肺癌是全世界最致命和最常见的恶性肿瘤。虽然吸烟是一个确定的原因，但仍然缺乏确定其他致病因素的证据。目前的研究表明，慢性炎症与肿瘤发生和癌症发展有关，但炎症细胞因子在肺癌发病机制中作用的具体机制仍不清楚。本研究采用孟德尔随机化 (MR) 分析来调查循环细胞因子对肺癌发展的因果影响。我们利用公开的全基因组关联研究摘要统计数据对欧洲人进行了两个样本的 MR 分析。选择与细胞因子显着相关的单核苷酸多态性作为遗传工具变量。趋化因子白介素18（IL-18）的遗传预测水平（OR = 0.942，95% CI：0.897-0.990，P = 0.018）产生显着的负因果效应本分析中的总体肺癌风险。检查特定的组织学亚型揭示了遗传关联的进一步证据。干细胞因子（SCF）（OR = 1.150，95% CI：1.021-1.296，P = 0.021）和白介素-1β（IL-1β）（OR = 1.152，95% CI：1.003-1.325，P = 0.046）尽管没有炎症因子显示与鳞状细胞肺癌风险存在因果关系，但与肺腺癌风险呈正相关。按吸烟状况分层，干扰素 γ 诱导蛋白 10 (IP-10)（OR = 0.861，95% CI：0.781-0.950，P = 0.003）呈负相关，而 IL-1β（OR = 1.190，95% CI：1.023）呈负相关。 -1.384，P = 0.024）与曾经吸烟者的肺癌风险呈正相关。在从不吸烟者中，肺癌风险与 SCF 呈正相关（OR = 1.474，95% CI：1.105-1.964，P = 0.008）。重要的是，这些因果推论在多种互补 MR 方法中仍然保持稳健，包括 MR-Egger、加权中值、加权模式和简单模式回归。敏感性分析还排除了多效性带来的潜在偏差。这项 MR 研究发现了初步证据，表明基因预测的四种炎症细胞因子（SCF、IL-1β、IL-18 和 IP-10）的水平可能会影响肺癌的总体风险和风险。亚型特定方式，以及按吸烟状况分层。识别这些可能促进肺癌发生的细胞因子途径代表了预防、早期检测和治疗这种致命恶性肿瘤的潜在新目标。版权所有 © 2024 Luo、Gong、Zhan 和 Lin。

Lung cancer is the deadliest and most prevalent malignancy worldwide. While smoking is an established cause, evidence to identify other causal factors remains lacking. Current research indicates chronic inflammation is involved in tumorigenesis and cancer development, though the specific mechanisms underlying the role of inflammatory cytokines in lung cancer pathogenesis remain unclear. This study implemented Mendelian randomization (MR) analysis to investigate the causal effects of circulating cytokines on lung cancer development.We performed a two-sample MR analysis in Europeans utilizing publicly available genome-wide association study summary statistics. Single nucleotide polymorphisms significantly associated with cytokine were selected as genetic instrumental variables.Genetically predicted levels of the chemokine interleukin-18 (IL-18) (OR = 0.942, 95% CI: 0.897-0.990, P = 0.018) exerted significant negative causal effects on overall lung cancer risk in this analysis. Examining specific histologic subtypes revealed further evidence of genetic associations. Stem cell factor (SCF) (OR = 1.150, 95% CI: 1.021-1.296, P = 0.021) and interleukin-1beta (IL-1β) (OR = 1.152, 95% CI: 1.003-1.325, P = 0.046) were positively associated with lung adenocarcinoma risk, though no inflammatory factors showed causal links to squamous cell lung cancer risk. Stratified by smoking status, interferon gamma-induced protein 10 (IP-10) (OR = 0.861, 95% CI: 0.781-0.950, P = 0.003) was inversely associated while IL-1β (OR = 1.190, 95% CI: 1.023-1.384, P = 0.024) was positively associated with lung cancer risk in ever smokers. Among never smokers, a positive association was observed between lung cancer risk and SCF (OR = 1.474, 95% CI: 1.105-1.964, P = 0.008). Importantly, these causal inferences remained robust across multiple complementary MR approaches, including MR-Egger, weighted median, weighted mode and simple mode regressions. Sensitivity analyses also excluded potential bias stemming from pleiotropy.This MR study found preliminary evidence that genetically predicted levels of four inflammatory cytokines-SCF, IL-1β, IL-18, and IP-10-may causally influence lung cancer risk in an overall and subtype-specific manner, as well as stratified by smoking status. Identifying these cytokine pathways that may promote lung carcinogenesis represents potential new targets for the prevention, early detection, and treatment of this deadly malignancy.Copyright © 2024 Luo, Gong, Zhan and Lin.