Our analyses of tolerance indicate that being a woman and smoking less are related to slower progression to tolerance, while later age of daily smoking predicts acceleration. In the time‐to‐event analysis, we detected a genome‐wide significant association with rs11031684 residing on 11p13 in a pseudogene RP1‐65P5.1, and located 100 kb downstream of WT1. WT1 is a transcription factor involved in the regulation of human cell growth and differentiation, and is an established tumor suppressor gene. Exposure to heavy smoking influences the methylation pattern of CpG islands in WT1 (Bruno et al. 2012), providing a plausible mechanism for smoking induced cancers. In addition to affecting methylation, heavy smoking is suggested to affect the development of tolerance (Aceto et al. 1986). In order to evaluate whether the detected association was independent of smoking quantity, we included measures of smoking quantity as covariates in the follow‐up analysis. The signal on 11p13 no longer was significant at a genome‐wide level (P = 4.04e‐06); further, mediation analysis suggested that rs11031684 affects the hazard of progression to tolerance partly through smoking quantity. Interestingly, in the follow‐up
