Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review
  • Published:

Overview of the pharmacogenomics of cigarette smoking

Abstract

Cigarette smoking increases the risk of numerous health problems, including cancer, cardiovascular and pulmonary disorders, making smoking the leading cause of preventable death in the world. Nicotine is primarily responsible for the highly addictive properties of cigarettes. Although the majority of smokers express a desire to quit, few are successful in doing so. Twin and family studies have indicated substantial genetic contributions to smoking behaviors. One major research focus has been to elucidate the specific genes involved; this has been accomplished primarily through genome-wide linkage analyses and candidate gene association studies. Much attention has focused on genes involved in the neurotransmitter pathways for the brain reward system and genes altering nicotine metabolism. This paper reviews the current state of knowledge for genetic factors implicated in smoking behaviors, and examines how genetic variations may affect therapeutic outcomes for drugs used to assist smoking cessation.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

References

  1. Why is tobacco a public health priority?. World Health Organization: Tobacco Free Initiative 2006 [cited April 10, 2006]; Available from: http://www.who.int/tobacco/health_priority/en/index.html.

  2. Li MD . The genetics of nicotine dependence. Curr Psychiatry Rep 2006; 8: 158–164.

    Article  CAS  PubMed  Google Scholar 

  3. Trosclair A, Caraballo R, Malarcher A, Husten C, Pechacek T . Cigarette smoking among adults – United States, 2003. Morbid Mort Wkly Rep 2005; 54: 509–513.

    Google Scholar 

  4. Baillie AJ, Mattick RP, Hall W . Quitting smoking: estimation by meta-analysis of the rate of unaided smoking cessation. Aust J Public Health 1995; 19: 129–131.

    Article  CAS  PubMed  Google Scholar 

  5. Diagnostic and Statistical Manual. Text Revision IV: American Psychiatric Associations: Washington, DC, 2000.

  6. Henningfield JE, Fant RV, Buchhalter AR, Stitzer ML . Pharmacotherapy for nicotine dependence. CA Cancer J Clin 2005; 55: 281–299.

    Article  PubMed  Google Scholar 

  7. Silagy C, Lancaster T, Stead L, Mant D, Fowler G . Nicotine replacement therapy for smoking cessation. Cochrane Database Syst Rev 2004; 3: CD000146.

    Google Scholar 

  8. Jorenby DE, Leischow SJ, Nides MA, Rennard SI, Johnston JA, Hughes AR et al. A controlled trial of sustained-release bupropion, a nicotine patch, or both for smoking cessation. N Engl J Med 1999; 340: 685–691.

    Article  CAS  PubMed  Google Scholar 

  9. Hurt RD, Sachs DPL, Glover ED, Offord KP, Johnston JA, Dale LC et al. A comparison of sustained-release bupropion and placebo for smoking cessation. N Engl J Med 1997; 337: 1195–1202.

    Article  CAS  PubMed  Google Scholar 

  10. Malaiyandi V, Sellers EM, Tyndale RF . Implications of CYP2A6 genetic variation for smoking behaviors and nicotine dependence. Clin Pharmacol Therapeut 2005; 77: 145.

    Article  CAS  Google Scholar 

  11. Mayhew KP, Flay BR, Mott JA . Stages in the development of adolescent smoking. Drug Alcohol Depend 2000; 59 (Suppl 1): 61.

    Article  Google Scholar 

  12. True WR, Heath AC, Scherrer JF, Waterman B, Goldberg J, Lin N et al. Genetic and environmental contributions to smoking. Addiction 1997; 92: 1277–1288.

    Article  CAS  PubMed  Google Scholar 

  13. Heath AC, Martin NG . Genetic models for the natural history of smoking: evidence for a genetic influence on smoking persistence. Addict Behav 2003; 18: 19–34.

    Article  Google Scholar 

  14. Kendler KS, Neale MC, Sullivan P, Corey LA, Gardner CO, Prescott CA . A population-based twin study in women of smoking initiation and nicotine dependence. Psychol Med 1999; 29: 299–308.

    Article  CAS  PubMed  Google Scholar 

  15. Heath AC, Cates R, Martin NG, Meyer J, Hewitt JK, Neale MC et al. Genetic contribution to risk of smoking initiation: comparisons across birth cohorts and across cultures. J Substance Abuse 1993; 5: 221–246.

    Article  CAS  Google Scholar 

  16. Madden PAF, Heath AC, Pedersen NL, Kaprio J, Koskenvuo MJ, Martin NG . The genetics of smoking persistence in men and women: a multicultural study. Behav Genet 1999; 29: 423.

    Article  CAS  PubMed  Google Scholar 

  17. Maes HH, Sullivan PF, Bulik CM, Neale MC, Prescott CA, Eaves LJ et al. A twin study of genetic and environmental influences on tobacco initiation, regular tobacco use and nicotine dependence. Psychol Med 2004; 34: 1251–1261.

    Article  PubMed  Google Scholar 

  18. Sullivan PF, Kendler KS . The genetic epidemiology of smoking. Nicotine Tobacco Res 1999; 1 (Suppl 2): S51–S57; discussion S69–S70.

    Article  Google Scholar 

  19. Vink JM, Willemsen G, Boomsma DI . Heritability of smoking initiation and nicotine dependence. Behav Genet 2005; 35: 397.

    Article  PubMed  Google Scholar 

  20. Li MD, Cheng R, Ma JZ, Swan GE . A meta-analysis of estimated genetic and environmental effects on smoking behavior in male and female adult twins. Addiction 2003; 98: 23–31.

    Article  PubMed  Google Scholar 

  21. Lessov CN, Swan GE, Ring HZ, Khroyan TV, Lerman C . Genetics and drug use as a complex phenotype. Subst Use Misuse 2004; 39: 1515.

    Article  PubMed  Google Scholar 

  22. Koopmans JR, Slutske WS, Heath AC, Neale MC, Boomsma DI . The genetics of smoking initiation and quantity smoked in Dutch adolescent and young adult twins. Behav Genet 1999; 29: 383–393.

