Shi Wenbin, Zhang Anan, Xu Yuli, Liu Shuhua, Jia Xiqun, Hu Ziyang
Department of Stomatology, Shenzhen Longhua District Central Hospital, Shenzhen, China.
Department of Neonatal, Shenzhen Longhua District Central Hospital, Shenzhen, China.
Medicine (Baltimore). 2025 Jun 6;104(23):e42642. doi: 10.1097/MD.0000000000042642.
This study aimed to elucidate the causal relationship between cytokines and oral cancer using Mendelian randomization (MR) analysis. Utilizing genetic data from genome-wide association studies (GWAS) and publicly available datasets, we conducted a bidirectional 2-sample MR analysis. The study design employed single nucleotide polymorphisms as genetic instruments to investigate the link between cytokines and oral cancer. The analysis was based on data from 2 cohorts with total 132 cytokines: 41 cytokines from comprehensive GWAS meta-analysis data, 91 cytokines from GWAS summary statistics for circulating inflammatory cytokines. Oral cancer genetic association data was sourced from the FinGen R10 datasets. To discern the causal relationship between cytokines and oral cancer, 5 MR methodologies, including inverse variance weighted and MR-Egger regression, weighted median, weighted mode, and simple mode were applied. The MR analysis revealed nominal associations between certain cytokines and the risk of oral cancer. Specifically, increased levels of C-X-C motif chemokine ligand 9 (odd ratios [OR] = 0.760, 0.600-0.962, 95% confidence interval [CI] 0.600-0.962, P = .023), monocyte chemoattractant protein 1 (OR = 0.78, 95% CI 0.32-0.99, P = .046), and TNF related activation induced cytokine (OR = 0.792, 95% CI 0.630-0.994, P = .044) were associated with a reduced risk of oral cancer, while higher levels of monocyte chemoattractant protein 2 (OR = 1.164, 95% CI 1.001-1.353, P = .048) and CC motif chemokine 25 (OR = 1.434, 95% CI 1.106-1.858, P = .006) were linked to an increased risk. The reverse analysis suggested a possible effect of oral cancer on the level of circulating cytokines, particularly Fractalkine (OR = 0.942, 95% CI 0.897-0.990, P = .019). No evidence of heterogeneity or significant pleiotropy was detected, validating the instrumental variables used. The findings support a causal relationship between specific cytokines and the risk of oral cancer, highlighting the complex interplay between inflammatory mediators and cancer development. These results underscore the importance of individualized immune profiling in treating oral cancer patients and pave the way for future research into targeted therapies based on cytokine profiles.
本研究旨在通过孟德尔随机化（MR）分析阐明细胞因子与口腔癌之间的因果关系。利用全基因组关联研究（GWAS）的遗传数据和公开可用数据集，我们进行了双向双样本MR分析。该研究设计采用单核苷酸多态性作为遗传工具，以研究细胞因子与口腔癌之间的联系。分析基于来自2个队列的132种细胞因子的数据：41种细胞因子来自综合GWAS荟萃分析数据，91种细胞因子来自循环炎症细胞因子的GWAS汇总统计数据。口腔癌遗传关联数据来自芬兰基因（FinGen）R10数据集。为了识别细胞因子与口腔癌之间的因果关系，应用了5种MR方法，包括逆方差加权法和MR-Egger回归法、加权中位数法、加权众数法和简单众数法。MR分析揭示了某些细胞因子与口腔癌风险之间的名义关联。具体而言，C-X-C基序趋化因子配体9水平升高（比值比[OR]=0.760，0.600 - 0.962，95%置信区间[CI]0.600 - 0.962，P = 0.023）、单核细胞趋化蛋白1（OR = 0.78，95% CI 0.32 - 0.99，P = 0.046）和肿瘤坏死因子相关激活诱导细胞因子（OR = 0.792，95% CI 0.630 - 0.994，P = 0.044）与口腔癌风险降低相关，而单核细胞趋化蛋白2水平升高（OR = 1.164，95% CI 1.001 - 1.353，P = 0.048）和CC基序趋化因子25（OR = 1.434，95% CI 1.106 - 1.858，P = 0.006）与风险增加相关。反向分析表明口腔癌可能对循环细胞因子水平有影响，特别是 fractalkine（OR = 0.942，95% CI 0.897 - 0.990，P = 0.019）。未检测到异质性或显著多效性的证据，验证了所使用的工具变量。这些发现支持特定细胞因子与口腔癌风险之间的因果关系，突出了炎症介质与癌症发展之间复杂的相互作用。这些结果强调了在治疗口腔癌患者时进行个体化免疫谱分析的重要性，并为基于细胞因子谱的靶向治疗的未来研究铺平了道路。
