Zhu Jiahao, Wang Yifan, Liu Houpu, Wang Meng, Wang Jing, Ding Lilu, Zhou Dan, Li Yingjun
Department of Epidemiology and Health Statistics, School of Public Health, Hangzhou Medical College, Hangzhou, China.
Department of Psychology, University of Toronto Scarborough, Toronto, Ontario, Canada.
Ann Am Thorac Soc. 2025 Jun;22(6):887-896. doi: 10.1513/AnnalsATS.202409-906OC.
Tobacco smoking is a well-established risk factor for idiopathic pulmonary fibrosis (IPF), yet the influence of early-life tobacco exposure on future IPF risk remains poorly understood. We sought to test the hypothesis that early-life tobacco exposure may elevate the risk of developing IPF, with this effect potentially modified by genetic susceptibility to IPF and mediated through accelerated biological aging. Using data from over 430,000 participants in the UK Biobank, we performed a prospective cohort study to examine the associations of maternal smoking around birth and age of smoking initiation with IPF risk. We evaluated the combined effects and interactions between early-life tobacco exposure and genetic susceptibility to IPF, which were quantified using polygenic risk scores. We assessed biological aging, as measured by telomere length and phenotypic age, as potential mediators in the associations between early-life tobacco exposure and IPF risk. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). Maternal smoking around birth was associated with a higher risk of IPF (HR = 1.26; 95% CI = 1.11-1.43). Compared with never-smokers, individuals who initiated smoking in childhood (HR = 3.65; 95% CI = 3.02-4.41), adolescence (HR = 2.64; 95% CI = 2.28-3.05), and adulthood (HR = 2.09; 95% CI = 1.79-2.44) exhibited increased IPF risk ( for trend <0.001). An additive interaction was observed between age of smoking initiation and genetic risk for IPF. Individuals with high genetic risk, maternal smoking exposure, and childhood smoking initiation had a 16-fold greater risk of IPF (HR = 16.47; 95% CI = 9.57-28.32), compared with those with low genetic risk and no tobacco exposure. Telomere length and phenotypic age each mediated approximately 10% of the effect of maternal smoking on IPF, with weaker mediation effects observed for later ages of smoking initiation. Early-life tobacco exposure may elevate the risk of IPF, with effects modified by genetic susceptibility and partially mediated through accelerated biological aging.
吸烟是特发性肺纤维化（IPF）公认的风险因素，但早年烟草暴露对未来IPF风险的影响仍知之甚少。我们试图检验这样一个假设，即早年烟草暴露可能会增加患IPF的风险，这种影响可能会因IPF的遗传易感性而改变，并通过加速生物衰老介导。利用英国生物银行超过43万名参与者的数据，我们进行了一项前瞻性队列研究，以检查出生前后母亲吸烟和开始吸烟年龄与IPF风险之间的关联。我们评估了早年烟草暴露与IPF遗传易感性之间的联合效应和相互作用，使用多基因风险评分进行量化。我们评估了以端粒长度和表型年龄衡量的生物衰老，作为早年烟草暴露与IPF风险之间关联的潜在中介因素。使用Cox比例风险模型来估计风险比（HRs）和95%置信区间（CIs）。出生前后母亲吸烟与IPF风险较高相关（HR = 1.26；95% CI = 1.11 - 1.43）。与从不吸烟者相比，童年开始吸烟的个体（HR = 3.65；95% CI = 3.02 - 4.41）、青少年（HR = 2.64；95% CI = 2.28 - 3.05）和成年（HR = 2.09；95% CI = 1.79 - 2.44）患IPF的风险增加（趋势P < 0.001）。在开始吸烟年龄与IPF遗传风险之间观察到相加相互作用。与低遗传风险且无烟草暴露的个体相比，高遗传风险、母亲有吸烟暴露且童年开始吸烟的个体患IPF的风险高16倍（HR = 16.47；95% CI = 9.57 - 28.32）。端粒长度和表型年龄各自介导了母亲吸烟对IPF影响的约10%，开始吸烟年龄越大，中介效应越弱。早年烟草暴露可能会增加患IPF的风险，其影响因遗传易感性而改变，并部分通过加速生物衰老介导。
