Han Shasha, Chen Qiong, Zhu Qiang, Han Wenxiu
Department of Neurology, Jiaozhou Central Hosptital of Qingdao, Qingdao 266300, Shandong, China.
Department of Emergency, Jiaozhou Central Hosptital of Qingdao, Qingdao 266300, Shandong, China.
J Stroke Cerebrovasc Dis. 2025 Jan;34(1):108163. doi: 10.1016/j.jstrokecerebrovasdis.2024.108163. Epub 2024 Dec 4.
A correlation between inflammation and cerebral small vessel disease (CSVD) has been hypothesized by earlier observational research, while this correlation has not been well established. Considering the significant clinical value of this causality determination, Mendelian randomization (MR) was implemented to investigate the causality between inflammatory cytokines and CSVD radiological lesions.
Using the publicly available Genome-Wide Association Study (GWAS) datasets, a bidirectional two-sample MR analysis was employed to infer causality between 91 inflammatory cytokines and CSVD phenotypes [white matter hyperintensity (WHM), fractional anisotropy (FA), mean diffusivity (MD), cerebral microbleeds (CMBs), and lacunar stroke]. A set of methods was used for sensitivity analysis, including Cochran's Q test, MR-Egger intercept method, and MR pleiotropy residual sum and outlier (MR-PRESSO) global test. Furthermore, the strength of causality was assessed using the Bonferroni correction.
Our research discovered a mutually predictive bidirectional link between CSVD phenotypes and inflammatory cytokines. Following the application of the Bonferroni correction, fibroblast growth factor 21 (FGF-21) was significantly inversely correlated with an increased risk of CMBs (OR = 0.579, 95 % CI = 0.425-0.789, P = 0.00055). Using sensitivity analysis, heterogeneity, and horizontal pleiotropy were not detected.
In this investigation, we established the causality between CSVD and inflammatory cytokines, with FGF-21 in particular significantly reducing the risk of CMBs. With further validation, these findings may provide new targets for the prevention, detection, and intervention of CSVD.
早期的观察性研究推测炎症与脑小血管疾病（CSVD）之间存在关联，但这种关联尚未得到充分证实。鉴于确定这种因果关系具有重大的临床价值，因此采用孟德尔随机化（MR）方法来研究炎性细胞因子与CSVD影像学病变之间的因果关系。
利用公开可用的全基因组关联研究（GWAS）数据集，采用双向双样本MR分析来推断91种炎性细胞因子与CSVD表型[白质高信号（WHM）、各向异性分数（FA）、平均扩散率（MD）、脑微出血（CMB）和腔隙性卒中]之间的因果关系。使用了一组方法进行敏感性分析，包括 Cochr an's Q检验、MR-Egger截距法和MR多效性残差和离群值（MR-PRESSO）全局检验。此外，使用Bonferroni校正评估因果关系的强度。
我们的研究发现CSVD表型与炎性细胞因子之间存在相互预测的双向联系。应用Bonferroni校正后，成纤维细胞生长因子21（FGF-21）与CMB风险增加显著负相关（OR = 0.579，95%CI = 0.425 - 0.789，P = 0.00055）。通过敏感性分析，未检测到异质性和水平多效性。
在本研究中，我们确立了CSVD与炎性细胞因子之间的因果关系，尤其是FGF-21可显著降低CMB的风险。经过进一步验证，这些发现可能为CSVD的预防、检测和干预提供新的靶点。
