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

TLDR

Early initiation of daily smoking increases the risk of long‑term nicotine addiction. The study tested whether associations between nicotinic acetylcholine receptor genetic variants and nicotine dependence are stronger in adults who began daily smoking during adolescence. Researchers assessed nicotine dependence in 2,827 long‑term smokers from Utah, Wisconsin, and the NHLBI Lung Health Study using a candidate‑gene panel of common coding variants and haplotypes in eight alpha and three beta nAChR subunit genes. In smokers who started daily smoking at or before age 16, common CHRNA5‑A3‑B4 haplotypes were strongly associated with nicotine dependence severity (OR 1.82, p = 2 × 10⁻⁵), whereas no such association was seen in those who began after age 16, confirming an age‑dependent genetic risk for adult 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 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.