    Article  CAS  PubMed  Google Scholar 

  23. Swan GE, Carmelli D, Rosenman RH, Fabsitz RR, Christian JC . Smoking and alcohol consumption in adult male twins: genetic heritability and shared environmental influences. J Subst Abuse 1990; 2: 39–50.

    Article  CAS  PubMed  Google Scholar 

  24. Swan GE, Carmelli D, Cardon LR . The consumption of tobacco, alcohol, and coffee in Caucasian male twins: a multivariate genetic analysis. J Subst Abuse 1996; 8: 19–31.

    Article  CAS  PubMed  Google Scholar 

  25. Swan GE, Carmelli D, Cardon LR . Heavy consumption of cigarettes, alcohol and coffee in male twins. J Stud Alcohol 1997; 58: 182–190.

    Article  CAS  PubMed  Google Scholar 

  26. Vink JM, Beem AL, Posthuma D, Neale MC, Willemsen G, Kendler KS et al. Linkage analysis of smoking initiation and quantity in Dutch sibling pairs. Pharmacogenomics J 2004; 4: 274–282.

    Article  CAS  PubMed  Google Scholar 

  27. True WR, Xian H, Scherrer JF, Madden PAF, Bucholz KK, Heath AC et al. Common genetic vulnerability for nicotine and alcohol dependence in men. Arch Gen Psychiatry 1999; 56: 655–661.

    Article  CAS  PubMed  Google Scholar 

  28. Broms U, Silventoinen K, Madden PA, Heath AC, Kaprio J . Genetic architecture of smoking behavior: a study of Finnish adult twins. Twins Res Hum Genet 2006; 9: 64–72.

    Article  Google Scholar 

  29. Xian H, Scherrer J, Madden P, Lyons M, Tsuang M, True W et al. The heritability of failed smoking cessation and nicotine withdrawal in twins who smoked and attempted to quit. Nicotine Tobacco Res 2003; 5: 245.

    Article  CAS  Google Scholar 

  30. Lessov CN, Martin NG, Statham DJ, Todorov AA, Slutske WS, Bucholz KK et al. Defining nicotine dependence for genetic research: evidence from Australian twins. Psychol Med 2004; 34: 865–879.

    Article  PubMed  Google Scholar 

  31. Heath AC, Martin NG, Lynskey MT, Todorov AA, Madden PA . Estimating two-stage models for genetic influences on alcohol, tobacco or drug use initiation and dependence vulnerability in twin and family data. Twins Res 2002; 5: 113–124.

    Article  Google Scholar 

  32. Vink JM, Posthuma D, Neale MC, Eline Slagboom P, Boomsma DI . Genome-wide linkage scan to identify loci for age at first cigarette in dutch sibling pairs. Behav Genet 2006; 36: 100.

    Article  PubMed  Google Scholar 

  33. Morley K, Medland S, Ferreira M, Lynskey M, Montgomery G, Heath A et al. A possible smoking susceptibility locus on chromosome 11p12: evidence from sex-limitation linkage analyses in a sample of Australian twin families. Behav Genet 2006; 36: 87.

    Article  PubMed  Google Scholar 

  34. Kendler KS, Thornton LM, Pedersen NL . Tobacco consumption in Swedish twins reared apart and reared together. Arch Gen Psychiatry 2000; 57: 886–892.

    Article  CAS  PubMed  Google Scholar 

  35. Tyndale RF . Genetics of alcohol and tobacco use in humans. Ann Med 2003; 35: 94–121.

    Article  CAS  PubMed  Google Scholar 

  36. Hall W, Madden P, Lynskey M . The genetics of tobacco use: methods, findings and policy implications. Tob Control 2002; 11: 119–124.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Straub RE, Sullivan PF, Ma Y, Myakishev MV, Harris-Kerr C, Wormley B et al. Susceptibility genes for nicotine dependence: a genome scan and follow up in an independent sample suggest that regions on chromosomes 2, 4, 10, 16, 17 and 18 merit further study. Mol Psychiatry 1999; 4: 129–144.

    Article  CAS  PubMed  Google Scholar 

  38. Sullivan PF, Neale BM, van den Oord E, Miles MF, Neale MC, Bulik CM et al. Candidate genes for nicotine dependence via linkage, epistasis, and bioinformatics. Am J Med Genet B: Neuropsychiatr Genet 2004; 126B: 23–36.

    Article  Google Scholar 

  39. Swan GE, Hops H, Wilhelmsen KC, Lessov-Schlaggar CN, Cheng LS, Hudmon KS et al. A genome-wide screen for nicotine dependence susceptibility loci. Am J Med Genet B: Neuropsychiatr Genet 2006; 141B: 354–360.

    Article  Google Scholar 

  40. Saccone N, Neuman R, Saccone S, Rice J . Genetic analysis of maximum cigarette-use phenotypes. BMC Genet 2003; 4 (Suppl 1): S105.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Duggirala R, Almasy L, Blangero J . Smoking behavior is under the influence of a major quantitative trait locus on human chromosome 5q. Genet Epidemiol 1999; 17 (Suppl 1): S139–S144.

    Article  PubMed  Google Scholar 

  42. Bierut LJ, Rice JP, Goate A, Hinrichs AL, Saccone NL, Foroud T et al. A genomic scan for habitual smoking in families of alcoholics: common and specific genetic factors in substance dependence. Am J Med Genet A 2004; 124A: 19–27.

    Article  PubMed  Google Scholar 

  43. Goode E, Badzioch M, Kim H, Gagnon F, Rozek L, Edwards K et al. Multiple genome-wide analyses of smoking behavior in the Framingham Heart Study. BMC Genet 2003; 4 (Suppl 1): S102.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Ehlers C, Wilhelmsen K . Genomic screen for loci associated with tobacco usage in Mission Indians. BMC Med Genet 2006; 7: 9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Gelernter J, Liu X, Hesselbrock V, Page GP, Goddard A, Zhang H . Results of a genomewide linkage scan: support for chromosomes 9 and 11 loci increasing risk for cigarette smoking. Am J Med Genet B: Neuropsychiatr Genet 2004; 128B: 94–101.

