Airway tree structure modifies systemic markers of cigarette smoke uptake

Rationale: The adverse health effects of cigarette smoke are legion, but there is heterogeneity in disease susceptibility. The airway tree filters noxious particulates, and variation in airway tree structure is common in the general population. We hypothesized that airway tree caliber, quantified by computed tomography (CT), would modify the association of cigarette smoking with urine cotinine concentration and blood mononuclear cell (PBMCs) DNA methylation. Methods: We performed a cross-sectional analysis of participants in the Multi-Ethnic Study of Atherosclerosis (MESA) Lung Study. Airway tree caliber was assessed by inspiratory CT and quantified as the mean ratio of airway lumen diameter in cm divided by the cube-root of total lung volume in cm3 at 19 standard anatomic locations (trachea to subsegments). Cigarette smoking status was questionnaireassessed, and same-day urine cotinine concentration was measured by Immulite 2000 Nicotine Metabolite immunoassay. PBMCs DNA methylation at the aryl hydrocarbon receptor repressor (AHRR) cg05575921 locus, was measured using the Illumina HumanMethylation450 BeadChip, and quantified as an M-value. Airway tree structure modification of current cigarette smoking-associated urine cotinine concentration and PBMCs AhRR methylation was assessed in a linear regression model adjusted for demographics, smoking and occupational exposure status and duration. Non-linear interactions were assessed by quantile analysis. Results: Among 879 participants (mean age: 69 ± 9 years, 47% male, 7% current smokers), the mean airway tree caliber was 0.34 ± 0.04. The mean log-transformed urine cotinine concentration was 2.6 ± 1.7 ng/mL, and mean AhRR methylation M-value 2.2 ± 0.8. There was statistical evidence that airway tree caliber modified cigarette smoke-associated levels of urine cotinine and PBMCs AhRR methylation (p-interaction < 0.001 and 0.028, respectively), and was nonlinear by quantile analysis. Independent of daily number of cigarettes smoked and other co-variables, current smokers in the lowest quartile of airway tree caliber exhibited 338 ng/mL (95%CI 144-668 ng/mL) higher cotinine concentration, and 35% (95%CI: 10-60%) lower AhRR methylation when compared with smokers in the higher quartiles of airway tree caliber. Conclusion: Airway tree caliber modifies the association of cigarette smoking with biomarkers of systemic uptake and may help to explain some of the heterogeneity in susceptibility to inhaled noxious particulates.