CHRNA5-A3-B4 and DRD2 Genes and Smoking Cessation Throughout Adulthood: A Longitudinal Study of Women

Abstract

Introduction: Smoking cessation is more than 50% heritable. Genetic studies of smoking cessation have been limited by short-term follow-up or cross-sectional design.

Aims and methods: This study tests single nucleotide polymorphism (SNP) associations with cessation during long-term follow-up throughout adulthood in women. The secondary aim tests whether genetic associations differ by smoking intensity. Associations between 10 SNPs in CHRNA5, CHRNA3, CHRNB2, CHRNB4, DRD2, and COMT and the probability of smoking cessation over time were evaluated in two longitudinal cohort studies of female nurses, the Nurses' Health Study (NHS) (n = 10 017) and NHS-2 (n = 2793). Participant follow-up ranged from 2 to 38 years with data collected every 2 years.

Results: Women with the minor allele of either CHRNA5 SNP rs16969968 or CHRNA3 SNP rs1051730 had lower odds of cessation throughout adulthood [OR = 0.93, p-value = .003]. Women had increased odds of cessation if they had the minor allele of CHRNA3 SNP rs578776 [OR = 1.17, p-value = .002]. The minor allele of DRD2 SNP rs1800497 was associated with lower odds of cessation in moderate-to-heavy smokers [OR = 0.92, p-value = .0183] but increased odds in light smokers [OR = 1.24, p-value = .096].

Conclusions: Some SNP associations with short-term smoking abstinence observed in prior studies were shown in the present study to persist throughout adulthood over decades of follow-up. Other SNP associations with short-term abstinence did not persist long-term. The secondary aim findings suggest genetic associations may differ by smoking intensity.

Implications: The results of the present study expand on previous studies of SNP associations in relation to short-term smoking cessation to demonstrate some of these SNPs were associated with smoking cessation throughout decades of follow-up, whereas other SNP associations with short-term abstinence did not persist long-term. The rate of relapse to smoking remains high for several years after quitting smoking, and many smokers experience multiple quit attempts and relapse episodes throughout adulthood. Understanding genetic associations with long-term cessation has potential importance for precision medicine approaches to long-term cessation management.

Figure 1.

Smoking status over time of six participants from the Nurses’ Health Study from 1976 to 2014. Smoking status (former versus current smoker) was collected every 2 years.

Figure 2.

SNP associations with odds of smoking cessation, timepoints where participants are <65 years old. Controlling for year, age, smoking intensity (<5 or ≥5 cigarettes per day), early initiation of smoking (NHS = <16 years of age, NHS-2 = <15 years of age), menopausal status, use of hormone replacement therapy, body mass index. † FDR < 0.05, accounting for multiple comparisons for all genetic models and SNPs analyzed. ‡ FDR < 0.05, accounting for multiple comparisons of the selected genetic model for all 10 SNPs. SNP = single nucleotide polymorphism, NHS = Nurses' Health Study, NHS-2 = Nurses' Health Study 2.

Figure 3.

The probability of former smoker status over time by SNP genotype for CHRNA5 SNP rs16969968 and CHRNA3 SNP rs578776. Controlling for year, age, smoking intensity (<5 or ≥5 cigarettes per day), early initiation of smoking (NHS = <16 years of age, NHS-2 = <15 years of age), menopausal status, use of hormone replacement therapy, body mass index. The odds ratios of smoking cessation between genotypes are consistent over time; however, participants of all genotypes have higher probability of being a former smoker at later timepoints.

Figure 4.

Genetic associations with odds of smoking cessation by smoking intensity. SNP = single nucleotide polymorphism, NHS = Nurses’ Health Study, NHS-2 = Nurses’ Health Study 2. Light smoking <5 cigarettes per day (CPD), Moderate/Heavy smoking ≥5 CPD. Adjusted for year, age, smoking intensity, genotype × smoking intensity interaction, early initiation of smoking (NHS = <16 years of age, NHS -2 = <15 years of age), menopausal status, use of hormone replacement therapy, and body mass index. Assessing timepoints in which participants are <65 years of age.

Figure 5.

SNP associations with odds of smoking cessation, NHS participants <65 and ≥65 years old. Controlling for baseline age, year, smoking intensity (<5 or ≥5 cigarettes per day), early initiation of smoking (<16 years of age), menopausal status (for <65 years of age), and hormone replacement therapy use. SNP = Single Nucleotide Polymorphism, NHS = Nurses’ Health Study.