2008 - 2009 Publications > Genetics on Nicotine Addiction

Genetics on nicotine addiction

Portugal et al (2008) Neurobiol Learn Mem. Feb;89(2):106-13 and Jackson (2008) J Pharmacol Exp Ther. Jan 9 report that nicotinic receptors containing a beta2 subunit mediates the affective component of nicotine withdrawal but not the physical symptoms of withdrawal.    Mice lacking the beta 2 receptor treated with nicotine for 14 days show defects in conditioned place aversion did not show nicotine withdrawal-related deficits in contextual fear conditioning. 

Convergent results support CHRNA5/A3/B4 gene cluster association with nicotine dependence.

Berrettini et al Mol Psychiatry. 2008 Apr;13(4):368-73; Thorgeirsson et al Nature. 2008 Apr 3;452(7187):638-42; Sherva et al Addiction. 2008 Sep;103(9):1544-52; Weiss et al PLoS Genet. 2008 Jul 11;4(7):e1000125; Beirut et al Hum Mol Genet. 2007 Jan 1;16(1):24-35; Chen et al Am J Med Genet B Neuropsychiatr Genet. 2009 Jan 8. [Epub ahead of print]; Stevens et al Cancer Epidemiol Biomarkers Prev. 2008 Dec;17(12):3517-25  and Saccone et al Hum Mol Genet. 2007 Jan 1;16(1):36-49 report the discovery that CHRNA5/A3/B4 Gene Cluster Associated with nicotine dependence replicated.

CHRNA5/A3/B4 Gene Cluster associated with lung cancer, COPD, peripheral artery disease

Others report CHRNA5/A3/B4 Gene Cluster association is associated with lung cancer and it is not clear whether effect is direct or indirect consequence of smoking. Huang et al Nature. 2008 Apr 3;452(7187):633-7 and Amos et al Nature Gen 2008 May;40(5):616-22.  These reports argue that they have controlled for smoking frequency.  However, individuals with the variants in CHRNA3 and CHRNA5 have higher levels of nicotine and the carcinogenic 4-(methylnitrosamino)-I-(3-pyridyl)-1-butanone (NNK) suggesting that individuals carrying these receptor variants smoke more intensely.  The results also suggest that number of cigarettes smoked does not correlate well with smoking intensity. Le Marchand et al Cancer Res. 2008 Nov 15;68(22):9137-40.  Young et al Eur Respir J. 2008 Nov;32(5):1158-64 suggests that the association between CHRNA5 SNP polymorphism and lung cancer may, in part be confounded by COPD, which has a two fold greater prevalence in lung cancer than smoking controls.  Thorgeirsson et al Nature. 2008 Apr 3;452(7187):638-42 also reports CHRNA5/A3/B4 associated with lung cancer and peripheral artery disease.

Functional Significance of CHRNA5/A3/B4

• α4α5β2 expressed in cortex, hippocampus, striatum, and VTA

• α3β3β4 habenula and interpeduncular nucleus

• α3β4  hippocampus, medial habenula, cerebellum, locus coereleus, pineal gland

• Saccone et al identified a non-synonymous SNP in CHRNA5, D398N.  The N398 decreases calcium influx according to unpublished results by Dr. Jerry Stitzel that were presented at last council. 

• Jackson et al J. Pharmacol Exp Ther 2008 Jan 9 [Epub ahead of print] chronically treated CHRNβ2,CHRNα7, and CHRNα5 knockout mice with nicotine for 14 days.  When withdrawn from nicotine CHRNβ2 blocked the affective signs of anxiety and aversion while the CHRNα7, and CHRNα5 displayed a loss of physical withdrawal signs such as hyperalgesia and somatic signs. 

• Liang et al Neurogenetics. 2005 Feb;6(1):37-44 identified four functional variants in the human CHRNβ4:Thr to Ile at codon 91 (T91I), Arg to Trp at codon 136 (R136W), Ser to Gly at codon 140 (S140G), and Met to Val at codon 467 (M467V), respectively.  R136W and M467V variants had higher sensitivity to cholinergic agonists while T91I had a lower sensitivity to nicotine.   The T91I, R136W, and M467V mutations (or variants) also showed a slightly greater degree of steady-state desensitization than the wild-type

• Liang et al Neurogenetics. 2005 Feb;6(1):37-44 identified four functional variants in the human CHRNβ4: Thr to Ile at codon 91 (T91I), Arg to Trp at codon 136 (R136W), Ser to Gly at codon 140 (S140G), and Met to Val at codon 467 (M467V), respectively.  R136W and M467V variants had higher sensitivity to cholinergic agonists while T91I had a lower sensitivity to nicotine.   The T91I, R136W, and M467V mutations (or variants) also showed a slightly greater degree of steady-state desensitization than the wild-type

Nicotine Dependence Pharmacogenetics

• Role of Genetic Variation in nicotine-metabolizing enzymes: Phenotypic measure of CYP2A6 enzyme activity, defined as the ratio of the nicotine metabolites 3'hydroxycotinine/cotinine, can help tailor treatment for nicotine depencence.  Slow metabolizers of nicotine do better on nicotine replacement therapy while fast metabolizers show better response with buproprion.  Ray et al J Neurogenet. 2009 Jan 23:1-10. [Epub ahead of print]

• In a double blind placebo controlled smoking cessation trial the major allele (GG) of the the SNP (rs2072661) in the 3' UTR region of the β2 nicotinic acetylcholine receptor subunit (CHRNB2) predicted end of treatment response at the end of treatment and abstinence at 6 months. Conti et al Hum Mol Genet. 2008 Sep 15;17(18):2834-48

• Uhl et al Arch Gen Psychiatry. 2008 Jun;65(6):683-93 conducted a genome wide association study for smoking cessation in smoking cessation trials with European Americans using NRT, bupropion, or placebo. Variants in quit-success genes are likely to alter cell adhesion, enzymatic, transcriptional, structural, and DNA, RNA, and/or protein-handling functions.  Quit success is polygenic and overlaps with gene associate with substance dependence and memory.

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