Possible Association of Nicotinic Acetylcholine Receptor Gene (CHRNA4 and CHRNB2) Polymorphisms with Nicotine Dependence in Japanese Males: An Exploratory Study

H.-I. Chen; T. Shinkai; K. Utsunomiya; K. Yamada; S. Sakata; Y. Fukunaka; R. Hwang; V. De Luca; O. Ohmori; J. L. Kennedy; H.-Y. Chuang; J. Nakamura

doi:10.1055/s-0032-1323678

Pharmacopsychiatry, Table of Contents

Pharmacopsychiatry 2013; 46(02): 77-82
DOI: 10.1055/s-0032-1323678

Original Paper

Possible Association of Nicotinic Acetylcholine Receptor Gene (CHRNA4 and CHRNB2) Polymorphisms with Nicotine Dependence in Japanese Males: An Exploratory Study

H.-I. Chen

¹Department of Psychiatry, School of Medicine, University of Occupational and Environmental Health, Yahatanishi-ku, Kitakyushu, Japan

²Department of Public Health, Kaohsiung Medical University, Kaohsiung, Taiwan

,

T. Shinkai

¹Department of Psychiatry, School of Medicine, University of Occupational and Environmental Health, Yahatanishi-ku, Kitakyushu, Japan

,

K. Utsunomiya

¹Department of Psychiatry, School of Medicine, University of Occupational and Environmental Health, Yahatanishi-ku, Kitakyushu, Japan

,

K. Yamada

¹Department of Psychiatry, School of Medicine, University of Occupational and Environmental Health, Yahatanishi-ku, Kitakyushu, Japan

,

S. Sakata

¹Department of Psychiatry, School of Medicine, University of Occupational and Environmental Health, Yahatanishi-ku, Kitakyushu, Japan

,

Y. Fukunaka

¹Department of Psychiatry, School of Medicine, University of Occupational and Environmental Health, Yahatanishi-ku, Kitakyushu, Japan

,

R. Hwang

³Neurogenetics Section, Centre for Addiction and Mental Health, Department of Psychiatry, University of Toronto, Toronto, ON, Canada

,

V. De Luca

³Neurogenetics Section, Centre for Addiction and Mental Health, Department of Psychiatry, University of Toronto, Toronto, ON, Canada

,

O. Ohmori

¹Department of Psychiatry, School of Medicine, University of Occupational and Environmental Health, Yahatanishi-ku, Kitakyushu, Japan

⁴Wakato Hospital, Wakamatsu-ku, Kitakyushu, Japan

,

J. L. Kennedy

³Neurogenetics Section, Centre for Addiction and Mental Health, Department of Psychiatry, University of Toronto, Toronto, ON, Canada

,

H.-Y. Chuang

²Department of Public Health, Kaohsiung Medical University, Kaohsiung, Taiwan

⁵Environmental and Occupational Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan

,

J. Nakamura

¹Department of Psychiatry, School of Medicine, University of Occupational and Environmental Health, Yahatanishi-ku, Kitakyushu, Japan

› Author Affiliations

Abstract

Introduction:

Smoking is a leading global cause of avoidable mortality. It has been reported that the nicotinic acetylcholine receptor (CHRNA4 and CHRNB2) genes might be associated with smoking behavior in several ethnic populations. However, no study between the 2 genes and nicotine dependence (ND) using a Japanese population has been reported.

Methods:

We examined the association between ND and 5 single nucleotide polymorphisms (SNPs) within the CHRNA4 and 3 SNPs within the CHRNB2 using a well characterized sample of 558 Japanese healthy male workers with a relatively homogeneous background. The Fagerström test for nicotine dependence (FTND) was used to quantify the degree of ND. Additionally, we explored the effect of gene-gene interactions of the 2 genes on ND.

