A Candidate Gene Approach Identifies the CHRNA5-A3-B4 Region as a Risk Factor for Age-Dependent Nicotine Addiction

Abstract

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 α and three β 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 = 2.0×10−5; 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.

Exploring Alternate Processes Contributing to the Association Between Maternal Smoking and the Smoking Behavior Among Young Adult Offspring

“…Parental smoking increases rates of smoking initiation (Bricker et al, 2007;Burchfiel, Higgins, Keller, Butler, & Donahue, Rosenman, Fabsitz, & Christian, 1990), such as inheritable personality characteristics (Heath, Madden, Slutske, & Martin, 1995) and gene variants that affect one's nicotine response (Arinami, Ishiguro, & Onaivi, 2000;O'Loughlin et al, 2004;Timberlake et al, 2006;Weiss et al, 2008).…”

“…Additionally, mother's lifetime smoking may transmit separate genetic risks than does MSP, since specific genetic factors influence different aspects of smoking independently (Maes et al, 2004). In particular, genetic factors associated smoking initiation (Kendler et al, 1999;Koopmans et al, 1999), risk-taking/disinhibited behavior (Hopfer, Crowley, & Hewitt, 2003;Keyes, Legrand, Iacono, & McGue, 2008), or ND (Greenbaum et al, 2010;O'Loughlin et al, 2004;Weiss et al, 2008) may partially explain the effects of mother's lifetime smoking on adolescent smoking frequency and ND.…”

Differential contribution of genetic variation in multiple brain nicotinic cholinergic receptors to nicotine dependence: recent progress and emerging open questions

“…12,81 Age of SI (and its influence on later life smoking behavior) is another phenotype that has been studied from the genetic perspective (Table 2). 82,83 Development of ND requires exposure to nicotine. Therefore, the most appropriate controls for studying factors that influence severity of ND in smokers are individuals who initiated smoking and had sufficient exposure to develop ND but did not.…”

Association of nicotinic acetylcholine receptor subunit α4 polymorphisms with nicotine dependence in 5500 Germans

“…13 With accumulating data, appropriate meta-analytic studies will allow a more definite assessment of the CHRNA4-smoking association in the relatively near future. The study presented here had a large sample size, allowing rather precise effect estimation, and the genotyping in three independent samples allowed the replication of effect directions to emerge as additional support for the validity of our results.…”