- The nicotinic cholinergic receptor contains five subunits. In the mammalian brain there are 9 alpha subunits (alpha 2 through alpha 10), and 3 beta subunits (beta 2 through beta 4). Although there are a large number of possible combinations a limited number of subtypes appear to account for most biologic effects. Variations in different nicotinic cholinergic receptor sub units could affect smoking behavior at several levels including initiation, smoking intensity, withdrawal and response to treatment.
- Genetic variations in the alpha 5 nicotinic acetylcholine receptor gene relate to smoking quantity, lung cancer and chronic obstructive pulmonary disease.
Alpha 5 Subunit and Smoking, Lung cancer and COPD

Genetic Variations in the Region of the Alpha 5 Nicotinic Acetylcholine Receptor Gene (CHRNA5) Relate to Smoking Quantity, Lung Cancer and Chronic Obstructive Pulmonary Disease (COPD)Findings were obtained from 34 data sets of subjects with European-ancestry. Cigarettes per day was dichotomous (less that 10 or over 20 cigarettes per day), the diagnosis or not of lung cancer and COPD was in smokers. Findings for rs578776 and rs588765 remained after adjusting for rs16969968. Findings for lung cancer and COPD were significant after adjusting for cigarettes per day.(Constructed from data in Saccone, N.L. et al. PLoS Genetics, 6: 1 - 16, 2010) ©2011 NBEP
- The alpha 3 nicotinic acetylcholine receptor is involved in smoking quantity and ability to quit.
Nicotinic Acetylcholine Receptor and Smoking

A Polymorphism in the Area of the Alpha 3 Nicotinic Acetylcholine Receptor Gene (CHRNA3) Is Associated with Increased Smoking Quantity and Independently with Decreased Smoking Cessation during PregnancyIn 2 large prospective studies of a total of 2,845 pregnant women of European descent in the South-West of England, smoking behavior was obtained from questionnaires and genotype of the single nucleotide polymorphism (SNP rs1051730) that lies within the CHNA3 gene was obtained. CNRA3 is in a linkage disequilibrium block that contains CHRNA5 and CHRNA4 that are also strong candidate genes for smoking behavior. Women are most likely to quit smoking during pregnancy and the data indicate that genetic factors play a role in their ability to stop smoking during pregnancy.(Constructed from data in Freathy, R.M. et al. Human Molecular Genetics, 18: 2922 - 2927, 2009) ©2011 NBEP
- Variations in individual acetylcholine receptor subunits can result in haplotypes that interact with smoking quanitity and response to treatment.
Haplotypes of the Nicotinic Acetylcholine Receptor and Smoking Cessation

Haplotypes Variants in Genes for Subunits of the Nicotinic Acetylcholine Receptor Predict Smoking Cessation during 8 Weeks of Placebo but Not during 8 Weeks of Pharmacologic Treatment. Increased risk haplotypes (2 and 3) in the nicotinic receptor gene cluster CHRNA5-CHRNA3-CHRNB4 were associated with increased smoking quantity compared to low risk haplotype (1). Haplotype 3 was associated with later age of quitting smoking in the community based sample but this was accounted for by smoking quantity. Smoking quantity did not alter the significant relationship between haplotype and treatment. Type of pharmacologic treatment (bupropion, nicotine replacement, combined) did not alter haplotype effects. Smokers with the high risk haplotype smoke more and have difficulty quitting on their own but they show the most benefit from pharmacologic treatment (3 times that of low risk haplotype). (Constructed from data in Chen, L. et al. Am J Psychiatry, 169: 735 – 242, 2012) ©2012 NBEP