Results:

We found CHRNB2 rs4845652 genotypes to be associated with FTND scores under an additive genetic model: rs4845652 T-allele carriers had lower ND levels (p=0.038; when adjusted for smoking duration: p=0.052). Furthermore, we demonstrated a possible gene-gene interaction of CHRNA4 and CHRNB2 on ND in a dose-dependent manner: those smokers with CHRNA4 rs1044397 GG or GA genotypes along with CHRNB2 rs4845652 CC genotype are likely to demonstrate higher ND scores.

Discussion:

These findings suggest that CHRNB2 rs4845652 T-allele carriers may be associated with lower levels of ND, and that certain allelic combinations of CHRNA4 and CHRNB2 might be correlated with higher ND levels. This preliminary study has certain limitations (issues such as sample size/power and multiple testing) that need to be taken into account, and the present work thus has an experimental nature.

Key words

nicotine dependence - CHRNA4 - CHRNB2 - association study - gene-gene interaction - polymorphism

Full Text

References

References
1 Jha P. Avoidable global cancer deaths and total deaths from smoking. Nat Rev Cancer 2009; 9: 655-664
2 Jorenby DE, Hays JT, Rigotti NA et al. Efficacy of varenicline, an alpha4beta2 nicotinic acetylcholine receptor partial agonist, vs placebo or sustained-release bupropion for smoking cessation: a randomized controlled trial. JAMA 2006; 296: 56-63
3 Hogg RC, Bertrand D. Neuroscience. What genes tell us about nicotine addiction. Science 2004; 306: 983-985
4 Drago J, McColl CD, Horne MK et al. Neuronal nicotinic receptors: insights gained from gene knockout and knockin mutant mice. Cell Mol Life Sci 2003; 60: 1267-1280
5 Fowler CD, Arends MA, Kenny PJ. Subtypes of nicotinic acetylcholine receptors in nicotine reward, dependence, and withdrawal: evidence from genetically modified mice. Behav Pharmacol 2008; 19: 461-484
6 Marubio LM, Gardier AM, Durier S et al. Effects of nicotine in the dopaminergic system of mice lacking the alpha4 subunit of neuronal nicotinic acetylcholine receptors. Eur J Neurosci 2003; 17: 1329-1337
7 Picciotto MR, Zoli M, Rimondini R et al. Acetylcholine receptors containing the beta2 subunit are involved in the reinforcing properties of nicotine. Nature 1998; 391: 173-177
8 Lena C, Changeux JP. The role of beta 2-subunit-containing nicotinic acetylcholine receptors in the brain explored with a mutant mouse. Ann N Y Acad Sci 1999; 868: 611-616
9 Maskos U, Molles BE, Pons S et al. Nicotine reinforcement and cognition restored by targeted expression of nicotinic receptors. Nature 2005; 436: 103-107
10 Tapper AR, McKinney SL, Nashmi R et al. Nicotine activation of alpha4* receptors: sufficient for reward, tolerance, and sensitization. Science 2004; 306: 1029-1032
11 Brody AL, Mandelkern MA, London ED et al. Cigarette smoking saturates brain alpha 4 beta 2 nicotinic acetylcholine receptors. Arch Gen Psychiatry 2006; 63: 907-915
12 Wullner U, Gundisch D, Herzog H et al. Smoking upregulates alpha4beta2* nicotinic acetylcholine receptors in the human brain. Neurosci Lett 2008; 430: 34-37
13 Hutchison KE, Allen DL, Filbey FM et al. CHRNA4 and tobacco dependence: from gene regulation to treatment outcome. Arch Gen Psychiatry 2007; 64: 1078-1086
14 Winterer G, Musso F, Konrad A et al. Association of attentional network function with exon 5 variations of the CHRNA4 gene. Hum Mol Genet 2007; 16: 2165-2174
15 Chu CJ, Yang YC, Wei JX et al. Association of nicotinic acetylcholine receptor subunit alpha-4 polymorphisms with smoking behaviors in Chinese male smokers. Chin Med J (Engl) 2011; 124: 1634-1638
