These findings may explain discrepancies in prior studies of these genetic variants and smoking cessation. Some previous studies indicate that the chromosome 15q25 region is associated with smoking cessation (16-20), whereas other studies do not (21-23). Given our findings, we believe that genetic risk varies by pharmacologic intervention and weaker (or even no) genetic effect will be seen in pharmacologic trials if an interaction effect with treatment (active treatment versus placebo) is not included. We believe that the effect of this genetic locus will be seen most clearly in placebo arms, or in a sample where pharmacotherapy use is rare. For example, Sarginson et al reported very little association between CHRNA5-CHRNA3-CHRNB4 variants and cessation during the pharmacologic treatment phase of the trial, but the association increased at the 1-year follow-up after a maintenance phase with no medication. Our present findings suggest that a genetic risk by environmental interaction might account for such inconsistency because the targeted genetic effects are most strongly expressed in environments that provide little support for cessation (e.g., no effective pharmacotherapy). None of the previous studies has
