Zhang Chaoyang, Zhang Fangfang, Zheng Xiaofei, Cao Chunhui, Qian Bei, Zhang Chu, Wu Jingyu, Shi Xiaoyu, Chen Jian
Department of Gastrointestinal Surgery, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310000, China.
Department of Anesthesiology, Hefei BOE Hospital, Hefei, 230000, China.
Discov Oncol. 2025 Jun 18;16(1):1146. doi: 10.1007/s12672-025-02864-x.
Observational studies have shown that TNF-related apoptosis-inducing ligand (TRAIL) levels and vascular endothelial growth factor (VEGF) levels are associated with colon cancer risk, and TRAIL antagonizes VEGF-induced tumor angiogenesis. We aim to determine whether there is a causal relationship between TRAIL/VEGF levels and colon cancer by Mendelian randomization analysis.
Genome-wide association studies (GWAS) of 21,758 individuals of European ancestry were conducted to identify single nucleotide polymorphisms (SNPs) associated with TRAIL/VEGF. MR-Egger regression, heterogeneity test, pleiotropy test and leave-one-out sensitivity tests were used for sensitivity analysis, in addition to inverse variance weighting (IVW) as the main Mendelian-randomization (MR) analysis method.
Univariate MR analysis using IVW indicated an inverse association between genetically predicted TRAIL levels and colon cancer risk (OR = 0.805, 95%CI = 0.681-0.953, P = 0.011), while VEGF levels showed a positive association (OR = 1.337, 95%CI = 1.163-1.536, P < 0.001). In addition, the MR Steiger test showed that the effect of TRAIL/VEGF levels on colon cancer were correct causality (P < 0.001). In multivariate MR analysis, TRAIL levels had an independent causal effect on colon cancer risk after controlling for VEGF levels (OR = 0.802, P = 0.002); likewise, the causal effect of VEGF levels on colon cancer risk remained after controlling for TRAIL levels (OR = 1.328, P < 0.001).
There was a inverse association between genetic variants in TRAIL levels and colon cancer risk, but a positive association between genetic variants in VEGF levels and colon cancer risk. Further research is needed to explore the mechanisms behind this putative causal relationship.
观察性研究表明，肿瘤坏死因子相关凋亡诱导配体（TRAIL）水平和血管内皮生长因子（VEGF）水平与结肠癌风险相关，并且TRAIL可拮抗VEGF诱导的肿瘤血管生成。我们旨在通过孟德尔随机化分析确定TRAIL/VEGF水平与结肠癌之间是否存在因果关系。
对21758名欧洲血统个体进行全基因组关联研究（GWAS），以鉴定与TRAIL/VEGF相关的单核苷酸多态性（SNP）。除了采用逆方差加权（IVW）作为主要的孟德尔随机化（MR）分析方法外，还使用MR-Egger回归、异质性检验、多效性检验和留一法敏感性检验进行敏感性分析。
使用IVW的单变量MR分析表明，遗传预测的TRAIL水平与结肠癌风险呈负相关（OR = 0.805，95%CI = 0.681-0.953，P = 0.011），而VEGF水平呈正相关（OR = 1.337，95%CI = 1.163-1.536，P < 0.001）。此外，MR Steiger检验表明，TRAIL/VEGF水平对结肠癌的影响具有正确的因果关系（P < 0.001）。在多变量MR分析中，在控制VEGF水平后，TRAIL水平对结肠癌风险具有独立的因果效应（OR = 0.802，P = 0.002）；同样，在控制TRAIL水平后，VEGF水平对结肠癌风险的因果效应仍然存在（OR = 1.328，P < 0.001）。
TRAIL水平的基因变异与结肠癌风险呈负相关，但VEGF水平的基因变异与结肠癌风险呈正相关。需要进一步研究以探索这种假定因果关系背后的机制。
