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空气污染与肺癌之间关系的因果验证:一项双向孟德尔随机化研究与荟萃分析。

Causal validation of the relationship between air pollution and lung cancer: A bidirectional Mendelian randomization study and meta-analysis.

作者信息

Wang Xiaomin, Xiao Guihua, Xu Wanxian, Ni Changguo

机构信息

The First People's Hospital of Kunming City and Calmette Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China.

Zhoupu Hospital, Pudong New District, Shanghai, China.

出版信息

Medicine (Baltimore). 2025 May 23;104(21):e42450. doi: 10.1097/MD.0000000000042450.


DOI:10.1097/MD.0000000000042450
PMID:40419866
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12113920/
Abstract

Recent studies suggest a link between air pollution and lung cancer, but causality remains uncertain due to confounding and reverse causation. Mendelian randomization (MR) reduces such bias and offers a new way to explore this relationship. MR is a method that uses genetic variants as instrumental variables to assess the causal relationship between an exposure and an outcome, effectively controlling for confounding and reverse causation. The inverse-variance weighted method is a commonly used approach in MR analysis, which estimates the overall causal effect by weighting the effect ratios of multiple single nucleotide polymorphisms, assuming all instruments are valid. Based on 2-sample MR, this study incorporated 5 air pollution indices and conducted MR analyses with lung cancer outcome data from 2 different sources. Subsequently, a meta-analysis was performed on the primary inverse-variance weighted results, followed by multiple corrections of the thresholds after the meta-analysis to ensure accuracy. Finally, reverse causality was tested through MR analysis for air pollution indices significantly associated with lung cancer. And the selection criteria for instrumental variables were: P < 5 × 10⁻⁶, F > 10, minor allele frequency > 0.01, clump_kb = 10,000, and clump_r2 = 0.001. Five air pollution indices were analyzed using MR analysis and meta-analysis with lung cancer data from the FinnGen R12 and OpenGWAS databases. Multiple corrections were applied to the significance threshold results after the meta-analysis. The final results showed that only nitrogen dioxide (NO₂) exhibited a significant association, with an OR of 3.426 (95% CI: 1.897-6.186, P = 2.21 × 10⁻⁴). Additionally, the positive air pollution index NO₂ showed no evidence of reverse causality with lung cancer from either data source. This study demonstrates a significant causal association between NO₂ and lung cancer, indicating that NO₂ may be a potential risk factor for lung cancer.

摘要

近期研究表明空气污染与肺癌之间存在联系,但由于混杂因素和反向因果关系,因果关系仍不确定。孟德尔随机化(MR)减少了此类偏差,并为探索这种关系提供了一种新方法。MR是一种使用基因变异作为工具变量来评估暴露与结局之间因果关系的方法,能有效控制混杂因素和反向因果关系。逆方差加权法是MR分析中常用的方法,该方法通过对多个单核苷酸多态性的效应比进行加权来估计总体因果效应,假设所有工具变量都是有效的。基于两样本MR,本研究纳入了5个空气污染指数,并对来自2个不同来源的肺癌结局数据进行了MR分析。随后,对主要的逆方差加权结果进行了荟萃分析,然后在荟萃分析后对阈值进行多次校正以确保准确性。最后,通过MR分析对与肺癌显著相关的空气污染指数进行反向因果关系检验。工具变量的选择标准为:P < 5×10⁻⁶,F > 10,次要等位基因频率 > 0.01,clump_kb = 10,000,clump_r2 = 0.001。使用MR分析和荟萃分析对来自芬兰基因R12和开放全基因组关联研究(OpenGWAS)数据库的肺癌数据进行了5个空气污染指数的分析。对荟萃分析后的显著性阈值结果进行了多次校正。最终结果表明,只有二氧化氮(NO₂)呈现出显著关联,比值比(OR)为3.426(95%置信区间:1.897 - 6.186,P = 2.21×10⁻⁴)。此外,空气污染正指数NO₂在两个数据源中均未显示出与肺癌存在反向因果关系的证据。本研究证明了NO₂与肺癌之间存在显著的因果关联,表明NO₂可能是肺癌的一个潜在危险因素。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8aa4/12113920/8585a1bed027/medi-104-e42450-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8aa4/12113920/753d19a9a991/medi-104-e42450-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8aa4/12113920/35f94b55d9d2/medi-104-e42450-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8aa4/12113920/da2af9f0a20f/medi-104-e42450-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8aa4/12113920/8585a1bed027/medi-104-e42450-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8aa4/12113920/753d19a9a991/medi-104-e42450-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8aa4/12113920/35f94b55d9d2/medi-104-e42450-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8aa4/12113920/da2af9f0a20f/medi-104-e42450-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8aa4/12113920/8585a1bed027/medi-104-e42450-g004.jpg

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[1]
Causal validation of the relationship between air pollution and lung cancer: A bidirectional Mendelian randomization study and meta-analysis.

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[10]
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本文引用的文献

[1]
The relationship between amino acids and gastroesophageal reflux disease: evidence from a mendelian randomization analysis combined with a meta-analysis.

Front Immunol. 2025-3-4

[2]
Quantitative source apportionment and health risk assessment for polycyclic aromatic hydrocarbon and their derivatives in indoor dust from housing and public buildings of a mega-city in China.

J Hazard Mater. 2025-3-15

[3]
The role of PM2.5 exposure in lung cancer: mechanisms, genetic factors, and clinical implications.

EMBO Mol Med. 2025-1

[4]
Amino acid metabolism-related genes as potential biomarkers and the role of MATN3 in stomach adenocarcinoma: A bioinformatics, mendelian randomization and experimental validation study.

Int Immunopharmacol. 2024-12-25

[5]
Metabolic Characteristics of Gut Microbiota and Insomnia: Evidence from a Mendelian Randomization Analysis.

Nutrients. 2024-9-2

[6]
The Proposed Ninth Edition TNM Classification of Lung Cancer.

Chest. 2024-10

[7]
Impact of ambient air pollution on colorectal cancer risk and survival: insights from a prospective cohort and epigenetic Mendelian randomization study.

EBioMedicine. 2024-5

[8]
Exploring causal correlations between inflammatory cytokines and ankylosing spondylitis: a bidirectional mendelian-randomization study.

Front Immunol. 2023

[9]
Causal effects of exposure to ambient air pollution on cancer risk: Insights from genetic evidence.

Sci Total Environ. 2024-2-20

[10]
Mendelian-randomization study reveals causal relationships between nitrogen dioxide and gut microbiota.

Ecotoxicol Environ Saf. 2023-11-15

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