Genetic variation in CHRNA7 and CHRFAM7A is associated with nicotine dependence and response to varenicline treatment

Abstract

The role of nicotinic acetylcholine receptors (nAChR) in nicotine dependence (ND) is well established; CHRNA7, encoding the α7 subunit, has a still uncertain role in ND, although it is implicated in a wide range of neuropsychiatric conditions. CHRFAM7A, a hybrid gene containing a partial duplication of CHRNA7, is possibly involved in modulating α7 nAChR function. The aim of this study was to investigate the role of CHRNA7 and CHRFAM7A genetic variants in ND and to test the hypothesis that α7 nAChR variation may modulate the efficacy of varenicline treatment in smoking cessation. We assessed CHRNA7 and CHRFAM7A copy number, CHRFAM7A exon 6 ∆2 bp polymorphism, and sequence variants in the CHRNA7 proximal promoter in an Italian sample of 408 treatment-seeking smokers. We conducted case-control and quantitative association analyses using two smoking measures (cigarettes per day, CPD, and Fagerström Test for Nicotine Dependence, FTND). Next, driven by the hypothesis that varenicline may exert some of its therapeutic effects through activation of α7 nAChRs, we restricted the analysis to a subgroup of 142 smokers who received varenicline treatment. The CHRNA7 promoter variant rs28531779 showed association with both smoking quantitative measures (FNTD p = 0.026, β = 0.89, 95% CI 0.11-1.67; CPD p = 0.006, β = 4.82 95% CI 1.42-8.22). Moreover, in the varenicline-treated subgroup we observed association of CHRFAM7A copy number with 6 months smoking abstinence (p = 0.035, OR = 3.18, 95% CI = 1.09-9.30). Thus, our study points to a possible role of genetic variation in CHRNA7 and CHRFAM7A in tobacco addiction mechanisms and response to varenicline treatment.

Identification of tRNA-Derived Small RNAs and their Potential Roles in the Hippocampus of Nicotine Exposure Rats

“…In recent years, genetic factors is becoming the research focus about nAChRs, and variants in the CHRNA5-CHRNA3-CHRNB4 gene cluster are the most studied associated with nicotine' actions [35,36]. Besides, Cameli et al pointed out that genetic variations in CHRNA7 and CHRFAM7A were related to nicotine addiction [10].In our study, we found that tRF-5c-Glu-CTC-1, tRF-5c-Glu-CTC-3, tRF-5c-Glu-TTC-4 might be involved in the cholinergic synapse pathway, and in turn influence the excitability of neurons and glial cells.…”

Identification of tRNA-derived small RNAs and their potential roles in the hippocampus of nicotine exposure rats

“…In recent years, genetic factors is becoming the research focus about nAChRs, and variants in the CHRNA5-CHRNA3-CHRNB4 gene cluster are the most studied associated with nicotine' actions [35,36]. Besides, Cameli et al pointed out that genetic variations in CHRNA7 and CHRFAM7A were related to nicotine addiction [10].In our study, we found that tRF-5c-Glu-CTC-1, tRF-5c-Glu-CTC-3, tRF-5c-Glu-TTC-4 might be involved in the cholinergic synapse pathway, and in turn in uence the excitability of neurons and glial cells. Further analysis indicated that the putative genes of these above tsRNAs included CHRM1, CHRM3, CHRNA3, CHRNA4 and CHRNA7, which encoded variant subunits of nAChRs.…”

“…In brief, nicotine can bind and activate nicotinic acetylcholine receptors (nAChRs), which are widely distributed throughout the nervous system and body, and thus result in the release of a variety of neurotransmitters (dopamine, gamma-aminobutyric acid (GABA), serotonin, glutamate etc) in the brain, particularly dopamine [7,8]. Besides, nicotine exposure can also produce additional neuroadaptations, including neuronal homeostatic mechanisms, neuronal scaffolding proteins expression and epigenetic regulations [9][10][11]. However, there is still much to be learned and done in order to fully understand how nicotine functions.…”

The effect of genetic variations in the choline acetyltransferase gene (ChAT) on waterpipe tobacco smoking dependence

“…Results of previous studies on cigarette smoking have identified different genetic variants among genes incorporated with several neuronal pathways associated with smoking behavior phenotypes, including initiation, dependence, and cessation [24][25][26][27] . Nicotine is associated with tobacco dependence by affecting the release of different neurotransmitters including acetylcholine and dopamine in the central reward pathway of the brain 23,25 .…”

“…Findings of previous studies on cigarette smoking have identified different genetic variants associated with smoking behavior phenotypes, including initiation, dependence, and cessation [24][25][26][27] . Studies examining the influence of genetic variation on WS behavior are lacking.…”