Department of Ophthalmology, The Jinan Second People's Hospital, Jinan, China.
Medicine (Baltimore). 2024 Jul 26;103(30):e39067. doi: 10.1097/MD.0000000000039067.
An increasing body of evidence supports the involvement of inflammation and immune responses in the occurrence and development of keratoconus (KC). However, the causal relationship between inflammatory factors and KC remains unclear. We employed a 2-way Mendelian randomization (MR) approach to investigate the interaction between KC and inflammatory factors. Instrumental variables for 41 circulating inflammatory regulators and 12 matrix metalloproteinases (MMPs) were selected from genome-wide association studies of European ancestry. Summary statistics for KC were obtained from a genome-wide association study comprising 2116 cases and 24,626 controls of European ancestry. The primary analytical method for assessing causality was the inverse-variance weighted method. Two additional MR methods (MR-Egger and weighted median) were employed to complement the inverse-variance weighted results. In addition, several sensitivity analyses were conducted to evaluate heterogeneity, horizontal pleiotropy, and stability. Our findings indicated that genetically predicted higher levels of macrophage inflammatory protein-1β (odds ratio = 1.126, 95% confidence interval: 1.029-1.232, P = .01) and MMP-13 (odds ratio = 1.211, 95% confidence interval: 1.070-1.371, P = .003) were positively associated with an elevated risk of KC. Conversely, genetically predicted KC was associated with increased levels of interferon-gamma, interleukin-4, and MMP-1. Our current study provided suggestive evidence supporting causal associations of macrophage inflammatory protein-1β and MMP-13 with the risk of KC. In addition, KC appeared to affect the expression of interferon-gamma, interleukin-4, and MMP-1.
越来越多的证据表明炎症和免疫反应参与了圆锥角膜（KC）的发生和发展。然而，炎症因子与 KC 之间的因果关系仍不清楚。我们采用双向孟德尔随机化（MR）方法来研究 KC 与炎症因子之间的相互作用。从欧洲血统的全基因组关联研究中选择了 41 种循环炎症调节剂和 12 种基质金属蛋白酶（MMPs）的工具变量。KC 的汇总统计数据来自一项全基因组关联研究，该研究包括 2116 例欧洲血统的病例和 24626 例对照。评估因果关系的主要分析方法是逆方差加权法。另外两种 MR 方法（MR-Egger 和加权中位数）用于补充逆方差加权结果。此外，还进行了几项敏感性分析，以评估异质性、水平多效性和稳定性。我们的研究结果表明，遗传预测的巨噬细胞炎症蛋白-1β（OR=1.126，95%置信区间：1.029-1.232，P=0.01）和 MMP-13（OR=1.211，95%置信区间：1.070-1.371，P=0.003）水平升高与 KC 风险增加呈正相关。相反，遗传预测的 KC 与干扰素-γ、白细胞介素-4 和 MMP-1 水平升高相关。我们的研究提供了有说服力的证据，支持巨噬细胞炎症蛋白-1β和 MMP-13 与 KC 风险之间存在因果关系。此外，KC 似乎影响了干扰素-γ、白细胞介素-4 和 MMP-1 的表达。
