Lin Shan, Luo Yuling, Zhan Qingyuan
Department of Respiratory and Critical Care Medicine, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan, China.
Department of Pulmonary and Critical Care Medicine, Guangzhou Institute of Respiratory Health, National Clinical Research Center for Respiratory Disease, National Center for Respiratory Medicine, State Key Laboratory of Respiratory Diseases, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
Medicine (Baltimore). 2025 Jul 18;104(29):e43364. doi: 10.1097/MD.0000000000043364.
Although some observational studies have linked circulating cytokine levels to asthma, their exact causal relationship(s) remain elusive. To address this knowledge gap, a Mendelian randomization (MR) study was performed to explore potential causal associations between circulating cytokine levels and asthma susceptibility using genetic instrumental variables. To investigate potential causal associations between circulating cytokines and asthma risk, a 2-sample MR analysis was performed using data from European participants from publicly available genome-wide association study summary statistics. Single nucleotide polymorphisms demonstrating significant associations with cytokine levels in previous studies were selected as instrumental genetic variables. A range of complementary MR approaches, including inverse variance weighted, weighted median, MR-Egger, weighted mode, simple mode, and MR pleiotropy residual sum and outlier (i.e., "MR-PRESSO") methods, were implemented to comprehensively investigate causality. Genetically predicted levels of the chemokines RANTES (regulated on activation, normal T-cell expressed and secreted [CCL5]), monocyte chemoattractant protein-1 (MCP-1), and growth-regulated protein alpha (GRO-α) exhibited significant causal associations with reduced asthma susceptibility, as evidenced by odds ratios (OR) of 0.935 (95% confidence interval [CI] 0.895-0.978; P = .003), 0.951 (95% CI 0.916-0.986; P = .007), and 0.968 (95% CI 0.944-0.992; P = .011), respectively. In contrast, beta-nerve growth factor (β-NGF; OR 1.043 [95% CI 1.000-1.087], P = .048), tumor necrosis factor-alpha (TNF-α; OR 1.040 [95% CI 1.001-1.081], P = .042), and macrophage colony stimulating factor (M-CSF; OR 1.032 [95% CI 1.001-1.064], P = .043) conferred increased causal risks for the development of asthma. These causal inferences remain robust across multiple complementary MR approaches, including MR-Egger, weighted median, weighted mode, and simple mode regressions. Sensitivity analyses excluded bias from horizontal pleiotropy. This MR analysis provides initial genomic evidence supporting genetically predicted causal relationships between circulating levels of RANTES, MCP-1, GRO-α, β-NGF, TNF-α, and M-CSF and altered susceptibility to asthma. These findings highlight the potential immunopathogenic roles of these cytokines in the onset and development of asthma.
尽管一些观察性研究已将循环细胞因子水平与哮喘联系起来，但其确切的因果关系仍不明确。为填补这一知识空白，开展了一项孟德尔随机化（MR）研究，以利用基因工具变量探索循环细胞因子水平与哮喘易感性之间的潜在因果关联。为研究循环细胞因子与哮喘风险之间的潜在因果关联，使用来自公开可用的全基因组关联研究汇总统计数据中的欧洲参与者数据进行了两样本MR分析。在先前研究中显示与细胞因子水平有显著关联的单核苷酸多态性被选为工具基因变量。实施了一系列互补的MR方法，包括逆方差加权、加权中位数、MR-Egger、加权模式、简单模式以及MR多效性残差总和与异常值（即“MR-PRESSO”）方法，以全面研究因果关系。趋化因子调节激活正常T细胞表达和分泌因子（RANTES，即CCL5）、单核细胞趋化蛋白-1（MCP-1）以及生长调节蛋白α（GRO-α）的基因预测水平与哮喘易感性降低呈现显著因果关联，优势比（OR）分别为0.935（95%置信区间[CI] 0.895 - 0.978；P = 0.003）、0.951（95% CI 0.916 - 0.986；P = 0.007）和0.968（95% CI 0.944 - 0.992；P = 0.011）。相比之下，β-神经生长因子（β-NGF；OR 1.043 [95% CI 1.000 - 1.087]，P = 0.048）、肿瘤坏死因子-α（TNF-α；OR 1.040 [95% CI 1.001 - 1.081]；P = 0.042）以及巨噬细胞集落刺激因子（M-CSF；OR 1.032 [95% CI 1.001 - 1.064]，P = 0.043）赋予哮喘发生增加的因果风险。这些因果推断在包括MR-Egger、加权中位数、加权模式和简单模式回归在内的多种互补MR方法中均保持稳健。敏感性分析排除了水平多效性导致的偏差。这项MR分析提供了初步的基因组证据，支持RANTES、MCP-1、GRO-α、β-NGF、TNF-α和M-CSF的循环水平与哮喘易感性改变之间的基因预测因果关系。这些发现突出了这些细胞因子在哮喘发病和发展中的潜在免疫致病作用。
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