In the current study populations, only limited assessment of nicotine addiction is available: (i) whether subjects were still smoking at the time of study participation, and (ii) their lifetime smoking intensity. Thus, we have limited ability to disentangle a genetic determinant of smoking behavior from a genetic determinant of COPD through an alternative pathway. There are several pieces of evidences to suggest that there could be a direct effect of CHRNA3/5 locus on COPD, independent of smoking behavior. First, to the extent that smoking behavior is captured in pack-years, this effect should be factored out by the statistical design in which the discovery analyses used a logistic regression model incorporating pack-years, age and gender as covariates. The adjustments for pack-years smoked, age and gender were also performed in all the replication analyses. However, pack-years smoked only partially capture smoking behavior. Many other factors, such as depth of inhalation, number of puffs per cigarette, and age of starting smoking are also likely to affect the toxicant exposure and effect. Second, we also tested directly for an association between the amount of
