Zheng Kai, Lin Lingmin, Cui Pan, Liu Tao, Chen Lin, Yang Chunsheng, Jiang Wei
Department of Neurology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin, China.
School of Brain Science and Brain Medicine, Zhejiang University, Hangzhou, China.
Front Genet. 2020 Dec 23;11:608517. doi: 10.3389/fgene.2020.608517. eCollection 2020.
Fibroblast growth factor 23 (FGF23), which is involved in the regulation of vitamin D, is an emerging independent risk factor for cardiovascular diseases. Previous studies have demonstrated a positive association between FGF23 and stroke. In this study, we aimed to assess the association of FGF23 with ischemic stroke and its subtypes by applying a Mendelian randomization (MR) framework. Five genetic variants obtained from a genome-wide association study involving 16,624 European subjects were used as valid instruments of circulating FGF23 levels. MR was applied to infer the causality of FGF23 levels and the risk of ischemic stroke using data from the MEGASTROKE consortium. Subsequently, several MR analyses, including inverse-variance weighted meta-analysis, MR-Egger, weighted median estimate (WME), MR Pleiotropy Residual Sum and Outlier were performed. The heterogeneity test analysis, including Cochran's Q, test and leave-one-out analysis were also applied. Furthermore, potential horizontal/vertical pleiotropy was assessed. Lastly, the power of MR analysis was tested. Three validated variants were found to be associated with circulating FGF23 levels and were used for further investigation. We found that high expression level of FGF23 was not associated with any ischemic stroke. However, a causal association between genetically predicted FGF23 levels and the risk of large-artery atherosclerotic stroke (LAS) was significant, with an odds ratio of 1.74 (95% confidence interval = 1.08-2.81) per standard deviation increase in circulating FGF23 levels. Our findings provide support for the causal association between FGF23 and LAS, and therefore, offer potential therapeutic targets for LAS. The specific roles of FGF23 in LAS and associated molecules require further investigation.
成纤维细胞生长因子23（FGF23）参与维生素D的调节，是心血管疾病新出现的独立危险因素。既往研究已证实FGF23与中风之间存在正相关。在本研究中，我们旨在通过应用孟德尔随机化（MR）框架来评估FGF23与缺血性中风及其亚型的关联。从一项涉及16624名欧洲受试者的全基因组关联研究中获得的5个基因变异被用作循环FGF23水平的有效工具。使用来自MEGASTROKE联盟的数据，应用MR来推断FGF23水平与缺血性中风风险之间的因果关系。随后，进行了多项MR分析，包括逆方差加权荟萃分析、MR-Egger分析、加权中位数估计（WME）分析、MR多效性残差和离群值分析。还应用了异质性检验分析，包括Cochran's Q检验和留一法分析。此外，评估了潜在的水平/垂直多效性。最后，对MR分析的效能进行了检验。发现3个经过验证的变异与循环FGF23水平相关，并用于进一步研究。我们发现FGF23的高表达水平与任何缺血性中风均无关联。然而，遗传预测的FGF23水平与大动脉粥样硬化性中风（LAS）风险之间的因果关联显著，循环FGF23水平每增加1个标准差，比值比为1.74（95%置信区间=1.08-2.81）。我们的研究结果支持FGF23与LAS之间的因果关联，因此为LAS提供了潜在的治疗靶点。FGF23在LAS中的具体作用及相关分子有待进一步研究。
