Abstract
Cigarette smoking is a leading cause of preventable death throughout the world. Nicotine, the primary addictive compound in tobacco, plays a vital role in the initiation and maintenance of its use. Nicotine exerts its pharmacological roles through nicotinic acetylcholine receptors (nAChRs), which are ligand-gated ion channels consisting of five membrane-spanning subunits. Besides the CHRNA4, CHRNB2 and CHRNA5/A3/B4 cluster on chromosome 15, which has been investigated intensively, recent evidence from both genome-wide association studies and candidate gene-based association studies has revealed the crucial roles of the CHRNB3–CHRNA6 gene cluster on chromosome 8 in nicotine dependence (ND). These studies demonstrate two distinct loci within this region. The first one is tagged by rs13277254, upstream of the CHRNB3 gene, and the other is tagged by rs4952, a coding single nucleotide polymorphism in exon 5 of that gene. Functional studies by genetic manipulation in mice have shown that α6*-nAChRs, located in the ventral tegmental area (VTA), are of great importance in controlling nicotine self-administration. However, when the α6 subunit is selectively re-expressed in the VTA of the α6−/− mouse by a lentiviral vector, the reinforcing property of nicotine is restored. To further determine the role of α6*-nAChRs in the process of nicotine-induced reward and withdrawal, genetic knock-in strains have been examined, which showed that replacement of Leu with Ser in the 9′ residue in the M2 domain of α6 produces nicotine-hypersensitive mice (α6 L9′S) with enhanced dopamine release. Moreover, nicotine-induced upregulation may be another ingredient in the pathology of nicotine addiction although the effect of chronic nicotine exposure on the expression of α6-containing receptors is controversial. To gain a better understanding of the pathological processes underlying ND and ND-related behaviors and to promote the development of effective smoking cessation therapies, we here present the most recent studies concerning the genetic effects of the CHRNB3–CHRNA6 gene cluster in ND.
Highlights
Cigarette smoking is one of the leading causes of preventable morbidity and death worldwide,[1] being responsible for approximately five million deaths annually, mostly caused by smokingrelated cancers and cardiovascular and respiratory diseases.[2]Because of the continuous effort of legislation against tobacco smoking and public realization of its health consequences, the prevalence of cigarette smoking is lower than in the past but has been relatively stable since the mid-1990 s;3 the smoking cessation rate still is relatively low
Nicotine exerts its pharmacological roles through nicotinic acetylcholine receptors, which are ligand-gated ion channels consisting of five membrane-spanning subunits
The nicotinic acetylcholine receptors (nAChRs), widely distributed in the central and peripheral nervous systems, are ligand-gated ion channels consisting of five membrane-spanning subunits[13] that can modulate the release of neurotransmitters[14] and mediate fast signal transmission at synapses.[15]
Summary
Cigarette smoking is one of the leading causes of preventable morbidity and death worldwide,[1] being responsible for approximately five million deaths annually, mostly caused by smokingrelated cancers and cardiovascular and respiratory diseases.[2]. Rice et al.[21,28] reported that CHRNB3 was more strongly associated with FTND than with CPD, pointing out the importance of selecting an appropriate phenotype for association analysis These authors carried out an independent GWAS with 1294 ND cases (defined by FTND score) and 2071 non-ND controls who had smoked at least 1 cigarette, revealing that the genetic locus most strongly associated with ND was rs1451240 in CHRNB3 (odds ratio (OR) 0.65; P = 2.4 × 10 − 8). Allele frequencies in AAs were different from those in EAs and subjects of Asian ancestry, where the last two ethnic samples appeared to be similar, we found that the genetic effect of seven SNPs in CHRNB3 are in the same direction among the three populations All these SNPs showed a significant association with ND. Besides the latest application of GWAS, significant efforts have replication studies in additional independent samples of different been made to identify susceptibility loci for ND and ND-related origins are warranted
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