    Article  Google Scholar 

  46. Li M, Ma J, Cheng R, Dupont R, Williams N, Crews K et al. A genome-wide scan to identify loci for smoking rate in the Framingham Heart Study population. BMC Genet 2003; 4 (Suppl 1): S103.

    Article  PubMed  PubMed Central  Google Scholar 

  47. Lockman PR, McAfee G, Geldenhuys WJ, Van der Schyf CJ, Abbruscato TJ, Allen DD . Brain uptake kinetics of nicotine and cotinine after chronic nicotine exposure. J Pharmacol Exp Ther 2005; 314: 636–642.

    Article  CAS  PubMed  Google Scholar 

  48. Wonnacott S . Presynaptic nicotinic ACh receptors. Trends Neurosci 1997; 20: 92.

    Article  CAS  PubMed  Google Scholar 

  49. Rossi S, Singer S, Shearman E, Sershen H, Lajtha A . The effects of cholinergic and dopaminergic antagonists on nicotine-induced cerebral neurotransmitter changes. Neurochem Res 2005; 30: 541.

    Article  CAS  PubMed  Google Scholar 

  50. Buisson B, Bertrand D . Nicotine addiction: the possible role of functional upregulation. Trends Pharmacolog Sci 2002; 23: 130.

    Article  CAS  Google Scholar 

  51. Flores CM, Davila-Garcia MI, Ulrich YM, Kellar KJ . Differential regulation of neuronal nicotinic receptor binding sites following chronic nicotine administration. J Neurochemistry 1997; 69: 2216.

    Article  CAS  Google Scholar 

  52. Perry DC, Davila-Garcia MI, Stockmeier CA, Kellar KJ . Increased nicotinic receptors in brains from smokers: membrane binding and autoradiography studies. J Pharmacol Exp Therapeut 1999; 289: 1545.

    CAS  Google Scholar 

  53. Epping-Jordan MP, Watkins SS, Koob GF, Markou A . Dramatic decreases in brain reward function during nicotine withdrawal. Nature 1998; 393: 76.

    Article  CAS  PubMed  Google Scholar 

  54. McMorrow MJ, Foxx RM . Nicotine's role in smoking: an analysis of nicotine regulation. Psychol Bull 1983; 93: 302–327.

    Article  CAS  PubMed  Google Scholar 

  55. Corrigall WA, Coen KM, Adamson KL . Self-administered nicotine activates the mesolimbic dopamine system through the ventral tegmental area. Brain Res 1994; 653: 278.

    Article  CAS  PubMed  Google Scholar 

  56. Corrigall W, Franklin K, Coen K, Clarke P . The mesolimbic dopaminergic system is implicated in the reinforcing effects of nicotine. Psychopharmacology 1992; 107: 285.

    Article  CAS  PubMed  Google Scholar 

  57. Cami J, Farre M . Drug Addiction. N Engl J Med 2003; 349: 975–986.

    Article  CAS  PubMed  Google Scholar 

  58. Neville MJ, Johnstone EC, Walton RT . Identification and characterization of ANKK1: a novel kinase gene closely linked to DRD2 on chromosome band 11q23.1. Hum Mutat 2004; 23: 540–545.

    Article  CAS  PubMed  Google Scholar 

  59. Grandy DK, Litt M, Allen L, Bunzow JR, Marchionni M, Makam H . The human dopamine D2 receptor gene is located on chromosome 11 at q22–q23 and identifies a TaqI RFLP. Am J Hum Genet 1989; 45: 778–785.

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Thompson J, Thomas N, Singleton A, Piggott M, Lloyd S, Perry EK et al. D2 dopamine receptor gene (DRD2) Taq1 A polymorphism: reduced dopamine D2 receptor binding in the human striatum associated with the A1 allele. Pharmacogenetics 1997; 7: 479–484.

    Article  CAS  PubMed  Google Scholar 

  61. Noble EP, Blum K, Ritchie T, Montgomery A, Sheridan PJ . Allelic association of the D2 dopamine receptor gene with receptor-binding characteristics in alcoholism. Arch Gen Psychiatry 1991; 48: 648–654.

    Article  CAS  PubMed  Google Scholar 

  62. Pohjalainen T, Rinne JO, Nagren K, Lehikoinen P, Anttila K, Syvalahti EK et al. The A1 allele of the human D2 dopamine receptor gene predicts low D2 receptor availability in healthy volunteers. Mol Psychiatry 1998; 3: 256.

    Article  CAS  PubMed  Google Scholar 

  63. Comings DE, Ferry L, Bradshaw-Robinson S, Burchette R, Chiu C, Muhleman D . The dopamine D2 receptor (DRD2) gene: a genetic risk factor in smoking. Pharmacogenetics 1996; 6: 73.

    Article  CAS  PubMed  Google Scholar 

  64. Noble EP, St Jeor ST, Ritchie T, Syndulko K, St Jeor SC, Fitch RJ et al. D2 dopamine receptor gene and cigarette smoking: a reward gene? Med Hypotheses 1994; 42: 257–260.

    Article  CAS  PubMed  Google Scholar 

  65. Spitz MR, Shi H, Yang F, Hudmon KS, Jiang H, Chamberlain RM et al. Case–control study of the D2 dopamine receptor gene and smoking status in lung cancer patients. J Natl Cancer Inst 1998; 90: 353–363.

    Article  Google Scholar 

  66. Wu X, Hudmon KS, Detry MA, Chamberlain RM, Spitz MR . D2 dopamine receptor gene polymorphisms among African-Americans and Mexican-Americans: a lung cancer case–control study. Cancer Epidemiol Biomarkers Prev 2000; 9: 1021–1026.

    CAS  PubMed  Google Scholar 

  67. Erblich J, Lerman C, Self DW, Diaz GA, Bovbjerg DH . Stress-induced cigarette craving: effects of the DRD2 TaqI RFLP and SLC6A3 VNTR polymorphisms. Pharmacogenomics J 2004; 4: 102–109.

