Threshold dose-response association between smoking pack-years and the risk of gallbladder cancer: A nationwide cohort study

Abstract

Background and aims The association between smoking and gallbladder cancer (GBC) risk is unclear. We investigated the association between smoking (including pack-years) and GBC risk. We also examined the combined effects of smoking and diabetes or prediabetes on GBC risk.

Methods This Korean nationwide cohort study included 9,520,629 adults without cancer who underwent national health screening in 2009 and were followed-up until 2018. Multivariable Cox proportional hazards models were used to determine risk estimates after adjusting for potential confounders.

Results During 78.4 million person-years (mean 8.2 ± 0.9 years) of follow-up, we identified 6066 patients with newly diagnosed GBC. Current and former smokers were associated with increased GBC risk (hazard ratio [HR], 95% confidence interval [CI]: 1.117, 1.029–1.212 and 1.105, 1.016–1.202, respectively). Smoking of 20 to <30 and ≥30 pack-years was independently associated with increased GBC risk compared with never smoking (HR, 95% CI; 1.241, 1.100–1.400 and 1.231, 1.107–1.370, respectively). However, smoking of <10 and 10 to <20 pack-years was not. This threshold dose–response association between smoking pack-years and GBC risk was observed regardless of the glycaemic status (all P < 0.01). Furthermore, smoking of ≥20 pack-years and hyperglycaemia had a synergistic effect on the GBC risk (all P < 0.01). Smokers with ≥20 pack-years with diabetes had the highest risk of GBC compared to never smokers with normoglycaemia (HR, 1.658; 95% CI, 1.437–1.914).

Conclusions Smoking was associated with increased GBC risk with a threshold dose–response effect for smoking pack-years. The risk of GBC increases synergistically when smoking and hyperglycaemia coexist. More individualised cancer prevention education is required to reduce GBC risk.