Date of Award

1-1-2022

Embargo Period

4-22-2022

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Public Health Sciences

College

College of Graduate Studies

First Advisor

Beth J. Wolf

Second Advisor

Anthony J. Alberg

Third Advisor

Kristin Wallace

Fourth Advisor

Brett Froeliger

Fifth Advisor

Matthew J. Carpenter

Abstract

Cigarette smoking is a leading cause of premature death and preventable illness; more than 480,000 deaths annually in the U.S. are attributable to smoking. Of the more than 34 million U.S. adult smokers, more than half make a quit attempt each year but more than 90% will relapse within 6 months. Twin studies show that smoking cessation is more than 50% heritable, thus genetics plays a significant role in cessation. However, the understanding of genetic susceptibility to cessation failure is still in its nascent stages. Genetic studies of smoking cessation have typically used short-term follow-up or cross-sectional design, study design characteristics that cannot account for multiple quit attempts and relapse episodes over time, a phenomenon common in smokers. Additionally, prior genetic studies have often excluded light smokers even though light smokers comprise 15% of U.S. adult smokers, and few studies have examined genetic associations specifically among women. These factors limit the understanding of genetic susceptibility in smoking cessation because mechanisms of addiction may vary between light and heavy smokers as well as between men and women. To overcome these limitations, we used existing high-quality genetic and phenotype data available in the Nurses’ Health Study (NHS) and NHS 2, two large all-female cohorts with up to 38 years of longitudinal measurement of cigarette smoking for nearly 13,000 former/current smokers. We conducted a systematic review of the current evidence of genetic associations with smoking cessation focusing on genetic variation within biological pathways influencing nicotine addiction to inform two complementary methods of single nucleotide polymorphism (SNP) selection: 1) a candidate SNP approach, and 2) a candidate gene approach selecting thorough coverage of SNPs within genes that influence mechanisms of nicotine addiction. We examined the selected SNPs associations with 1) the likelihood of smoking cessation throughout adulthood and 2) the likelihood of relapse during adulthood and the proportion of follow-up in relapse. Using this approach, SNPs were observed to be associated with smoking cessation throughout female adulthood. Several SNP associations provided evidence to suggest that the associations may differ between light versus moderate to heavy smokers. Furthermore, SNPs were observed to be associated with the likelihood of sustained abstinence after successful cessation and, among women who relapsed, with the proportion of follow-up in relapse. The findings also revealed that some SNP associations with proportion of follow-up in relapse were stronger in women who quit smoking post-menopause. This research advanced understanding of the role of genetics of persistent smoking throughout adulthood, specifically in women. The evidence holds relevance for guiding precision medicine approaches to smoking cessation and indicate the need for intervention approaches to long-term cessation management and relapse prevention.

Rights

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