    Article  CAS  PubMed  Google Scholar 

  68. Erblich J, Lerman C, Self DW, Diaz GA, Bovbjerg DH . Effects of dopamine D2 receptor (DRD2) and transporter (SLC6A3) polymorphisms on smoking cue-induced cigarette craving among African-American smokers. Mol Psychiatry 2004; 10: 407.

    Article  CAS  Google Scholar 

  69. Johnstone EC, Yudkin P, Griffiths SE, Fuller A, Murphy M, Walton R . The dopamine D2 receptor C32806T polymorphism (DRD2 Taq1A RFLP) exhibits no association with smoking behaviour in a healthy UK population. Addict Biol 2004; 9: 221–226.

    Article  CAS  PubMed  Google Scholar 

  70. Singleton AB, Thomson JH, Morris CM, Court JA, Lloyd S, Cholerton S . Lack of association between the dopamine D2 receptor gene allele DRD2*A1 and cigarette smoking in a United Kingdom population. Pharmacogenetics 1998; 8: 125–128.

    Article  CAS  PubMed  Google Scholar 

  71. Bierut LJ, Rice JP, Edenberg HJ, Goate A, Foroud T, Cloninger CR et al. Family-based study of the association of the dopamine D2 receptor gene (DRD2) with habitual smoking. Am J Med Genet 2000; 90: 299–302.

    Article  CAS  PubMed  Google Scholar 

  72. Berlin I, Covey LS, Jiang H, Hamer D . Lack of effect of D2 dopamine receptor TaqI A polymorphism on smoking cessation. Nicotine Tobacco Res 2005; 7: 725–728.

    Article  CAS  Google Scholar 

  73. Yoshida K, Hamajima N, Kozaki K-i, Saito H, Maeno K, Sugiura T et al. Association between the dopamine D2 receptor A2/A2 genotype and smoking behavior in the Japanese. Cancer Epidemiol Biomarkers Prev 2001; 10: 403–405.

    CAS  PubMed  Google Scholar 

  74. Hamajima N, Ito H, Matsuo K, Saito T, Tajima K, Ando M et al. Association between smoking habits and dopamine receptor D2 taqI A A2 allele in Japanese males: a confirmatory study. J Epidemiol 2002; 12: 297–304.

    Article  PubMed  Google Scholar 

  75. Munafo M, Clark T, Johnstone E, Murphy M, Walton R . The genetic basis for smoking behavior: a systematic review and meta-analysis. Nicotine Tobacco Res 2004; 6: 583–597.

    Article  CAS  Google Scholar 

  76. Smith SS, O’Hara BF, Persico AM, Gorelick DA, Newlin DB, Vlahov D et al. Genetic vulnerability to drug abuse. The D2 dopamine receptor Taq I B1 restriction fragment length polymorphism appears more frequently in polysubstance abusers. Arch Gen Psychiatry 1992; 49: 723–727.

    Article  CAS  PubMed  Google Scholar 

  77. Hauge XY, Grandy DK, Eubanks JH, Evans GA, Civelli O, Litt M . Detection and characterization of additional DNA polymorphisms in the dopamine D2 receptor gene. Genomics 1991; 10: 527–530.

    Article  CAS  PubMed  Google Scholar 

  78. Kidd KK, Morar B, Castiglione CM, Zhao H, Pakstis AJ, Speed WC et al. A global survey of haplotype frequencies and linkage disequilibrium at the DRD2 locus. Hum Genet 1998; 103: 211.

    Article  CAS  PubMed  Google Scholar 

  79. Shields PG, Lerman C, Audrain J, Bowman ED, Main D, Boyd NR et al. Dopamine D4 receptors and the risk of cigarette smoking in African-Americans and Caucasians. Cancer Epidemiol Biomarkers Prev 1998; 7: 453–458.

    CAS  PubMed  Google Scholar 

  80. Hutchison KE, LaChance H, Niaura R, Bryan A, Smolen A . The DRD4 VNTR polymorphism influences reactivity to smoking cues. J Abnorm Psychol 2002; 111: 134–143.

    Article  PubMed  Google Scholar 

  81. Laucht M, Becker K, El-Faddagh M, Hohm E, Schmidt MH . Association of the DRD4 exon III polymorphism with smoking in fifteen-year-olds: a mediating role for novelty seeking? J Am Acad Child Adolesc Psychiatry 2005; 44: 477–484.

    Article  PubMed  Google Scholar 

  82. Huang S, Cook DG, Hinks LJ, Chen XH, Ye S, Gilg JA et al. CYP2A6, MAOA, DBH, DRD4, and 5HT2A genotypes, smoking behaviour and cotinine levels in 1518 UK adolescents. Pharmacogenet Genomics 2005; 15: 839–850.

    Article  CAS  PubMed  Google Scholar 

  83. Comings DE, Gade R, Wu S, Chiu C, Dietz G, Muhleman D et al. Studies of the potential role of the dopamine D1 receptor gene in addictive behaviors. Mol Psychiatry 1997; 2: 44–56.

    Article  CAS  PubMed  Google Scholar 

  84. Le Foll B, Sokoloff P, Stark H, Goldberg SR . Dopamine D3 receptor ligands block nicotine-induced conditioned place preferences through a mechanism that does not involve discriminative-stimulus or antidepressant-like effects. Neuropsychopharmacology 2005; 30: 720–730.

    Article  CAS  PubMed  Google Scholar 

  85. Comings DE, Gonzalez N, Wu S, Saucier G, Johnson P, Verde R et al. Homozygosity at the dopamine DRD3 receptor gene in cocaine dependence. Mol Psychiatry 1999; 4: 484–487.

    Article  CAS  PubMed  Google Scholar 

  86. Arinami T, Ishiguro H, Onaivi ES . Polymorphisms in genes involved in neurotransmission in relation to smoking. Eur J Pharmacol 2000; 410: 215.

    Article  CAS  PubMed  Google Scholar 

  87. Sullivan PF, Neale MC, Silverman MA, Harris-Kerr C, Myakishev MV, Wormley B et al. An association study of DRD5 with smoking initiation and progression to nicotine dependence. Am J Med Genet 2001; 105: 259–265.

