Bidirectional Mendelian randomization and mediation analysis of million-scale data reveal causal relationships between thyroid-related phenotypes,smoking,and lung cancer
Xiang Wang1
Xuan Wang2
Mengsheng Zhao2
Lijuan Lin2
Yi Li3
Ning Xie2
Yanru Wang2
Aoxuan Wang2
Xiaowen Xu2
Can Ju2
Qiuyuan Chen2
Jiajin Chen2
Ruili Hou2
Zhongwen Zhang2
David C.Christiani4
Feng Chen1
Yongyue Wei5
Ruyang Zhang6
1.Department of Biostatistics,Center for Global Health,School of Public Health,Nanjing Medical University,Nanjing,Jiangsu 211166,China;China International Cooperation Center for Environment and Human Health,Nanjing Medical University,Nanjing,Jiangsu 211166,China;Jiangsu Key Lab of Cancer Biomarkers,Prevention and Treatment,Cancer Center,Collaborative Innovation Center for Cancer Personalized Medicine,Nanjing Medical University,Nanjing,Jiangsu 211166,China2.Department of Biostatistics,Center for Global Health,School of Public Health,Nanjing Medical University,Nanjing,Jiangsu 211166,China3.Department of Biostatistics,University of Michigan,Ann Arbor,MI 48109,USA4.Pulmonary and Critical Care Division,Department of Medicine,Massachusetts General Hospital and Harvard Medical School,Boston,MA 02114,USA;Department of Environmental Health,Harvard T.H.Chan School of Public Health,Boston,MA 02115,USA5.Department of Biostatistics,Center for Global Health,School of Public Health,Nanjing Medical University,Nanjing,Jiangsu 211166,China;Center for Public Health and Epidemic Preparedness & Response,Peking University Beijing 100191,China6.Department of Biostatistics,Center for Global Health,School of Public Health,Nanjing Medical University,Nanjing,Jiangsu 211166,China;China International Cooperation Center for Environment and Human Health,Nanjing Medical University,Nanjing,Jiangsu 211166,China;Changzhou Medical Center,Nanjing Medical University Changzhou,Jiangsu 213164,China
摘要：Emerging evidence highlights the role of thyroid hormones in cancer,although findings are controversial.Research on thyroid-related traits in lung carcinogenesis is limited.Using UK Biobank data,we performed bidirectional Mendelian randomization(MR)to assess causal associations between lung cancer risk and thyroid dysfunction(hypothyroidism and hyperthyroidism)or functional traits(free thyroxine[FT4]and normal-range thyroid-stimulating hormone[TSH]).Furthermore,in the smoking-behavior-stratified MR analysis,we evaluated the mediating effect of thyroid-related phenotypes on the association between smoking behaviors and lung cancer.We demonstrated significant associations between lung cancer risk and hypothyroidism(hazard ratio[HR]=1.14,95％confidence interval[CI]=1.03-1.26,P=0.009)and hyperthyroidism(HR=1.55,95％CI=1.29-1.87,P=1.90 × 10-6)in the UKB.Moreover,the MR analysis indicated a causal effect of thyroid dysfunction on lung cancer risk(ORinverse variance weighted[IVW]=1.09,95％CI=1.05-1.13,P=3.12 × 10-6 for hypothyroidism;ORIVW=1.08,95％CI=1.04-1.12,P=8.14×10-5 for hyperthyroidism).We found that FT4 levels were protective against lung cancer risk(ORIVW=0.93,95％CI=0.87-0.99,P=0.030).Additionally,the stratified MR analysis demonstrated distinct causal effects of thyroid dysfunction on lung cancer risk among smokers.Hyperthyroidism mediated the effect of smoking behaviors,especially the age of smoking initiation(17.66％mediated),on lung cancer risk.Thus,thyroid dysfunction phenotypes play causal roles in lung cancer development exclusively among smokers and act as mediators in the causal pathway from smoking to lung cancer.
机标关键词：analysisbetweencancerdatabidirectionalcausallungmediation
分类号：R734.2(呼吸系肿瘤)
论文发表日期：2025-09-30
在线出版日期：2025-12-01（本平台首次上网日期，不代表文献的发表时间）
页数：11( 441-451 )
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