此前已经进行了几项观察性或回顾性研究来探索肺癌与人乳头瘤病毒（HPV）感染之间可能存在的关联。然而，由于研究设计和HPV检测方法的差异，数据和结论可能存在不一致。目前尚无研究提供确凿证据支持HPV参与肺癌的发生和发展。因此，HPV与肺癌之间的关系仍然存在争议和不确定。本研究旨在通过系统地进行双向两样本孟德尔随机化 (TSMR) 分析，探讨 HPV 感染是否与肺癌风险存在因果关系。在国际肺癌联盟 (ILCCO) 全基因组关联研究数据集中，我们纳入了11,348例肺癌（LUCA）病例，其中3275例鳞状细胞癌（LUSC）病例、3442例腺癌（LUAD）病例和15,861例对照病例。使用与 HPV E7 蛋白相关的遗传变异作为工具变量，我们总结了 MRC IEU OpenGWAS 数据库中与 HPV 感染相关的统计数据，其中包括 HPV-16 E7 蛋白和 HPV-18 E7 蛋白。两样本孟德尔随机化（MR）结果表示为比值比（OR）和95%置信区间（CI）。基于对公共数据库的全基因组关联研究（GWAS）数据的综合分析，我们主要使用逆向-方差加权（IVW）估计因果关系，同时以MR-Egger、加权中位数、简单模式和加权模式等四种方法作为补充。两样本 MR 分析显示，暴露因素（HPV-16 E7 蛋白和 HPV-18 E7 蛋白）与结果因素（肺癌 (LUCA) 及其亚型鳞状细胞癌 (LUSC) 和腺癌 (LUAD)）之间没有因果关系。采用IVW方法进行正向MR分析。HPV-16 E7蛋白及其LUCA及其亚型LUSC和LUAD的IVW方法结果：[OR] = 1.002； 95%[CI]：0.961 - 1.045； p = 0.920； [或] = 1.023； 95%[CI]：0.966 - 1.084； p = 0.438； [或] = 0.994； 95%[CI]：0.927 - 1.066； p = 0.872); IVW法检测HPV-18 E7蛋白及LUCA及其亚型LUSC和LUAD结果：[OR] = 0.965； 95%[CI]：0.914 - 1.019； p = 0.197； [或] = 0.933； 95%[CI]：0.834 - 1.043； p = 0.222； [或] = 1.028； 95%[CI]：0.945 - 1.118； p = 0.524。通过反向MR观察，以LUCA及其亚型LUSC和LUAD为暴露因素，以HPV感染（HPV-16 E7蛋白和HPV-18 E7蛋白）为结果因素，IVW方法结果为LUCA与HPV-16 E7蛋白和HPV-18 E7蛋白IVW法结果：[OR] = 1.036； 95%[CI]：0.761 - 1.411； p = 0.82； [或] = 1.318； 95%[CI]：0.949 - 1.830； p = 0.099； IVW法LUSC与HPV-16 E7蛋白和HPV-18 E7蛋白结果：[OR] = 1.123； 95% [CI]0.847 - 1.489； p = 0.421； [或] = 0.931； 95%[CI]：0.660 - 1.313； p = 0.682； IVW法检测LUAD与HPV-16 E7蛋白和HPV-18 E7蛋白结果：[OR] = 1.182； 95% [CI] 0.983 - 1.421； p = 0.075； [或] = 1.017； 95%[CI]：0.817 - 1.267； p = 0.877。我们的结果表明，基因预测的HPV感染与LUCA及其亚型LUSC和LUAD之间不存在因果关系。此外，在反向MR分析中，我们没有观察到LUCA及其亚型LUSC和LUAD与HPV感染之间存在显着的因果关系。我们的研究结果不支持HPV感染与肺癌之间的遗传关联。© 2024。作者（ s）。

Several observational or retrospective studies have previously been conducted to explore the possible association between lung cancer and human papillomavirus (HPV) infection. However, there may be inconsistencies in the data and conclusions due to differences in study design and HPV testing methods. There are currently no studies that provide conclusive evidence to support the involvement of HPV in the occurrence and development of lung cancer. Therefore, the relationship between HPV and lung cancer remains controversial and uncertain. This study aimed to explore whether HPV infection is causally related to lung cancer risk by systematically performing a two-way Two-Sample Mendelian Randomization (TSMR) analysis.In the International Lung Cancer Consortium (ILCCO) genome-wide association study dataset, we included 11,348 lung cancer (LUCA) cases, including 3275 squamous cell carcinoma (LUSC) cases, 3442 adenocarcinoma (LUAD) cases, and 15,861 cases of control. Using genetic variants associated with the HPV E7 protein as instrumental variables, we summarized statistics associated with HPV infection in the MRC IEU OpenGWAS database, which included the HPV-16 E7 protein and the HPV-18 E7 protein. Two-sample Mendelian randomization (MR) results are expressed as odds ratios (OR) and 95% confidence intervals (CI).Based on a comprehensive analysis of genome-wide association study (GWAS) data from public databases, we mainly used inverse-variance weighted (IVW) to estimate causal relationships, while using MR-Egger, weighted median, simple mode, and weighted mode, and other four methods as supplements. Two-sample MR Analysis revealed no causal relationship between exposure factors (HPV-16 E7 protein and HPV-18 E7 protein) and outcome factors (lung cancer (LUCA) and its subtypes squamous cell carcinoma (LUSC) and adenocarcinoma (LUAD)) in forward MR Analysis using the IVW approach.HPV-16 E7 protein and LUCA and its subtypes LUSC and LUAD by IVW method results: [OR] = 1.002; 95% [CI]: 0.961 - 1.045; p = 0.920; [OR] = 1.023; 95% [CI]: 0.966 - 1.084; p = 0.438; [OR] = 0.994; 95% [CI]: 0.927 - 1.066; p = 0.872); HPV-18 E7 protein and LUCA and its subtypes LUSC and LUAD by IVW method results: [OR] = 0.965; 95% [CI]: 0.914 - 1.019; p = 0.197; [OR] = 0.933; 95% [CI]: 0.834 - 1.043; p = 0.222; [OR] = 1.028; 95% [CI]: 0.945 - 1.118; p = 0.524. It was observed through reverse MR that LUCA and its subtypes LUSC and LUAD were used as exposure factors, and HPV infection (HPV-16 E7 protein and HPV-18 E7 protein) was used as the outcome factors, the results of the IVW method are also invalid.LUCA and HPV-16 E7 protein and HPV-18 E7 protein by IVW method results: [OR] = 1.036; 95% [CI]: 0.761 - 1.411; p = 0.82; [OR] = 1.318; 95% [CI]: 0.949 - 1.830; p = 0.099; LUSC and HPV-16 E7 protein and HPV-18 E7 protein by IVW method results: [OR] = 1.123; 95% [CI]0.847 - 1.489; p = 0.421; [OR] = 0.931; 95% [CI]: 0.660 - 1.313; p = 0.682; LUAD and HPV-16 E7 protein and HPV-18 E7 protein by IVW method results: [OR] = 1.182; 95% [CI] 0.983 - 1.421; p = 0.075; [OR] = 1.017; 95% [CI]: 0.817 - 1.267; p = 0.877.Our results indicate that there is no causal relationship between genetically predicted HPV infection and LUCA and its subtypes LUSC and LUAD. In addition, in the reverse MR analysis, we did not observe a significant causal relationship between LUCA and its subtypes LUSC and LUAD on HPV infection.Our findings do not support a genetic association between HPV infection and lung cancer.© 2024. The Author(s).