The association of epigenetic age acceleration with internal smoking dose, risk of lung cancer, and all-cause mortality in cigarette smokers: the Multiethnic Cohort study.

[BACKGROUND] Among cigarette smokers, higher internal smoking dose is associated with elevated lung cancer risk and mortality, independent of smoking pack-years. Some measures of epigenetic age acceleration (EAA) are associated with cigarette smoking status and exposure, as well as lung cancer risk and overall mortality. No study has examined the association between EAA measures and internal smoking dose (total nicotine equivalents (TNE; nmol/mL)), and their shared relationship with lung cancer incidence and mortality in a multiethnic population.

[METHODS] From a subgroup of Multiethnic Cohort Study participants who smoked cigarettes at the time of biospecimen collection (n = 1969), six epigenetic clocks were computed using blood-based DNA methylation (DNAm) array data. EAA measures were computed by calculating the residuals that results from regressing an epigenetic clock on chronological age. The association of urinary TNE with EAA measures were assessed using linear regression models, adjusted for age, sex, body mass index (BMI; kg/m), DNAm-based estimates of blood cell composition, population stratification, and self-reported pack-years of cigarette smoking. To evaluate the associations of EAA with incident lung cancer risk (n = 176 cases) and all-cause mortality (n = 780 deaths) (from 13 years of follow-up), Cox proportional hazard models, with age as the time metric, adjusted for decade of birth, sex, BMI, years of education, creatinine, DNAm-based estimates of blood cell composition, population stratification, self-reported pack-years, and urinary TNE, were used.

[RESULTS] A standard deviation (SD) increase of log-TNE was statistically significantly associated with increased AgeAccelPheno (beta = 0.416, 95% Confidence Interval (CI)=0.134-0.698)), AgeAccelGrim (beta = 0.771, 95%CI=0.603-0.939), and DunedinPACE (beta = 0.015, 95%CI=0.010-0.020). A SD increase of AgeAccelGrim (Hazard Ratio (HR) = 1.40; 95% CI   1.16-1.71) and DunedinPACE (HR = 1.31; 95% CI  1.11-1.55) were associated with a risk of lung cancer, whereas a SD increase of AgeAccelDNAm-based telomere length was inversely associated with lung cancer risk (HR = 0.79; 95% CI  0.67-0.93). These findings were similar for the hazard of all-cause mortality.

[CONCLUSIONS] Our study suggests that circulating methylation-based biomarkers of biological aging may provide information on lung cancer risk and all-cause mortality beyond that of self-reported pack-years and a (short-term) biomarker of internal smoking dose. If replicated, our findings suggest that epigenetic clocks may inform higher risk groups for prevention strategies.