    Article  CAS  PubMed  Google Scholar 

  88. VanNess S, Owens M, Kilts C . The variable number of tandem repeats element in DAT1 regulates in vitro dopamine transporter density. BMC Genet 2005; 6: 55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Vandenbergh DJ, Persico AM, Hawkins AL, Griffin CA, Li X, Jabs EW et al. Human dopamine transporter gene (DAT1) maps to chromosome 5p15.3 and displays a VNTR. Genomics 1992; 14: 1104.

    Article  CAS  PubMed  Google Scholar 

  90. Vandenbergh DJ, Persico AM, Uhl GR . A human dopamine transporter cDNA predicts reduced glycosylation, displays a novel repetitive element and provides racially-dimorphic TaqI RFLPs. Mol Brain Res 1992; 15: 161.

    Article  CAS  PubMed  Google Scholar 

  91. Doucette-Stamm LA, Blakely DJ, Tian J, Mockus S, Mao JI . Population genetic study of the human dopamine transporter gene (DAT1). Genet Epidemiol 1995; 12: 303–308.

    Article  CAS  PubMed  Google Scholar 

  92. Mitchell RJ, Howlett S, Earl L, White NG, McComb J, Schanfield MS et al. Distribution of the 3′ VNTR polymorphism in the human dopamine transporter gene in world populations. Hum Biol 2000; 72: 295–304.

    CAS  PubMed  Google Scholar 

  93. Mill J, Asherson P, Craig I, D’Souza U . Transient expression analysis of allelic variants of a VNTR in the dopamine transporter gene (DAT1). BMC Genet 2005; 6: 3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Lerman C, Caporaso NE, Audrain J, Main D, Bowman ED, Lockshin B et al. Evidence suggesting the role of specific genetic factors in cigarette smoking. Health Psychol 1999; 18: 14–20.

    Article  CAS  PubMed  Google Scholar 

  95. Sabol SZ, Nelson ML, Fisher C, Gunzerath L, Brody CL, Hu S et al. A genetic association for cigarette smoking behavior. Health Psychol 1999; 18: 7–13.

    Article  CAS  PubMed  Google Scholar 

  96. Vandenbergh DJ, Bennett CJ, Grant MD, Strasser AA, O’Connor R, Stauffer RL et al. Smoking status and the human dopamine transporter variable number of tandem repeats (VNTR) polymorphism: failure to replicate and finding that never-smokers may be different. Nicotine Tobacco Res 2002; 4: 333–340.

    Article  Google Scholar 

  97. Jorm AF, Henderson AS, Jacomb PA, Christensen H, Korten AE, Rodgers B et al. Association of smoking and personality with a polymorphism of the dopamine transporter gene: results from a community survey. Am J Med Genet 2000; 96: 331–334.

    Article  CAS  PubMed  Google Scholar 

  98. Ling D, Niu T, Feng Y, Xing H, Xu X . Association between polymorphism of the dopamine transporter gene and early smoking onset: an interaction risk on nicotine dependence. J Hum Genet 2004; 49: 35.

    Article  CAS  PubMed  Google Scholar 

  99. Albanese V, Biguet NF, Kiefer H, Bayard E, Mallet J, Meloni R . Quantitative effects on gene silencing by allelic variation at a tetranucleotide microsatellite. Hum Mol Genet 2001; 10: 1785–1792.

    Article  CAS  PubMed  Google Scholar 

  100. Olsson C, Anney R, Forrest S, Patton G, Coffey C, Cameron T et al. Association between dependent smoking and a polymorphism in the tyrosine hydroxylase gene in a prospective population-based study of adolescent health. Behav Genet 2004; 34: 85.

    Article  PubMed  Google Scholar 

  101. Anney RJ, Olsson CA, Lotfi-Miri M, Patton GC, Williamson R . Nicotine dependence in a prospective population-based study of adolescents: the protective role of a functional tyrosine hydroxylase polymorphism. Pharmacogenetics 2004; 14: 73–81.

    Article  CAS  PubMed  Google Scholar 

  102. Lerman C, Shields PG, Main D, Audrain J, Roth J, Boyd NR et al. Lack of association of tyrosine hydroxylase genetic polymorphism with cigarette smoking. Pharmacogenetics 1997; 7: 521–524.

    Article  CAS  PubMed  Google Scholar 

  103. McKinney EF, Walton RT, Yudkin P, Fuller A, Haldar NA, Mant D et al. Association between polymorphisms in dopamine metabolic enzymes and tobacco consumption in smokers. Pharmacogenetics 2000; 10: 483–491.

    Article  CAS  PubMed  Google Scholar 

  104. Johnstone EC, Clark TG, Griffiths SE, Murphy MF, Walton RT . Polymorphisms in dopamine metabolic enzymes and tobacco consumption in smokers: seeking confirmation of the association in a follow-up study. Pharmacogenetics 2002; 12: 585–587.

    Article  PubMed  Google Scholar 

  105. Sabol SZ, Hu S, Hamer D . A functional polymorphism in the monoamine oxidase A gene promoter. Hum Genet 1998; 103: 273.

    Article  CAS  PubMed  Google Scholar 

  106. Ito H, Hamajima N, Matsuo K, Okuma K, Sato S, Ueda R et al. Monoamine oxidase polymorphisms and smoking behaviour in Japanese. Pharmacogenetics 2003; 13: 73–79.

    Article  CAS  PubMed  Google Scholar 

  107. Jin Y, Chen D, Hu Y, Guo S, Sun H, Lu A et al. Association between monoamine oxidase gene polymorphisms and smoking behaviour in Chinese males. Int J Neuropsychopharmacol 2005; 9: 557–564.

    Article  CAS  PubMed  Google Scholar 

  108. Lotta T, Vidgren J, Tilgmann C, Ulmanen I, Melén K, Julkunen I et al. Kinetics of human soluble and membrane-bound catechol O-methyltransferase: a revised mechanism and description of the thermolabile variant of the enzyme. Biochemistry 1995; 34: 4202–4210.

