Department of Epidemiology, School of Public Health and Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Medical College of Soochow University, Suzhou, China.
School of Nursing, Medical College of Soochow University, Suzhou, China.
Eur J Neurol. 2021 Aug;28(8):2543-2551. doi: 10.1111/ene.14878. Epub 2021 May 14.
Elevated serum matrix metalloproteinase-8 (MMP-8) concentrations are associated with high risk of vascular disease, but the causality remains unclear. A two-sample Mendelian randomization (MR) study was performed to examine the causal effect of serum MMP-8 concentrations on the risk of ischaemic stroke, ischaemic stroke subtypes and coronary artery disease.
Ten independent single-nucleotide polymorphisms related to serum MMP-8 concentrations were identified as instrumental variables from a genome-wide association study of 6049 European subjects. Genetic association estimates for ischaemic stroke were obtained from the Multiancestry Genome-wide Association Study of Stroke consortium with 446,696 European individuals. The inverse-variance weighted method was applied to assess the causal associations of serum MMP-8 with ischaemic stroke and its subtypes in the main analysis.
No significant causal association was observed for MMP-8 levels with total ischaemic stroke, large artery stroke or cardioembolic stroke. Genetically determined 1 - unit higher log-transformed serum MMP-8 concentration was associated with an increased risk of small vessel stroke (odds ratio 1.25; 95% confidence interval 1.12-1.39; p < 0.001). In secondary analysis, a similar adverse impact was reported for MMP-8 on coronary artery disease (odds ratio 1.05; 95% confidence interval 1.01-1.10; p = 0.017). Sensitivity analyses further confirmed the relationship between serum MMP-8 level and small vessel stroke and coronary artery disease. Mendelian randomization Egger regression showed no evidence of pleiotropic bias.
High serum MMP-8 concentrations were causally associated with increased risks of small vessel stroke and coronary artery disease. The mechanism underlying the effect of serum MMP-8 on the vascular system requires further investigation.
血清基质金属蛋白酶-8（MMP-8）浓度升高与血管疾病的高风险相关，但因果关系尚不清楚。进行了一项两样本孟德尔随机化（MR）研究，以检验血清 MMP-8 浓度对缺血性卒中、缺血性卒中亚型和冠心病风险的因果影响。
从 6049 名欧洲受试者的全基因组关联研究中确定了 10 个与血清 MMP-8 浓度相关的独立单核苷酸多态性作为工具变量。缺血性卒中的遗传关联估计值来自多民族全基因组关联研究中风联盟，其中包括 446696 名欧洲个体。在主要分析中，应用逆方差加权法评估血清 MMP-8 与缺血性卒中和其亚型的因果关联。
MMP-8 水平与总缺血性卒中、大动脉卒中和心源性栓塞性卒中之间没有显著的因果关联。遗传上确定的 1 个单位更高的对数转换血清 MMP-8 浓度与小血管卒中风险增加相关（优势比 1.25；95%置信区间 1.12-1.39；p<0.001）。在二次分析中，MMP-8 对冠心病也有类似的不利影响（优势比 1.05；95%置信区间 1.01-1.10；p=0.017）。敏感性分析进一步证实了血清 MMP-8 水平与小血管卒中和冠心病之间的关系。孟德尔随机化 Egger 回归未显示出存在偏倚的证据。
高血清 MMP-8 浓度与小血管卒中和冠心病风险增加有因果关系。血清 MMP-8 对血管系统的影响的机制需要进一步研究。
