Contribution of Variants in CHRNA5/A3/B4 Gene Cluster on Chromosome 15 to Tobacco Smoking: From Genetic Association to Mechanism

Abstract

Cigarette smoking is the major cause of preventable death and morbidity throughout the world. Many compounds are present in tobacco, but nicotine is the primary addictive one. Nicotine exerts its physiological and pharmacological roles in the brain through neuronal nicotinic acetylcholine receptors (nAChRs), which are ligand-gated ion channels consisting of five membrane-spanning subunits that can modulate the release of neurotransmitters, such as dopamine, glutamate, and GABA and mediate fast signal transmission at synapses. Considering that there are 12 nAChR subunits, it is highly likely that subunits other than α4 and β2, which have been intensively investigated, also are involved in nicotine addiction. Consistent with this hypothesis, a number of genome-wide association studies (GWAS) and subsequent candidate gene-based associated studies investigating the genetic variants associated with nicotine dependence (ND) and smoking-related phenotypes have shed light on the CHRNA5/A3/B4 gene cluster on chromosome 15, which encodes the α5, α3, and β4 nAChR subunits, respectively. These studies demonstrate two groups of risk variants in this region. The first one is marked by single nucleotide polymorphism (SNP) rs16969968 in exon 5 of CHRNA5, which changes an aspartic acid residue into asparagine at position 398 (D398N) of the α5 subunit protein sequence, and it is tightly linked SNP rs1051730 in CHRNA3. The second one is SNP rs578776 in the 3'-untranslated region (UTR) of CHRNA3, which has a low correlation with rs16969968. Although the detailed molecular mechanisms underlying these associations remain to be further elucidated, recent findings have shown that α5* (where "*" indicates the presence of additional subunits) nAChRs located in the medial habenulo-interpeduncular nucleus (mHb-IPN) are involved in the control of nicotine self-administration in rodents. Disruption of α5* nAChR signaling diminishes the aversive effects of nicotine on the mHb-IPN pathway and thereby permits more nicotine consumption. To gain a better understanding of the function of the highly significant genetic variants identified in this region in controlling smoking-related behaviors, in this communication, we provide an up-to-date review of the progress of studies focusing on the CHRNA5/A3/B4 gene cluster and its role in ND.

Neuropeptide systems and new treatments for nicotine addiction

“…Some of the first GWA studies showed that variations in the sequence of α3, α5, and β4 nAChR subunit genes affects the risk for developing and maintaining a nicotine addiction (Berrettini et al 2008; Chen et al 2009; Liu et al 2010; Wen et al 2016). More recent genetic studies revealed that variability in the α4 nAChR subunit gene affects the risk for developing nicotine addiction in humans (Hancock et al 2015; Thorgeirsson et al 2016).…”

Establishment of a Strong Link Between Smoking and Cancer Pathogenesis through DNA Methylation Analysis

“…One of the most robust findings in genome-wide association studies is that variants in the CHRNA5 / A3 / B4 cluster on chromosome 15q24-25.1 show a significant association with both nicotine dependence and lung cancer 10 . However, current genetics-based evidence is lacking for elucidating the carcinogenic mechanisms of cigarette smoking-associated cancers, which leads many researchers to focus on the function of smoking-associated DNA methylation (SA-DNAm).…”

The α3β4 nAChR partial agonist AT-1001 attenuates stress-induced reinstatement of nicotine seeking in a rat model of relapse and induces minimal withdrawal in dependent rats

“…From the various subtype combinations of nAChRs known, the highly abundant heteromeric α4β2* (* indicates possible other subunits present) subtype is linked to the positive reinforcing effects of nicotine [16–18] and is the target for varenicline, which acts as a partial agonist at this nAChR subtype to reduce the rewarding effect of nicotine in humans and in animal models of nicotine self-administration [11, 19]. Recent findings from human genetic studies and preclinical mouse models show that other nAChR subtypes present in the brain also play an important role in the dependence and reinforcing effects of nicotine [20–23]. …”