但发生脑出血的风险较高（OR：1.64，95％CI = 1.26-2.13）。遗传易感性导致较高的HDL-C，特别是中型高密度脂蛋白颗粒中的胆固醇，与小血管搏动的较低风险和较低的WMH量相关。这些分析表明，可以考虑采用HDL-C升高策略来预防缺血性小血管疾病，但是这种方法的净收益将需要在随机对照试验中进行测试。