16 Feng Y, Niu T, Xing H et al. A common haplotype of the nicotine acetylcholine receptor alpha 4 subunit gene is associated with vulnerability to nicotine addiction in men. Am J Hum Genet 2004; 75: 112-121
17 Breitling LP, Dahmen N, Mittelstrass K et al. Association of nicotinic acetylcholine receptor subunit alpha 4 polymorphisms with nicotine dependence in 5 500 Germans. Pharmacogenomics J 2009; 9: 219-224
18 Ehringer MA, Clegg HV, Collins AC et al. Association of the neuronal nicotinic receptor beta2 subunit gene (CHRNB2) with subjective responses to alcohol and nicotine. Am J Med Genet B Neuropsychiatr Genet 2007; 144B: 596-604
19 Wessel J, McDonald SM, Hinds DA et al. Resequencing of nicotinic acetylcholine receptor genes and association of common and rare variants with the Fagerstrom test for nicotine dependence. Neuropsychopharmacology 2010; 35: 2392-2402
20 Bierut LJ, Madden PA, Breslau N et al. Novel genes identified in a high-density genome wide association study for nicotine dependence. Hum Mol Genet 2007; 16: 24-35
21 Saccone NL, Saccone SF, Hinrichs AL et al. Multiple distinct risk loci for nicotine dependence identified by dense coverage of the complete family of nicotinic receptor subunit (CHRN) genes. Am J Med Genet B Neuropsychiatr Genet 2009; 150B: 453-466
22 Saccone SF, Hinrichs AL, Saccone NL et al. Cholinergic nicotinic receptor genes implicated in a nicotine dependence association study targeting 348 candidate genes with 3713 SNPs. Hum Mol Gene 2007; 16: 36-49
23 Ehringer MA, McQueen MB, Hoft NR et al. Association of CHRN genes with “dizziness” to tobacco. Am J Med Genet B Neuropsychiatr Genet 2010; 153B: 600-609
24 Liu JZ, Tozzi F, Waterworth DM et al. Meta-analysis and imputation refines the association of 15q25 with smoking quantity. Nat Genet 2010; 42: 436-440
25 Han S, Gelernter J, Luo X et al. Meta-analysis of 15 genome-wide linkage scans of smoking behavior. Biol Psychiatry 2010; 67: 12-19
26 Mineur YS, Picciotto MR. Genetics of nicotinic acetylcholine receptors: Relevance to nicotine addiction. Biochem Pharmacol 2008; 75: 323-333
27 Heatherton TF, Kozlowski LT, Frecker RC et al. The Fagerstrom test for nicotine dependence: a revision of the Fagerstrom tolerance questionnaire. Br J Addict 1991; 86: 1119-1127
28 Ciulla TA, Sklar RM, Hauser SL. A simple method for DNA purification from peripheral blood. Anal Biochem 1988; 174: 485-488
29 Rodriguez S, Gaunt TR, Day IN. Hardy-Weinberg equilibrium testing of biological ascertainment for Mendelian randomization studies. Am J Epidemiol 2009; 169: 505-514
30 Purcell S, Cherny SS, Sham PC. Genetic Power Calculator: design of linkage and association genetic mapping studies of complex traits. Bioinformatics 2003; 19: 149-150
31 Barrett JC, Fry B, Maller J et al. Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 2005; 21: 263-265
32 Dudbridge F. Likelihood-based association analysis for nuclear families and unrelated subjects with missing genotype data. Hum Hered 2008; 66: 87-98
33 Ramensky V, Bork P, Sunyaev S. Human non-synonymous SNPs: server and survey. Nucleic Acids Res 2002; 30: 3894-3900
34 Wjst M. Target SNP selection in complex disease association studies. BMC bioinformatics 2004; 5: 92
35 Reumers J, Schymkowitz J, Ferkinghoff-Borg J et al. SNPeffect: a database mapping molecular phenotypic effects of human non-synonymous coding SNPs. Nucleic Acids Res 2005; 33: D527-D532
36 Stevens VL, Bierut LJ, Talbot JT et al. Nicotinic receptor gene variants influence susceptibility to heavy smoking. Cancer Epidemiol Biomarkers Prev 2008; 17: 3517-3525

Supplementary Material

Supporting Information