Genetic Associations with Smoking Relapse and Proportion of Follow-up in Smoking Relapse throughout Adulthood in Pre- and Postmenopausal Women

Abstract

Abstract Genetics contribute to smoking cessation, which is important for cancer prevention. Prior genetic studies, limited by short-term follow-up, have not examined multiple quit attempts and relapse events experienced by most smokers. This research investigated genetic associations with smoking relapse throughout adulthood. Participants were from two, all-female longitudinal cohort studies and included 12,060 European ancestry ever-smokers with existing genotype data who quit smoking at ≥1 timepoint. Median follow-up was 32 years. Associations between selected SNPs and odds of relapse and, conditional on relapse, SNP associations with proportion of follow-up relapsed were modeled using zero-inflated beta regression. Genotype by menopausal status interactions were evaluated. Women with AA genotypes for CHRNA5 SNP rs16969968 G>A or CHRNA3 SNP rs1051730 G>A (P-value = 0.04 for both) had lower odds of relapse. Among women who relapsed, those with CC genotypes of CHRNA5 SNPs rs588765 T>C (P-value = 0.04) and rs680244 T>C (P-value = 0.048) and AA genotype of DRD2 SNP rs6277 G>A (P-value = 0.01) had higher proportion follow-up in relapse. Associations were stronger among postmenopausal women (genotype by menopause interactions: rs588765 P-value = 0.003, rs680244 P-value = 0.001, rs6277 P-value = 0.04). Women with AA or AG genotypes for COMT SNP rs4680 G>A (P-value = 0.03) had lower proportion follow-up relapsed. This study identified SNP associations with likelihood of relapse or proportion of follow-up in relapse. Several associations were stronger among postmenopausal women. The findings demonstrate the importance of long-term follow-up and factors unique to women when characterizing smoking phenotypes. Prevention Relevance: This study is the first to quantify genetic associations with smoking relapse among female smokers throughout adulthood. These findings could inform precision medicine approaches to improve long-term smoking relapse prevention to reduce smoking attributable cancer morbidity and mortality.