A candidate gene approach identifies the CHRNA5-A3-B4 region as a risk factor for age-dependent nicotine addiction

People who begin daily smoking at an early age are at greater risk of long-term nicotine addiction. We tested the hypothesis that associations between nicotinic acetylcholine receptor (nAChR) genetic variants and nicotine dependence assessed in adulthood will be stronger among smokers who began dail...

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Bibliographic Details
Published in:PLoS genetics 2008-07, Vol.4 (7), p.e1000125-e1000125
Main Authors: Weiss, Robert B, Baker, Timothy B, Cannon, Dale S, von Niederhausern, Andrew, Dunn, Diane M, Matsunami, Nori, Singh, Nanda A, Baird, Lisa, Coon, Hilary, McMahon, William M, Piper, Megan E, Fiore, Michael C, Scholand, Mary Beth, Connett, John E, Kanner, Richard E, Gahring, Lorise C, Rogers, Scott W, Hoidal, John R, Leppert, Mark F
Format: Article
Language:English
Subjects:
Addictions
Adolescent
Adult
Age Factors
Cohort Studies
European Continental Ancestry Group - genetics
Female
Genetic Predisposition to Disease
Genetics and Genomics/Complex Traits
Haplotypes
Humans
Logistic Models
Male
Middle Aged
Nerve Tissue Proteins - genetics
Neuroscience/Behavioral Neuroscience
Nicotine
Polymorphism, Single Nucleotide
Protein Subunits - genetics
Receptors, Nicotinic - genetics
Risk Factors
Smoking
Smoking - genetics
Studies
Teenagers
Tobacco Use Disorder - ethnology
Tobacco Use Disorder - genetics
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Summary:People who begin daily smoking at an early age are at greater risk of long-term nicotine addiction. We tested the hypothesis that associations between nicotinic acetylcholine receptor (nAChR) genetic variants and nicotine dependence assessed in adulthood will be stronger among smokers who began daily nicotine exposure during adolescence. We compared nicotine addiction-measured by the Fagerstrom Test of Nicotine Dependence-in three cohorts of long-term smokers recruited in Utah, Wisconsin, and by the NHLBI Lung Health Study, using a candidate-gene approach with the neuronal nAChR subunit genes. This SNP panel included common coding variants and haplotypes detected in eight alpha and three beta nAChR subunit genes found in European American populations. In the 2,827 long-term smokers examined, common susceptibility and protective haplotypes at the CHRNA5-A3-B4 locus were associated with nicotine dependence severity (p = 2.0x10(-5); odds ratio = 1.82; 95% confidence interval 1.39-2.39) in subjects who began daily smoking at or before the age of 16, an exposure period that results in a more severe form of adult nicotine dependence. A substantial shift in susceptibility versus protective diplotype frequency (AA versus BC = 17%, AA versus CC = 27%) was observed in the group that began smoking by age 16. This genetic effect was not observed in subjects who began daily nicotine use after the age of 16. These results establish a strong mechanistic link among early nicotine exposure, common CHRNA5-A3-B4 haplotypes, and adult nicotine addiction in three independent populations of European origins. The identification of an age-dependent susceptibility haplotype reinforces the importance of preventing early exposure to tobacco through public health policies.
ISSN:1553-7404
1553-7390
1553-7404
DOI:10.1371/journal.pgen.1000125