In summary, we have demonstrated that major CHRNA5-A3-B4 haplotypes identify countervailing susceptibility (HA) and protective (HC) determinants for long-term nicotine dependence. A substantial shift in haplotype frequency (A vs. C = 10%) and diplotype frequency (AA vs. BC = 17%, AA vs. CC = 27%) is observed when age of exposure to nicotine is used to define an at-risk subpopulation. Identifying this interaction of a common genetic risk factor with age of daily smoking onset among the complexity of factors that influence nicotine addiction indicates how genetics can augment public health approaches to the problem of smoking-related illness, because the risk is amenable to intervention. Identification of genetically high-risk individuals who would benefit from proactive interventions, such as adolescent education and cessation clinics, may result in a population with a lower rate of adult nicotine addiction.
