Early-life tobacco exposure, genetic susceptibility, and multiple digestive diseases: evidence from two large cohorts and genetic analyses.

BACKGROUND

Early-life tobacco exposure exerts adverse effects significantly impacting long-term health; however, the comprehensive association with multiple digestive diseases and its implications for accelerated disease progression remain unclear.

MATERIALS AND

METHODS

Early-life tobacco exposure was measured based on in utero exposure to tobacco and age of smoking initiation among participants from the UK Biobank and LifeLines. Outcomes were 11 digestive diseases. To analyze the link between early-life tobacco exposure and digestive diseases, logistic regression and Cox proportional hazards models were applied. A multistate model was applied to examine the impact of early tobacco exposure on the progression in digestive disease status. Mediation effects of biological aging acceleration and Linkage Disequilibrium Score Regression between early-life tobacco exposure and digestive diseases were additionally analyzed.

RESULTS

The hazard ratios and 95% confidence intervals for participants exposed to tobacco in utero or who began smoking during childhood were 1.10 (1.09-1.12) or 1.32 (1.28-1.35) for any digestive disease in the UK Biobank. Repeated analyses in the LifeLines cohort, and genetic correlation analysis confirmed these elevated risks. Accelerated biological aging plays a mediating role of 3% to 20% in these associations. The risks of digestive diseases were increased in all genetic risk categories, with a 17% to over fourfold increase in the high-risk group. Critically, childhood and adolescence smoking initiation increased the risk of transitioning from any digestive disease to death increased by 59% and 40%.

CONCLUSION

Early-life tobacco exposure significantly increases risks of digestive diseases in two large cohorts, independent of genetic susceptibility and mediated by biological aging acceleration. It also accelerates progression from digestive disease to death, leading to severe outcomes and higher surgical need. Our findings help the identification of high-risk individuals and highlight the importance of preventing tobacco exposure during early life to mitigate digestive disease risk and mortality, and associated surgical burden.