This study reveals an interaction between the genetic variants in CHRNA5-CHRNA3-CHRNB4and smoking cessation pharmacotherapy in relation to smoking cessation. Smokers with the high-risk genetic variants have a three-fold increased likelihood of responding to pharmacologic cessation treatments, compared to smokers with the low-risk genetic variants.
In addition to the interaction effect, this study showed that the genetic variants in the chromosome 15q25 region that predict heavy smoking and nicotine dependence also predict a later age of smoking cessation in a large community-based sample. Those with the high-risk genetic variants quit later than those at low genetic risk, manifested as a two-year delay in median quit age. Recruitment for the ARIC sample began in the late 1980′s when the population utilization of nicotine replacement therapy was quite low (36
), so most ARIC subjects quit smoking without any pharmacologic treatment, thus representing a “natural history” of smoking cessation. The observed association between haplotype status and quitting latency was no longer significant once smoking heaviness was taken into account. This suggests that the targeted risk haplotypes confer heightened risk of heavy smoking and that this, in turn, constitutes an obstacle to successful quitting.
The large smoking cessation trial offers a distinct, complementary test of the association between haplotype status and cessation. In this study, the genetic associations with smoking cessation are manifested in the placebo group, which is consistent with the results obtained in the ARIC “natural history” sample. In contrast, these genetic variants do not predict abstinence across active treatment conditions, and this reduced genetic effect in the context of active pharmacological treatments suggests that cessation treatments differ in effectiveness across the haplotypes and mitigate the genetic risks for cessation difficulty. Pharmacological cessation treatment significantly increased the likelihood of abstinence in individuals with the high-risk haplotype H3, but exerted little effect in individuals with the low-risk haplotype H1.
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
), whereas other studies do not (21
). 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 reported this interaction, which could potentially explain the apparently inconsistent results in this area. Such interactions between genetic variants and treatment can serve as the basis for personalized medicine. The TAG consortium examined a different cessation phenotype (former vs. current smoker) and reported a modest association with CHRNA5-CHRNA3-CHRNB4
The results of this study should be interpreted in the context of several limitations. First, there was relatively little power to compare the magnitude of the targeted genetic effects among different active treatment conditions. The genetic risk for cessation was similar across the different pharmacotherapy conditions, indicating that multiple cessation interventions have the potential to be effective with such high-risk individuals. It is unclear if pharmacotherapy mitigates particular biological processes that lead to cessation failure, or if the genetic effect is more likely expressed at high overall levels of quitting difficulty. Second, the placebo group in the cessation trial is fairly small, which adds to the importance of future replication. However, reported associations between these genetic variants and cessation in multiple samples suggest a valid relation between these variants and cessation in some environmental contexts. Third, the smoking reports in the ARIC sample were not supported by biochemical confirmation. However, such confirmation was obtained in the UW-TTURC trial, and research shows that self-report is a valid indicant of current smoking, especially when there are no strong incentives to deceive (38
). In addition, this work only studies one genetic locus and it is clear that multiple genes contribute to smoking cessation success. Future research should explore whether greater accuracy in predicting treatment response can be attained by the addition of other genetic variants implicated in differential treatment effects (39
). Finally, this study only included subjects of European descent while the frequency and effects of these genetic variants differ by ancestry.
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.
While acknowledging the limitations of our study, we note that this work complements and builds upon previous research on treatment and genetic effects on smoking cessation. Using diverse methods, this work underscores the relation between the targeted haplotypes and smoking cessation, shows a significant interaction between these haplotypes and treatment on cessation success, and reveals that cessation treatment effectiveness is modulated by the haplotypes.
In summary, our findings strengthen the case for the development and rigorous testing of treatments that target patients with different genetic risk profiles based on the chromosome 15q25 region that includes CHRNA5-CHRNA3-CHRNB4
. Those with the high/intermediate-risk haplotypes appear more biologically predisposed to have difficulty quitting without treatment, but this risk may be ameliorated by effective pharmacological treatment. Further research that identifies genes related to responsiveness to treatment for nicotine addiction may lead to treatment algorithms that further the promise of personalized medicine(40