Early-Life Exposure to Tobacco Smoke and the Risk of Idiopathic Pulmonary Fibrosis: A Population-Based Cohort Study

<b>Rationale:</b> 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. <b>Objectives:</b> 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. <b>Methods:</b> 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). <b>Results:</b> 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 (<i>P</i> 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. <b>Conclusions:</b> Early-life tobacco exposure may elevate the risk of IPF, with effects modified by genetic susceptibility and partially mediated through accelerated biological aging.