PO.PR01.03 · 预防研究
肺癌的吸烟与性别特异性蛋白质组学标志物：一项前瞻性队列研究
Smoking and sex specific proteomic markers of lung cancer: A prospective cohort study
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景 尽管循环蛋白有望阐明肺癌（LC）的病因，但全面评估其与LC风险关联的大规模研究仍然有限。至关重要的是，这些蛋白在不同性别和吸烟状态中的作用，尤其是在女性和非吸烟者（他们构成了LC病例中相当大的比例且病因独特）中，仍然缺乏充分的特征描述。
方法 我们将来自UK Biobank（UKB）队列的观察性分析（N=49,370，基线时无癌；444例新发LC病例；中位随访11年）与双样本孟德尔随机化（MR）相结合。基线时测定了2,920种蛋白的血浆水平。Cox回归鉴定与新发LC相关的蛋白，并按性别和吸烟状态进行分层分析。MR使用来自UKB-PPP和deCODE研究的cis-pQTL作为蛋白的工具变量，并使用来自FinnGen、TRICL和Pan-UKBB的LC GWAS数据。稳健的因果证据定义为显著的MR结果（IVW P<0.05）结合共定位后验概率（PPH4）> 0.75或显著的SMR结果（HEIDI P>0.01）。
结果 性别分层分析揭示男性中有532种显著蛋白，女性中有375种。其中，271种为男性特异性（如C1R，HR=5.48，95%CI：2.23-13.50），114种为女性特异性（如SMAD5，HR=4.53，95%CI：2.39-8.58）。仅261种蛋白为两性共有。吸烟分层分析在吸烟者中鉴定出683种显著蛋白，在非吸烟者中鉴定出39种。绝大多数（657种蛋白）为吸烟者特异性，包括最高风险蛋白SERPINA1（HR=24.62，95%CI：5.65-107.39）和最强保护蛋白GSN（HR=0.15，95%CI：0.09-0.27）。相比之下，仅13种蛋白为非吸烟者特异性，如风险蛋白CYTL1（HR=3.46，95%CI：1.11-10.82）和保护蛋白CNTN4（HR=0.17，95%CI：0.07-0.45）。MR分析为IL19在吸烟者中的LC作用提供了遗传学支持（cis-MR的OR=1.18，95%CI：1.03-1.35；SMR的OR=1.12，95%CI：1.01-1.23）。
结论 本研究揭示了按性别和吸烟状态划分的LC风险截然不同的蛋白质组学特征，主要集中于男性和吸烟者，并对IL19等关键候选蛋白提供了遗传学验证。这些发现凸显了病因异质性，并支持对LC风险预测和预防采取分层策略，有待在不同人群中进行外部验证。
查看英文原文 English abstract
Background While circulating proteins hold promise for elucidating lung cancer (LC) etiology, large-scale studies comprehensively assessing their associations with LC risk are limited. Crucially, the roles of these proteins across different sexes and smoking statuses, particularly in females and non-smokers who constitute a significant proportion of LC cases with distinct etiology, remain poorly characterized.
Methods We integrated observational analyses from the UK Biobank (UKB) cohort (N=49,370 cancer-free at baseline; 444 incident LC cases; median follow-up 11 years) with two-sample Mendelian randomization (MR). Plasma levels of 2,920 proteins were measured at baseline. Cox regression identified proteins associated with incident LC, with stratified analyses by sex and smoking status. MR used cis-pQTLs from UKB-PPP and deCODE studies as instruments for proteins and LC GWAS data from FinnGen, TRICL, and Pan-UKBB. Robust causal evidence was defined by a significant MR result (IVW P<0.05) combined with either a colocalization posterior probability (PPH4) > 0.75 or a significant SMR result (HEIDI P>0.01).
Results Sex-stratified analysis revealed 532 significant proteins in males and 375 in females. Among these, 271 were male-specific (e.g., C1R, HR=5.48, 95%CI: 2.23-13.50) and 114 were female-specific (e.g., SMAD5, HR=4.53, 95%CI: 2.39-8.58). Only 261 proteins were shared between sexes. Smoking-stratified analysis identified 683 significant proteins in smokers and 39 in non-smokers. A vast majority (657 proteins) were smoker-specific, including top risk protein SERPINA1 (HR=24.62, 95%CI: 5.65-107.39) and top protective protein GSN (HR=0.15, 95%CI: 0.09-0.27). In contrast, only 13 proteins were non-smoker-specific, such as risk protein CYTL1 (HR=3.46, 95%CI: 1.11-10.82) and protective protein CNTN4 (HR=0.17, 95%CI: 0.07-0.45). MR analysis provided genetic support for IL19 for LC among smokers (OR=1.18, 95%CI: 1.03-1.35 from cis-MR; OR=1.12, 95%CI: 1.01-1.23 from SMR).
Conclusion This study unveils strikingly distinct proteomic signatures of LC risk by sex and smoking status, predominantly in males and smokers, with genetic validation for key candidates like IL19. These findings underscore etiological heterogeneity and support stratified approaches to LC risk prediction and prevention, pending external validation in diverse populations.
利益披露 Disclosure
Z. Lyu, None..
X. Liu, None..
K. Chen, None.