Taylor-Bateman Victoria, Gill Dipender, Georgakis Marios K, Malik Rainer, Munroe Patricia, Traylor Matthew
From Clinical Pharmacology (V.T.-B., P.M., M.T.), William Harvey Research Institute, Queen Mary University of London; Department of Epidemiology and Biostatistics (D.P.), School of Public Health, and Department of Medicine (D.G.), Centre for Pharmacology and Therapeutics, Imperial College London; Novo Nordisk Research Centre (D.G., M.T.), Oxford; Clinical Pharmacology and Therapeutics Section (D.G.), Institute of Medical and Biomedical Education and Institute for Infection and Immunity, St. George's, University of London; Clinical Pharmacology Group (D.G.), Pharmacy and Medicines Directorate, St. George's University Hospitals NHS Foundation Trust, London, UK; Institute for Stroke and Dementia Research (M.G., R.M.), University Hospital of Ludwig-Maximilians-University, Munich, Germany; National Institute for Health Research Barts Cardiovascular Biomedical Research Centre (P.M.), Queen Mary University of London; The Barts Heart Centre and NIHR Barts Biomedical Research Centre-Barts Health NHS Trust (M.T.), William Harvey Research Institute, Queen Mary University London, UK; Center for Genomic Medicine (M.K.G.), Massachusetts General Hospital, Boston; and Program in Medical and Population Genetics (M.K.G.), Broad Institute of Harvard and the Massachusetts Institute of Technology, Boston.
Neurology. 2022 Jan 24;98(4):e343-e351. doi: 10.1212/WNL.0000000000013120.
Cardiovascular risk factors have been implicated in the etiology of cerebral small vessel disease (CSVD); however, whether the associations are causal remains unclear in part due to the susceptibility of observational studies to reverse causation and confounding. Here, we use mendelian randomization (MR) to determine which cardiovascular risk factors are likely to be involved in the etiology of CSVD.
We used data from large-scale genome-wide association studies of European ancestry to identify genetic proxies for blood pressure, blood lipids, body mass index (BMI), type 2 diabetes, smoking initiation, cigarettes per day, and alcohol consumption. MR was performed to assess their association with 3 neuroimaging features that are altered in CSVD (white matter hyperintensities [WMH], fractional anisotropy [FA], and mean diffusivity [MD]) using genetic summary data from the UK Biobank (N = 31,855). Our primary analysis used inverse-weighted median MR, with validation using weighted median, MR-Egger, and a pleiotropy-minimizing approach. Finally, multivariable MR was performed to study the effects of multiple risk factors jointly.
MR analysis showed consistent associations across all methods for higher genetically proxied systolic and diastolic blood pressures with WMH, FA, and MD and for higher genetically proxied BMI with WMH. There was weaker evidence for associations between total cholesterol, low-density lipoprotein, smoking initiation, pulse pressure, and type 2 diabetes liability and at least 1 CSVD imaging feature, but these associations were not reproducible across all validation methods used. Multivariable MR analysis for blood pressure traits found that the effect was primarily through genetically proxied diastolic blood pressure across all CSVD traits.
Genetic predisposition to higher blood pressure, primarily diastolic blood pressure, and to higher BMI is associated with a higher burden of CSVD, suggesting a causal role. Improved management and treatment of these risk factors could reduce the burden of CSVD.
心血管危险因素已被认为与脑小血管病（CSVD）的病因有关；然而，这些关联是否为因果关系仍不明确，部分原因是观察性研究易受反向因果关系和混杂因素的影响。在此，我们使用孟德尔随机化（MR）来确定哪些心血管危险因素可能参与CSVD的病因。
我们使用来自欧洲血统大规模全基因组关联研究的数据，来确定血压、血脂、体重指数（BMI）、2型糖尿病、开始吸烟、每日吸烟量和饮酒量的遗传代理指标。使用来自英国生物银行（N = 31,855）的遗传汇总数据，进行MR分析以评估它们与CSVD中改变的3种神经影像学特征（白质高信号[WMH]、分数各向异性[FA]和平均扩散率[MD]）的关联。我们的主要分析使用逆加权中位数MR，并通过加权中位数、MR-Egger和多效性最小化方法进行验证。最后，进行多变量MR以研究多种危险因素的联合作用。
MR分析表明，在所有方法中，遗传代理的收缩压和舒张压升高与WMH、FA和MD之间，以及遗传代理的BMI升高与WMH之间均存在一致的关联。总胆固醇、低密度脂蛋白、开始吸烟、脉压和2型糖尿病易感性与至少1种CSVD影像学特征之间的关联证据较弱，但这些关联在所有使用的验证方法中均不可重复。对血压特征的多变量MR分析发现，效应主要通过所有CSVD特征中遗传代理的舒张压产生。
高血压（主要是舒张压）和高BMI的遗传易感性与更高的CSVD负担相关，提示存在因果作用。改善这些危险因素的管理和治疗可减轻CSVD的负担。
