Why do young women smoke? I. Direct and interactive effects of environment, psychological characteristics and nicotinic cholinergic receptor genes

Abstract

Despite the health hazards, cigarette smoking is disproportionately frequent among young women. A significant contribution of genetic factors to smoking phenotypes is well established. Efforts to identify susceptibility genes do not generally take into account possible interaction with environment, life experience and psychological characteristics. We recruited 501 female Israeli students aged 20-30 years, obtained comprehensive background data and details of cigarette smoking and administered a battery of psychological instruments. Smoking initiators (n = 242) were divided into subgroups with high (n = 127) and low (n = 115) levels of nicotine dependence based on their scores on the Fagerstrom Tolerance Questionnaire and genotyped with noninitiators (n = 142) for single nucleotide polymorphisms (SNPs) in 11 nicotinic cholinergic receptor genes. We found nominally significant (P < 0.05) allelic and genotypic association with smoking initiation of SNP rs2072660 and multilocus haplotypes (P < 0.007-0.05) in CHRNB2 and nominal (P < 0.05) allelic or genotypic association of SNPs in CHRNA7 (rs1909884), CHRNA9 (rs4861065) and CHRNB3 (rs9298629) with nicotine dependence. Employing logistic regression and controlling for known risk factors, the bestfitting model for smoking initiation encompassed a 5 SNP haplotype in CHRNB2, neuroticism and novelty seeking (P = 5.9 Â 10 À14 , Nagelkerke r 2 = 0.30). For severity of nicotine dependence, two SNPs in CHRNA7 (rs1909884 and rs883473), one SNP in CHRNA5 (rs680244) and the interaction of a SNP in CHRNA7 (rs2337980) with neuroticism, were included in the model (P = 2.24 Â 10 À7 , Nagelkerke r 2 = 0.40). These findings indicate that background factors, psychological characteristics and genetic variation in nicotinic cholinergic receptors contribute independently or interactively to smoking initiation and to severity of nicotine dependence in young women.

β2 subunit containing acetylcholine receptors mediate nicotine withdrawal deficits in the acquisition of contextual fear conditioning

“…Mice with the A529 variant exhibited enhanced sensitivity to the effects of nicotine and increased consumption of nicotine, compared to mice with the T529 variant of the α4 nAChR subunit (Dobelis et al, 2002;Butt et al, 2003;Butt et al, 2005). In human research, polymorphisms in Chrna4 have been identified that may be protective against nicotine dependence (Feng et al, 2004;Li et al, 2005), and some evidence suggests that polymorphisms in the β2 nAChR subunit gene (Chrnb2) may be associated with smoking initiation (Greenbaum et al, 2006but see Lueders et al, 2002Silverman et al, 2000). Although polymorphisms in Chrna4 and Chrnb2 have been implicated in nicotine addiction, the effects of polymorphisms of Chrna4 or Chrnb2 on nicotine withdrawal remain unknown.…”

Overview of the pharmacogenomics of cigarette smoking

“…134,140 Several studies failed to find any associations between genetic variation in CHRNB2, which encodes the b 2 subunit, with smoking initiation or ND. 137,138,141,142 However, Greenbaum et al 139 found that rs2072660, which had been examined in other studies with negative results, and its haplotypes had a nominally significant protective effect against smoking initiation. SNPs in CHRNA7 (rs1909884), CHRNA9 (rs4861065) and CHRNB3 (rs9298629) also appeared protective against high levels of ND (FTQ X6), although none remained significant after correction for multiple testing.…”

“…A study in Chinese men found an association of two synonymous SNPs in exon 5 (rs1044396 and rs1044397) with a lower risk of ND, 137 but these findings were not confirmed in either male or female subjects of other ethnicities. 138,139 In an analysis of six SNPs (including rs1044396), only one (rs2236196), and its…”

“…SNPs in CHRNA7 (rs1909884), CHRNA9 (rs4861065) and CHRNB3 (rs9298629) also appeared protective against high levels of ND (FTQ X6), although none remained significant after correction for multiple testing. 139 The prevalence of smoking among schizophrenic patients is extremely high (B80%) 143 and this may represent an attempt to self-medicate. 144 Nicotine can transiently reduce deficit of the P50-auditory evoked-potential, a physiological indicator of the illness.…”

Evidence for a two-stage model of dependence using the NESARC and its implications for genetic association studies

“…Furthermore, a design that compares users (both dependent cases and non-dependent users) with abstainers addresses genetic influences that effect both initiation and dependence. A few studies involving nicotine have used this three-subject group design Greenbaum et al, 2006;Lerer et al, 2006;Sullivan et al, 2001a;Sullivan et al, 2001b;Zhang et al, 2006) and separately assessed genetic effects for initiation from those for dependence. These studies, conducted in the U.S. and Israel, also supported the two-stage model, providing further evidence of the value of such a design in genetic association studies of illicit substances.…”