    Article  CAS  PubMed  Google Scholar 

  109. Mannisto PT, Kaakkola S . Catechol-O-methyltransferase (COMT): biochemistry, molecular biology, pharmacology, and clinical efficacy of the new selective COMT inhibitors. Pharmacol Rev 1999; 51: 593–628.

    CAS  PubMed  Google Scholar 

  110. Lachman HM, Papolos DF, Saito T, Yu YM, Szumlanski CL, Weinshilboum RM . Human catechol-O-methyltransferase pharmacogenetics: description of a functional polymorphism and its potential application to neuropsychiatric disorders. Pharmacogenetics 1996; 6: 243–250.

    Article  CAS  PubMed  Google Scholar 

  111. Colilla S, Lerman C, Shields PG, Jepson C, Rukstalis M, Berlin J et al. Association of catechol-O-methyltransferase with smoking cessation in two independent studies of women. Pharmacogenet Genomics 2005; 15: 393–398.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Beuten J, Payne TJ, Ma JZ, Li MD . Significant association of catechol-O-methyltransferase (COMT) haplotypes with nicotine dependence in male and female smokers of two ethnic populations. Neuropsychopharmacology 2006; 31: 675–684.

    Article  CAS  PubMed  Google Scholar 

  113. David SP, Johnstone E, Griffiths SE, Murphy M, Yudkin P, Mant D et al. No association between functional catechol O-methyl transferase 1947A>G polymorphism and smoking initiation, persistent smoking or smoking cessation. Pharmacogenetics 2002; 12: 265–268.

    Article  CAS  PubMed  Google Scholar 

  114. Redden DT, Shields PG, Epstein L, Wileyto EP, Zakharkin SO, Allison DB et al. Catechol-O-methyl-transferase functional polymorphism and nicotine dependence: an evaluation of nonreplicated results. Cancer Epidemiol Biomarkers Prev 2005; 14: 1384–1389.

    Article  CAS  PubMed  Google Scholar 

  115. Porras G, Di Matteo V, Fracasso C, Lucas G, De Deurwaerdere P, Caccia S et al. 5-HT2A and 5-HT2C/2B receptor subtypes modulate dopamine release induced in vivo by amphetamine and morphine in both the rat nucleus accumbens and striatum. Neuropsychopharmacology 2002; 26: 311–324.

    Article  CAS  PubMed  Google Scholar 

  116. Ribeiro EB, Bettiker RL, Bogdanov M, Wurtman RJ . Effects of systemic nicotine on serotonin release in rat brain. Brain Res 1993; 621: 311.

    Article  CAS  PubMed  Google Scholar 

  117. Mihailescu S, Palomero-Rivero M, Meade-Huerta P, Maza-Flores A, Drucker-Colin R . Effects of nicotine and mecamylamine on rat dorsal raphe neurons. Eur J Pharmacol 1998; 360: 31.

    Article  CAS  PubMed  Google Scholar 

  118. Goldman D, Oroszi G, O’Malley S, Anton R . COMBINE genetics study: the pharmacogenetics of alcoholism treatment response: genes and mechanisms. J Stud Alcohol Suppl 2005; 15: 56–64; discussion 33.

    Article  Google Scholar 

  119. Edenberg HJ, Kranzler HR . The contribution of genetics to addiction therapy approaches. Pharmacol Therapeut 2005; 108: 86.

    Article  CAS  Google Scholar 

  120. White KJ, Walline CC, Barker EL . Serotonin transporters: implications for antidepressant drug development. AAPS J 2005; 7: E421–E433.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Courtet P, Jollant F, Castelnau D, Buresi C, Malafosse A . Suicidal behavior: relationship between phenotype and serotonergic genotype. Am J Med Genet C: Semin Med Genet 2005; 133C: 25–33.

    Article  Google Scholar 

  122. Heils A, Teufel A, Petri S, Stober G, Riederer P, Bengel D et al. Allelic variation of human serotonin transporter gene expression. J Neurochem 1996; 66: 2621–2624.

    Article  CAS  PubMed  Google Scholar 

  123. Ishikawa H, Ohtsuki T, Ishiguro H, Yamakawa-Kobayashi K, Endo K, Lin Y-L et al. Association between serotonin transporter gene polymorphism and smoking among Japanese males. Cancer Epidemiol Biomarkers Prev 1999; 8: 831–833.

    CAS  PubMed  Google Scholar 

  124. Kremer I, Bachner-Melman R, Reshef A, Broude L, Nemanov L, Gritsenko I et al. Association of the serotonin transporter gene with smoking behavior. Am J Psychiatry 2005; 162: 924–930.

    Article  PubMed  Google Scholar 

  125. Lerman C, Shields PG, Audrain J, Main D, Cobb B, Boyd NR et al. The role of the serotonin transporter gene in cigarette smoking. Cancer Epidemiol Biomarkers Prev 1998; 7: 253–255.

    CAS  PubMed  Google Scholar 

  126. Trummer O, Koppel H, Wascher TC, Grunbacher G, Gutjahr M, Stanger O et al. The serotonin transporter gene polymorphism is not associated with smoking behavior. Pharmacogenomics J 2006; 6: 397–400.

    Article  CAS  PubMed  Google Scholar 

  127. Gerra G, Garofano L, Zaimovic A, Moi G, Branchi B, Bussandri M et al. Association of the serotonin transporter promoter polymorphism with smoking behavior among adolescents. Am J Med Genet B: Neuropsychiatr Genet 2005; 135B: 73–78.

    Article  CAS  Google Scholar 

  128. Hu S, Brody CL, Fisher C, Gunzerath L, Nelson ML, Sabol SZ et al. Interaction between the serotonin transporter gene and neuroticism in cigarette smoking behavior. Mol Psychiatry 2000; 5: 181–188.

    Article  CAS  PubMed  Google Scholar 

  129. Lerman C, Caporaso NE, Bush A, Zheng YL, Audrain J, Main D et al. Tryptophan hydroxylase gene variant and smoking behavior. Am J Med Genet 2001; 105: 518–520.

