These results suggest that the biological effects of these haplotypes affect both smoking heaviness and a decreased ability to quit and that the interaction suggests that pharmacologic treatments are more effective for individuals who are biologically predisposed to have difficulty quitting. However, it is unclear whether the haplotypes are linked to both outcomes via the same mechanisms. In the ARIC sample, the effects of the targeted haplotypes on smoking heaviness mediated the influence of the haplotypes on cessation. Such a meditational role was not found in the UW-TTURC trial, indicating that more research is needed to clarify the causal paths from the haplotypes to cessation success. However, regardless of the specific causal paths that are ultimately determined, if the CHRNA5-CHRNA3-CHRNB4 haplotypes are indeed meaningfully related to both heaviness of smoking and cessation, it underscores their important role in the development and expression of nicotine dependence.
