Data_Sheet_1_Association of Fibroblast Growth Factor 23 With Ischemic Stroke and Its Subtypes: A Mendelian Randomization Study.xlsx

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, I2 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（Fibroblast growth factor 23, FGF23）是一种参与维生素D调控的物质，也是近年来新兴的心血管疾病独立危险因素。既往研究已证实FGF23与脑卒中存在正相关关联。本研究旨在借助孟德尔随机化（Mendelian randomization, MR）框架，评估FGF23与缺血性脑卒中及其亚型的关联。研究使用了一项纳入16624名欧洲受试者的全基因组关联研究中获取的5个遗传变异作为循环FGF23水平的有效工具变量。随后借助MEGASTROKE联盟的数据，通过孟德尔随机化分析推断循环FGF23水平与缺血性脑卒中发病风险的因果关联。后续开展了多项孟德尔随机化分析，包括逆方差加权荟萃分析、MR-Egger法、加权中位数估计（weighted median estimate, WME）以及孟德尔随机化多效性残差和离群值法（MR Pleiotropy Residual Sum and Outlier）。同时进行了包括Cochran Q检验、I²检验以及留一法分析在内的异质性检验分析，并评估了潜在的水平/垂直多效性。最后检验了本研究孟德尔随机化分析的效力。结果发现，3个经验证的遗传变异与循环FGF23水平相关，被用于后续分析。研究显示，FGF23高表达与任何类型的缺血性脑卒中均无显著关联，但遗传预测的FGF23水平与大动脉粥样硬化性脑卒中（large-artery atherosclerotic stroke, LAS）的发病风险存在显著因果关联：循环FGF23水平每增加1个标准差，其对应的比值比为1.74（95%置信区间：1.08~2.81）。本研究结果支持FGF23与LAS之间存在因果关联，为此类疾病提供了潜在的治疗靶点。而FGF23在LAS中的具体作用及相关分子机制仍有待进一步研究。