炎症相关血浆蛋白与脑卒中及其亚型的潜在因果关系:孟德尔随机化分析

Potential Causality between Inflammation-Related Plasma Proteins and Stroke and Its Subtypes:a Mendelian Randomization Analysis

目的采用孟德尔随机化(MR)分析方法分析炎症相关血浆蛋白与脑卒中及其亚型的潜在因果关系。方法炎症相关血浆蛋白遗传数据来自ZHAO等对14824名参与者91种炎症相关血浆蛋白进行的全基因组蛋白质数量性状位点(pQTL)研究,脑卒中及其亚型遗传数据来自MEGASTROKE联盟发布的脑卒中及其亚型全基因组关联研究(GWAS)汇总数据。采用逆方差加权法(IVW)进行MR分析,将加权中值法(WM)、MR-Egger回归作为IVW的补充方法;采用Cochran's Q检验、MR-Egger回归、MR多效性残差和离群值检验(MR-PRESSO)及留一法进行敏感性分析;采用Steiger方向检验分析炎症相关血浆蛋白与脑卒中及其亚型之间是否存在反向因果关系。结果IVW分析结果结合敏感性分析结果显示,成纤维细胞生长因子(FGF)5、抑瘤素M(OSM)升高是脑卒中的保护因素,而白血病抑制因子受体(LIFR)升高是脑卒中的危险因素(P<0.05);真核翻译起始因子4E结合蛋白1(4E-BP1)、神经鞘胚素(ARTN)、CD5、FGF5、IL-5、OSM升高是缺血性脑卒中的保护因素,LIFR升高是缺血性脑卒中的危险因素(P<0.05);CD5、潜伏期相关肽转化生长因子β1(LAP-TGF-β1)、MMP-1、OSM升高是心源性脑卒中的保护因素(P<0.05);MMP-10、程序性细胞死亡蛋白配体1(PD-L1)升高是大血管脑卒中的保护因素(P<0.05);趋化因子CCL28、FGF19、LAP-TGF-β1升高是小血管脑卒中的保护因素(P<0.05)。Steiger检验结果显示,上述炎症相关血浆蛋白与脑卒中及其亚型之间均无反向因果关系(P<0.01)。结论FGF5、OSM、4E-BP1、ARTN、CD5、IL-5、LAP-TGF-β1、MMP-1、MMP-10、PD-L1、趋化因子CCL28、FGF19升高是脑卒中或其亚型的保护因素,而LIFR升高是脑卒中、缺血性脑卒中的危险因素。

Objective To analyze the potential causality between inflammation-related plasma proteins and stroke and its subtypes by Mendelian randomization(MR)analysis method.Methods Genetic data of inflammation-related plasma proteins were derived from a genome-wide Protein Quantitative Trait Loci(pQTL)study of 91 plasma proteins in 14824 participants by ZHAO et al.Genetic data on stroke and its subtypes were obtained from the genome-wide association study(GWAS)summary data released by the MEGASTROKE Consortium.MR analysis was conducted using the inverse variance weighted(IVW),the weighted median(WM)and MR-Egger regression were as supplementary methods to IVW;sensitivity analysis was performed by Cochran's Q test,MR-Egger regression,MR pleiotropy residual sun and outlier(MR-PRESSO),and leave-oneout method;Steiger directional test was used to analyze whether there was a reverse causal relationship between inflammationrelated plasma proteins and stroke and its subtypes.Results The IVW analysis results combined with sensitivity analysis results showed that increased fibroblast growth factor(FGF)5 and oncostatin-M(OSM)were protective factors of stroke,while increased leukemia inhibitory factor receptor(LIFR)was a risk factor of stroke(P<0.05);increased eukaryotic translation initiation factor 4E-binding protein 1(4E-BP1),artemin(ARTN),CD5,FGF5,IL-5 and OSM were protective factors of ischemic stroke,and increased LIFR was a risk factor for ischemic stroke(P<0.05);increased CD5,latency-associated peptide transforming growth factorβ1(LAP-TGF-β1),MMP-1 and OSM were protective factors for cardioembolic stroke(P<0.05);increased MMP-10,and programmed cell death ligand 1(PD-L1)were protective factors of large vessel stroke(P<0.05);increased chemokine CCL28,FGF19 and LAP-TGF-β1 were protective factors of small vessel stroke(P<0.05).Steiger test results showed that there was no reverse causal relationship between the aforementioned inflammation-related plasma proteins and stroke and its subtypes(P<0.01).Conclusion Increased FGF5,OSM,4E-BP1,ARTN,CD5,IL-5,LAP-TGF-β1,MMP-1,MMP-10,PD-L1,chemokine CCL28 and FGF19 are protective factors for stroke or its subtypes,while increased LIFR is a risk factor for stroke and ischemic stroke.