协和医学杂志2026，Vol.17Issue(3)：663-676,14.DOI:10.12290/xhyxzz.2025-1388
睡眠与肺结节恶性风险的多源数据验证研究:问卷、队列与孟德尔随机化证据
Sleep Traits and Malignant Risk of Pulmonary Nodules:Evidence Triangulation From Questionnaire,Cohort,and Mendelian Randomization
摘要
Abstract
Objective To investigate the association between sleep-related phenotypes and the risk of malignancy in pulmonary nodules,and to provide complementary evidence from a general population cohort and genetic analyses.Methods This study comprised three parts.Part 1 was a cross-sectional study that consecutively enrolled patients with imaging-confirmed pulmonary nodules at the First Hospital of China Medical University from November 2024 to December 2025.Nine sleep domains were constructed using items from the Pittsburgh sleep quality index(PSQI),with domain severity coded on a 0-6 scale according to the frequency of occurrence.Benign or malignant status of pulmonary nodules was determined based on pathological results or clin-ical follow-up.Multivariable Logistic regression models with progressive adjustment were constructed.Stratified,interaction,and dose-response analyses(including categorical grouping and restricted cubic splines)were per-formed focusing on the insomnia symptom domain to explore the association between sleep-related phenotypes and the risk of malignant pulmonary nodules.Part 2 was a prospective cohort study using the China Health and Retire-ment Longitudinal Study(CHARLS)to investigate the association between sleep duration and incident lung canc-er risk in the general population.Part 3 comprised genetic causality analyses,including two-sample Mendelian randomization(MR)and linkage disequilibrium score regression(LDSC),using data from the OpenGWAS data-base,to assess whether directionally consistent genetic association signals exist between sleep-related phenotypes and lung cancer risk.Results In the cross-sectional study,a total of 800 patients with pulmonary nodules were included,of whom 288(36.0％)were in the malignant group.In the continuous-variable main model fully adjus-ted for baseline confounders,all nine sleep domains,imaging findings,and depression and anxiety status,the se-verity of the insomnia symptom domain showed a positive association signal with the risk of malignant pulmonary nodules(fully adjusted model:per 1-point increase,OR=1.147,95％CI:1.034-1.272,P= 0.010).However,categorical dose-response analysis and restricted cubic spline analysis revealed no clear monotonic trend for this association.Stratified analyses showed that the direction of the association between insomnia symptom domain se-verity and malignant nodule risk was generally consistent across subgroups.In interaction analyses,the interaction term between insomnia symptom domain severity and smoking status reached nominal statistical significance,sug-gesting potential effect heterogeneity.The prospective cohort study included 35 159 participants aged≥45 years,with a total follow-up of approximately 8.0×104 person-years,during which 96 patients developed incident lung cancer.Using a sleep duration of 6-8 hours as the reference group,the short sleep duration group(<6 hours)showed a trend toward increased lung cancer risk(HR=1.45,95％CI:0.55-3.83,P= 0.452),but this did not reach statistical significance.The long sleep duration group(>8 hours)did not show an increased risk of lung cancer(HR=0.82,95％CI:0.50-1.33,P= 0.414).In the genetic causality analyses,the primary inverse-va-riance weighted MR analysis showed that genetically predicted tendency to insomnia/difficulty falling asleep(OR=1.76,95％CI:1.00-3.10,P= 0.049)and longer sleep duration were both associated with an increased risk of lung cancer(OR=1.61,95％CI:1.02-2.56,P= 0.042).However,multiple alternative methods did not provide consistent evidence to support these findings.LDSC analysis revealed a stable positive genetic correlation between insomnia/difficulty falling asleep and lung cancer risk.Conclusions In patients with pulmonary nod-ules,an association signal exists between insomnia-related symptoms and the risk of malignancy,but the dose-re-sponse relationship remains unclear.The CHARLS cohort and genetic analyses provide supplementary directional clues for the above associations,albeit with limited statistical strength and result consistency.Definitive conclu-sions regarding the association between sleep phenotypes and the risk of malignant pulmonary nodules require fur-ther validation in prospective studies.关键词
睡眠时长/失眠,入睡困难/肺结节/关联性分析Key words
sleep duration/insomnia,initial insomnia/pulmonary nodules/association analysis分类
医药卫生引用本文复制引用
陈香雨,薛怡巧,刘梦晴,户亦乐,梁伟作,刘涵清,王艺铮,赵明芳..睡眠与肺结节恶性风险的多源数据验证研究:问卷、队列与孟德尔随机化证据[J].协和医学杂志,2026,17(3):663-676,14.基金项目
国家重点研发计划(2023YFC2508602) （2023YFC2508602）
国家自然科学基金(82373413) （82373413）
社会科学规划基金(L21BGL059) （L21BGL059）
辽宁省中央引导地方科技发展资金计划项目(2022010127-JH6/1001) （2022010127-JH6/1001）
辽宁省重点研发项目(民生科技类)(2024JH2/102500006) National Key R&D Program of China(2023YFC2508602) （民生科技类）
National Natural Science Foundation of China(82373413) （82373413）
Social Science Planning Fund Project(L21BGL059) （L21BGL059）
the Liaoning Provincial Central Government Guides Local Sci-ence and Technology Development Fund Project(2022010127-JH6/1001) （2022010127-JH6/1001）
Liaoning Provincial Key R&D Program(People's Live-lihood Science and Technology)(2024JH2/102500006) （People's Live-lihood Science and Technology）