    Article  CAS  PubMed  Google Scholar 

  130. Sullivan PF, Jiang Y, Neale MC, Kendler KS, Straub RE . Association of the tryptophan hydroxylase gene with smoking initiation but not progression to nicotine dependence. Am J Med Genet 2001; 105: 479–484.

    Article  CAS  PubMed  Google Scholar 

  131. Reuter M, Hennig J . Pleiotropic effect of the TPH A779C polymorphism on nicotine dependence and personality. Am J Med Genet: Neuropsychiatr Genet 2005; 134B: 20–24.

    Article  CAS  Google Scholar 

  132. Flores CM, Rogers SW, Pabreza LA, Wolfe BB, Kellar KJ . A subtype of nicotinic cholinergic receptor in rat brain is composed of alpha 4 and beta 2 subunits and is up-regulated by chronic nicotine treatment. Mol Pharmacol 1992; 41: 31–37.

    CAS  PubMed  Google Scholar 

  133. Peng X, Gerzanich V, Anand R, Whiting PJ, Lindstrom J . Nicotine-induced increase in neuronal nicotinic receptors results from a decrease in the rate of receptor turnover. Mol Pharmacol 1994; 46: 523–530.

    CAS  PubMed  Google Scholar 

  134. Picciotto MR, Zoli M, Rimondini R, Lena C, Marubio LM, Pich EM et al. Acetylcholine receptors containing the [beta]2 subunit are involved in the reinforcing properties of nicotine. Nature 1998; 391: 173.

    Article  CAS  PubMed  Google Scholar 

  135. Marubio LM, Gardier AM, Durier S, David D, Klink R, Arroyo-Jimenez MM 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.

    Article  CAS  PubMed  Google Scholar 

  136. Tapper AR, McKinney SL, Nashmi R, Schwarz J, Deshpande P, Labarca C et al. Nicotine activation of {alpha}4* receptors: sufficient for reward, tolerance, and sensitization. Science 2004; 306: 1029–1032.

    Article  CAS  PubMed  Google Scholar 

  137. Feng Y, Niu T, Xing H, Xu X, Chen C, Peng S 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Li MD, Beuten J, Ma JZ, Payne TJ, Lou X-Y, Garcia V et al. Ethnic- and gender-specific association of the nicotinic acetylcholine receptor {alpha}4 subunit gene (CHRNA4) with nicotine dependence. Hum Mol Genet 2005; 14: 1211–1219.

    Article  CAS  PubMed  Google Scholar 

  139. Greenbaum L, Kanyas K, Karni O, Merbl Y, Olender T, Horowitz A et al. Why do young women smoke? I. Direct and interactive effects of environment, psychological characteristics and nicotinic cholinergic receptor genes. Mol Psychiatry 2006; 11: 312.

    Article  CAS  PubMed  Google Scholar 

  140. Besson M, David V, Suarez S, Cormier A, Cazala P, Changeux JP et al. Genetic dissociation of two behaviors associated with nicotine addiction: beta-2 containing nicotinic receptors are involved in nicotine reinforcement but not in withdrawal syndrome. Psychopharmacology 2006; 187: 189–199.

    Article  CAS  PubMed  Google Scholar 

  141. Lueders KK, Hu S, McHugh L, Myakishev MV, Sirota LA, Hamer DH . Genetic and functional analysis of single nucleotide polymorphisms in the beta2-neuronal nicotinic acetylcholine receptor gene (CHRNB2). Nicotine Tobacco Res 2002; 4: 115–125.

    Article  CAS  Google Scholar 

  142. Silverman MA, Neale MC, Sullivan PF, Harris-Kerr C, Wormley B, Sadek H et al. Haplotypes of four novel single nucleotide polymorphisms in the nicotinic acetylcholine receptor beta 2-subunit (CHRNB2) gene show no association with smoking initiation or nicotine dependence. Am J Med Genet 2000; 96: 646–653.

    Article  CAS  PubMed  Google Scholar 

  143. Kalman D, Morissette SB, George T . Co-morbidity of smoking in patients with psychiatric and substance use disorders. Am J Addict 2005; 14: 106.

    Article  PubMed  PubMed Central  Google Scholar 

  144. Kumari V, Postma P . Nicotine use in schizophrenia: the self medication hypotheses. Neuroscience Biobehav Rev 2005; 29: 1021.

    Article  CAS  Google Scholar 

  145. Adler LE, Olincy A, Waldo M, Harris JG, Griffith J, Stevens K et al. Schizophrenia, sensory gating, and nicotinic receptors. Schiz Bull 1998; 24: 189–202.

    Article  CAS  Google Scholar 

  146. De Luca V, Wong AHC, Muller DJ, Wong GWH, Tyndale RF, Kennedy JL . Evidence of association between smoking and 7 nicotinic receptor subunit gene in schizophrenia patients. Neuropsychopharmacology 2004; 29: 1522–1526.

    Article  CAS  PubMed  Google Scholar 

  147. Faraone SV, Su J, Taylor L, Wilcox M, van Eerdewegh P, Tsuang MT . A novel permutation testing method implicates sixteen nicotinic acetylcholine receptor genes as risk factors for smoking in schizophrenia families. Hum Hered 2004; 57: 59–68.

    Article  CAS  PubMed  Google Scholar 

  148. Corrigall WA, Coen KM, Adamson KL, Chow BLC, Zhang J . Response of nicotine self-administration in the rat to manipulations of mu-opioid and gamma-aminobutyric acid receptors in the ventral tegmental area. Psychopharmacology 2000; 149: 107.

    Article  CAS  PubMed  Google Scholar 

  149. Beuten J, Ma JZ, Payne TJ, Dupont RT, Crews KM, Somes G et al. Single- and multilocus allelic variants within the GABA B receptor subunit 2 (GABAB2) gene are significantly associated with nicotine dependence. Am J Hum Genet 2005; 76: 859–864.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Berrendero F, Mendizabal V, Robledo P, Galeote L, Bilkei-Gorzo A, Zimmer A et al. Nicotine-induced antinociception, rewarding effects, and physical dependence are decreased in mice lacking the preproenkephalin gene. J Neurosci 2005; 25: 1103–1112.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Walters CL, Cleck JN, Kuo Y-c, Blendy JA . [mu]-opioid receptor and CREB activation are required for nicotine reward. Neuron 2005; 46: 933.

