Genetically Determined Levels of Circulating Cytokines and Risk of Stroke: Role of Monocyte Chemoattractant Protein-1
Genetically Determined Levels of Circulating Cytokines and Risk of Stroke: Role of Monocyte Chemoattractant Protein-1
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DOI：
10.1161/circulationaha.118.035905
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发表时间：
2019-01-08
期刊：
影响因子：
37.8
通讯作者：
Dichgans, Martin
中科院分区：
文献类型：
--
作者：
Georgakis, Marios K.;Gill, Dipender;Dichgans, Martin
背景：细胞因子和生长因子与血管疾病的发生和传播有关。观察性研究表明，它们的循环水平与中风有关。我们的目的是通过进行 2 个样本的孟德尔随机化 (MR) 研究，探讨基因决定的细胞因子和生长因子的循环水平是否与中风及其病因亚型相关。方法：41 种细胞因子和生长因子的遗传仪器是从 8293 名健康成年人的全基因组关联研究中获得的。应用逆方差加权荟萃分析、加权中值分析、孟德尔随机化-Egger 回归和多变量孟德尔随机化，在 MEGASTROKE 全基因组关联研究数据集（67162 例病例；454450 名对照）中评估了它们与中风和中风亚型的关联。英国生物银行队列被用作独立验证样本（4985 例病例；364434 例对照）。通过使用公开的全基因组关联研究数据，进一步测试了单核细胞趋化蛋白-1 (MCP-1/CCL2) 的遗传仪器与病因相关血管特征的关联。结果：较高 MCP-1 水平的遗传倾向与较高的中风风险相关（比值比 [OR] 每 1 个 SD 增加，1.06；95% CI，1.02-1.09； P=0.0009）、任何缺血性卒中（OR，1.06；95% CI，1.02-1.10；P=0.002）、大动脉卒中（OR，1.19；95% CI，1.09-1.30；P=0.0002）和心源性卒中（OR，1.14；95% CI， 1.06-1.23；P=0.0004），但不适用于小血管卒中或脑出血。敏感性分析结果稳定，并且在调整心血管危险因素后仍然显着。英国生物银行的分析显示，可用表型具有相似的关联性（任何中风：OR，1.08；95% CI，0.99-1.17；P=0.09；任何缺血性中风：OR，1.07；95% CI，0.97-1.18；P=0.17）。基因决定的较高 MCP-1 水平进一步与冠状动脉疾病（OR，1.04；95% CI，1.00-1.08；P=0.04）和心肌梗死（OR，1.05；95% CI，1.01-1.09；P=0.02）相关，但与心房颤动无关。一项观察性研究的荟萃分析显示，与对照组相比，中风患者的循环 MCP-1 水平较高。结论：MCP-1 循环水平升高的遗传倾向与较高的中风风险相关，特别是大动脉中风和心源性中风。靶向MCP-1或其受体是否可以降低中风发病率还需要进一步研究。
Background: Cytokines and growth factors have been implicated in the initiation and propagation of vascular disease. Observational studies have shown associations of their circulating levels with stroke. Our objective was to explore whether genetically determined circulating levels of cytokines and growth factors are associated with stroke and its etiologic subtypes by conducting a 2-sample Mendelian randomization (MR) study.Methods: Genetic instruments for 41 cytokines and growth factors were obtained from a genome-wide association study of 8293 healthy adults. Their associations with stroke and stroke subtypes were evaluated in the MEGASTROKE genome-wide association study data set (67162 cases; 454450 controls) applying inverse variance-weighted meta-analysis, weighted-median analysis, Mendelian randomization-Egger regression, and multivariable Mendelian randomization. The UK Biobank cohort was used as an independent validation sample (4985 cases; 364434 controls). Genetic instruments for monocyte chemoattractant protein-1 (MCP-1/CCL2) were further tested for association with etiologically related vascular traits by using publicly available genome-wide association study data.Results: Genetic predisposition to higher MCP-1 levels was associated with higher risk of any stroke (odds ratio [OR] per 1 SD increase, 1.06; 95% CI, 1.02-1.09; P=0.0009), any ischemic stroke (OR, 1.06; 95% CI, 1.02-1.10; P=0.002), large-artery stroke (OR, 1.19; 95% CI, 1.09-1.30; P=0.0002), and cardioembolic stroke (OR, 1.14; 95% CI, 1.06-1.23; P=0.0004), but not with small-vessel stroke or intracerebral hemorrhage. The results were stable in sensitivity analyses and remained significant after adjustment for cardiovascular risk factors. Analyses in the UK Biobank showed similar associations for available phenotypes (any stroke: OR, 1.08; 95% CI, 0.99-1.17; P=0.09; any ischemic stroke: OR, 1.07; 95% CI, 0.97-1.18; P=0.17). Genetically determined higher MCP-1 levels were further associated with coronary artery disease (OR, 1.04; 95% CI, 1.00-1.08; P=0.04) and myocardial infarction (OR, 1.05; 95% CI, 1.01-1.09; P=0.02), but not with atrial fibrillation. A meta-analysis of observational studies showed higher circulating MCP-1 levels in patients with stroke in comparison with controls.Conclusions: Genetic predisposition to elevated circulating levels of MCP-1 is associated with higher risk of stroke, in particular with large-artery stroke and cardioembolic stroke. Whether targeting MCP-1 or its receptors can lower stroke incidence requires further study.