Xu Cong, Xu Yonghong, Gao Ling, Wang Min, Wang Guangyan, Wang Guangming
School of Clinical Medicine, Dali University, Dali, Yunnan, 671000, People's Republic of China.
Department of General Surgery, Banan Hospital Affiliated to Chongqing Medical University, Banan, Chongqing, 401320, People's Republic of China.
J Multidiscip Healthc. 2025 Jul 31;18:4481-4495. doi: 10.2147/JMDH.S529168. eCollection 2025.
Stroke is the second leading cause of death and the third leading cause of disability worldwide. The role of fibroblast growth factor 5 (FGF5) in the occurrence and development of stroke remains unclear. We used bidirectional Mendelian randomization (MR) analysis to evaluate the mediating role of metabolites and causal association between inflammatory factors and stroke.
We analyzed the stroke dataset from the FinnGen database (v11) (cases: 43,132; Control: 297,867). Data on metabolites and inflammatory factors were obtained from the genome-wide Association Studies (GWAS) catalog of the European Institute for Bioinformatics (EBI). Using expression data of FGF5 mRNA and protein in the Comprehensive Gene Expression Database (GEO) and clinical data, expression level and clinical relevance of FGF5 in stroke were explored. The protein-protein interaction (PPI) network of FGF5-related genes was constructed, and various bioinformatics analyses (including functional enrichment, immune infiltration analysis, etc) were conducted to evaluate its functional mechanism.
FGF5 was significantly associated with stroke risk (inverse variance weighting method (IVW): odds ratio (OR) = 1.052, 95% confidence interval (CI): 1.021-1.084, P<0.01). Mediation analysis indicated that inflammatory factors influenced stroke risk through the metabolites 1-palmitoyl-phosphoglycerol (GPG) [effect: 0.00462 (-0.0102, 0.001); mediated effect: 9.09% (-20.2%, 1.97%)], 1-stearoyl-2-arachidonoyl-phosphoethanolamine (GPE) [effect: 0.00274 (-0.00212, 0.0076); mediated effect: 5.39% (4.17%, 14.9%). Among them, the mediating effect of 1-palmitoyl phosphatidylglycerol (GPG) was not significant. Furthermore, FGF5 is associated with epithelial cell proliferation, peptidyl-tyrosine phosphorylation, CD4+ primary T cells and M0 macrophages.
This study, by integrating multiple omics methods, such as Mendelian randomization, expression profiling analysis, and bioinformatics, has for the first time established FGF5 as a novel potential biomarker for stroke risk. Inflammatory factors can mediate the molecular pathways of stroke occurrence through metabolites such as GPE. The value of FGF5 as a novel biomarker for the diagnosis/prognosis of stroke and the new mechanism of stroke-related metabolic regulatory network provide a theoretical basis for targeted intervention of stroke.
中风是全球第二大致死原因和第三大致残原因。成纤维细胞生长因子5（FGF5）在中风发生发展中的作用尚不清楚。我们使用双向孟德尔随机化（MR）分析来评估代谢物的中介作用以及炎症因子与中风之间的因果关联。
我们分析了来自芬兰基因数据库（v11）的中风数据集（病例：43,132例；对照：297,867例）。代谢物和炎症因子的数据来自欧洲生物信息学研究所（EBI）的全基因组关联研究（GWAS）目录。利用综合基因表达数据库（GEO）中FGF5 mRNA和蛋白质的表达数据以及临床数据，探讨FGF5在中风中的表达水平和临床相关性。构建FGF5相关基因的蛋白质-蛋白质相互作用（PPI）网络，并进行各种生物信息学分析（包括功能富集、免疫浸润分析等）以评估其功能机制。
FGF-5与中风风险显著相关（逆方差加权法（IVW）：优势比（OR）=1.052，95%置信区间（CI）：1.021-1.084，P<0.01）。中介分析表明，炎症因子通过代谢物1-棕榈酰磷脂甘油（GPG）[效应：0.00462（-0.0102，0.001）；中介效应：9.09%（-20.2%，1.97%）]、1-硬脂酰-2-花生四烯酰磷脂乙醇胺（GPE）[效应：0.00274（-0.00212，0.0076）；中介效应：5.39%（4.17%，14.9%）]影响中风风险。其中，1-棕榈酰磷脂酰甘油（GPG）的中介效应不显著。此外，FGF5与上皮细胞增殖、肽基酪氨酸磷酸化、CD4+原始T细胞和M0巨噬细胞有关。
本研究通过整合孟德尔随机化、表达谱分析和生物信息学等多种组学方法，首次将FGF5确立为中风风险的新型潜在生物标志物。炎症因子可通过GPE等代谢物介导中风发生的分子途径。FGF5作为中风诊断/预后的新型生物标志物的价值以及中风相关代谢调控网络的新机制为中风的靶向干预提供了理论依据。
