TSpace Repository School of Graduate Studies – Theses Doctoral
The Interaction Between Genetics and Tobacco Consumption in Light Smokers
Tyndale, F. Rachel
CHRNA5-A3-B4; Cotinine; CYP2A6; Smokeless tobacco; Smoking
Smoking is the largest preventable cause of death globally. In North America, although the overall smoking prevalence has been declining, an increasing number of smokers consume less than 10 cigarettes per day and are referred to as light smokers. Today, light smokers represent more than 30% of the smoking population and are at risk for smoking related mortality and morbidity. For example, light smokers have approximately 15 times higher risk of developing chronic obstructive pulmonary disease and approximately 20 times higher risk of developing lung cancer compared to non-smokers. Yet despite the high prevalence and substantial negative health consequences, light smokers are generally excluded from smoking related studies. Genetic variants in CYP2A6, encoding for the major nicotine-metabolizing enzyme, and CHRNA5-A3-B4, encoding for alpha5, alpha3, and beta4 nicotinic receptors, are associated with altered tobacco consumption in heavy smokers, yet little is known about the influence of CYP2A6 and CHRNA5-A3-B4 genetic variants on tobacco consumption and smoking cessation in light smokers. In a cross sectional study of 400 Alaska Native individuals, we demonstrated that light smokers had similar nicotine exposure (as indicated by their urinary total nicotine equivalents) as heavy smokers despite self-reporting lower number of cigarettes per day. Like heavy smokers, these light smokers titrated their tobacco consumption according to their CYP2A6 activity and CHRNA5-A3-B4 genotype. In addition, gene variants in CYP2A6 and CHRNA5-A3-B4 acted in combination to modify tobacco consumption. Furthermore, our biomarker analyses showed that variation in CYP2A6 metabolic activity, such as those that exist between CYP2A6 genotypes or the sexes, altered cotinine removal to a greater extent than cotinine formation. As a result, cotinine accumulates in individuals with lower CYP2A6 activity resulting in substantially higher cotinine levels for a given tobacco exposure. Overall, the characterization of tobacco consumption levels and the genetic contribution to tobacco consumption in light smokers improved our understanding of smoking behaviors in this increasingly prevalent population and could aid the development of more efficacious smoking cessation strategies.
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