CHRNA5-A3-B4, CYP2A6, and DBH genetic associations with smoking cessation throughout adulthood within two longitudinal studies of women.

Introduction: Genetic studies of smoking cessation have been limited by short-term follow-up or cross-sectional design. Within seven genes (CHRNA3, CHRNA5, CHRNB2, CHRNB4, DRD2, DBH and CYP2A6) influencing biological mechanisms relevant to smoking, this study aimed to identify single nucleotide polymorphisms (SNPs) associated with smoking cessation throughout up to 38-years of follow-up.

Methods: Participants were from two all-female cohort studies, Nurses' Health Study (NHS) (n = 10,017) and NHS-2 (n = 2,793). For 132 SNPs providing coverage of these genes, genotype associations with the probability of quitting smoking over time were evaluated using generalized estimating equations models. For SNPs reaching nominal statistical significance (p < 0.05) within NHS, NHS-2 was used as the replication cohort to control for multiple testing (false discovery rate (FDR) < 0.05). SNP genotype by smoking intensity (lifetime light versus non-light smoking) interactions were also evaluated.

Results: Five SNPs identified in NHS were replicated in NHS-2 with FDR < 0.05. Women with the minor alleles of CHRNA5 SNPs rs637137 [OR = 1.21] and rs503464 [OR = 1.24] had increased odds of cessation. Women with the minor alleles of CYP2A6 SNPs rs56113850 [OR = 0.81] and rs56267346 [OR = 0.82] and DBH SNP rs6479643 [OR = 0.78] had lower odds of cessation throughout adulthood. An interaction with smoking intensity was indicated for three SNPs, CHRNB4 rs4887074, CHRNA3 SNP rs77438700, and CHRNA5 SNP rs76474922.

Conclusion: Genetic associations with smoking cessation over decades of follow-up were observed and may guide targeted approaches for smokers most at risk for long-term relapse.

Implications: This study identified single nucleotide polymorphisms (SNPs) within CHRNA5-A3-B4, CYP2A6, and DBH that were associated with smoking cessation in women over decades of follow-up. This study is the first to examine these genetic associations over years of follow-up. Some associations were novel while others replicated previous findings from short-term studies for the first time. Potential differences in some associations between light and non-light smokers were also observed. Genetic factors associated with long-term smoking behavior may help inform interventions modeled on long-term chronic disease management approaches; specifically, targeted maintenance interventions to sustain abstinence could be implemented among high-risk smokers.