Abstract
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.
Highlights
Stroke is one of the major causes of death and long-term disability worldwide (GBD 2016 Stroke Collaborators, 2019)
We identified significant association of high Fibroblast growth factor 23 (FGF23) levels with increased large-artery atherosclerotic stroke (LAS) risk (OR = 1.94, 95% confidence interval (CI) 1.35–2.27; p = 3.04E−04) but not with the other ischemic stroke (IS) subtypes or Any ischemic stroke (AIS) using the IVW method (Supplementary Table 4)
weighted median estimate (WME) suggested significant association between FGF23 levels and LAS risk with an odds ratio of 1.75, but not with the other IS subtypes or AIS (Supplementary Table 4)
Summary
Stroke is one of the major causes of death and long-term disability worldwide (GBD 2016 Stroke Collaborators, 2019). Several studies have demonstrated that an increased circulating FGF23 level was correlated with a higher risk (Wright et al, 2014) and a poorer outcome (Seiler et al, 2010) for stroke. A case–cohort study indicated that there was a graded association of FGF23 with the risk of cardioembolic stroke, but there was no significant association between FGF23 and other IS subtypes or with hemorrhagic strokes in community-dwelling adults (Panwar et al, 2015). A Multi-Ethnic Study of Atherosclerosis (MESA) showed that FGF-23 was not associated with carotid intima-media thickness or stroke (Kestenbaum et al, 2014). Until now, it is unclear whether FGF23 levels are causally associated with risk of IS. In this study, we aimed to investigate the possible causal relationships of FGF23 with IS and its subtypes and the potential research value of FGF23
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