    Article  CAS  PubMed  Google Scholar 

  152. O’Brien CP . Anticraving medications for relapse prevention: a possible new class of psychoactive medications. Am J Psychiatry 2005; 162: 1423–1431.

    Article  PubMed  Google Scholar 

  153. Ismail Z, el-Guebaly N . Nicotine and endogenous opioids: toward specific pharmacotherapy. Can J Psychiatry 1998; 43: 37–42.

    Article  CAS  PubMed  Google Scholar 

  154. Zadina JE, Hackler L, Ge LJ, Kastin AJ . A potent and selective endogenous agonist for the mu-opiate receptor. Nature 1997; 386: 499–502.

    Article  CAS  PubMed  Google Scholar 

  155. Davenport KE, Houdi AA, Van Loon GR . Nicotine protects against mu-opioid receptor antagonism by beta-funaltrexamine: evidence for nicotine-induced release of endogenous opioids in brain. Neurosci Lett 1990; 113: 40–46.

    Article  CAS  PubMed  Google Scholar 

  156. Boyadjieva NI, Sarkar DK . The secretory response of hypothalamic beta-endorphin neurons to acute and chronic nicotine treatments and following nicotine withdrawal. Life Sci 1997; 61: Pl59–P166.

    Article  CAS  PubMed  Google Scholar 

  157. O’Malley SS, Cooney JL, Krishnan-Sarin S, Dubin JA, McKee SA, Cooney NL et al. A controlled trial of naltrexone augmentation of nicotine replacement therapy for smoking cessation. Arch Intern Med 2006; 166: 667–674.

    Article  PubMed  Google Scholar 

  158. Mayer P, Hollt V . Pharmacogenetics of opioid receptors and addiction. Pharmacogenet Genomics 2006; 16: 1–7.

    Article  CAS  PubMed  Google Scholar 

  159. Marx J . Drug development: drugs inspired by a drug. Science 2006; 311: 322–325.

    Article  CAS  PubMed  Google Scholar 

  160. Ballon N, Leroy S, Roy C, Bourdel MC, Charles-Nicolas A, Krebs MO et al. (AAT)n repeat in the cannabinoid receptor gene (CNR1): association with cocaine addiction in an African-Caribbean population. Pharmacogenomics J 2005; 6: 126.

    Article  CAS  Google Scholar 

  161. Chiang KP, Gerber AL, Sipe JC, Cravatt BF . Reduced cellular expression and activity of the P129T mutant of human fatty acid amide hydrolase: evidence for a link between defects in the endocannabinoid system and problem drug use. Hum Mol Genet 2004; 13: 2113–2119.

    Article  CAS  PubMed  Google Scholar 

  162. Sipe JC, Chiang K, Gerber AL, Beutler E, Cravatt BF . A missense mutation in human fatty acid amide hydrolase associated with problem drug use. Proc Natl Acad Sci USA 2002; 99: 8394–8399.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Beuten J, Ma JZ, Payne TJ, Dupont RT, Quezada P, Huang W et al. Significant association of BDNF haplotypes in European-American male smokers but not in European-American female or African-American smokers. Am J Med Genet B: Neuropsychiatr Genet 2005; 139B: 73–80.

    Article  CAS  Google Scholar 

  164. Matsushita S, Kimura M, Miyakawa T, Yoshino A, Murayama M, Masaki T et al. Association study of brain-derived neurotrophic factor gene polymorphism and alcoholism. Alcohol: Clin Exp Res 2004; 28: 1609–1612.

    Article  CAS  Google Scholar 

  165. Liu QR, Walther D, Drgon T, Polesskaya O, Lesnick TG, Strain KJ et al. Human brain derived neurotrophic factor (BDNF) genes, splicing patterns, and assessments of associations with substance abuse and Parkinson's disease. Am J Med Genet B: Neuropsychiatr Genet 2005; 134B: 93–103.

    Article  Google Scholar 

  166. Itoh K, Hashimoto K, Shimizu E, Sekine Y, Ozaki N, Inada T et al. Association study between brain-derived neurotrophic factor gene polymorphisms and methamphetamine abusers in Japan. Am J Med Genet B: Neuropsychiatr Genet 2005; 132B: 70–73.

    Article  Google Scholar 

  167. Benowitz NL, Jacob P . Nicotine renal excretion rate influences nicotine intake during cigarette smoking. J Pharmacol Exp Ther 1985; 234: 153–155.

    CAS  PubMed  Google Scholar 

  168. Benowitz NL, Jacob III P, Kozlowski LT, Yu L . Influence of smoking fewer cigarettes on exposure to tar, nicotine, and carbon monoxide. N Engl J Med 1986; 315: 1310–1313.

    Article  CAS  PubMed  Google Scholar 

  169. Benowitz NL . Pharmacologic aspects of cigarette smoking and nicotine addiction. N Engl J Med 1988; 319: 1318–1329.

    Article  CAS  PubMed  Google Scholar 

  170. Benowitz NL, Jacob Pr . Metabolism of nicotine to cotinine studied by a dual stable isotope method. Clin Pharmacol Ther 1994; 56: 483–493.

    Article  CAS  PubMed  Google Scholar 

  171. Messina ES, Tyndale RF, Sellers EM . A major role for CYP2A6 in nicotine C-oxidation by human liver microsomes. J Pharmacol Exp Ther 1997; 282: 1608–1614.

    CAS  PubMed  Google Scholar 

  172. Nakajima M, Yamamoto T, Nunoya K, Yokoi T, Nagashima K, Inoue K et al. Role of human cytochrome P4502A6 in C-oxidation of nicotine. Drug Metab Dispos 1996; 24: 1212–1217.

    CAS  PubMed  Google Scholar 

  173. Nakajima M, Yamamoto T, Nunoya K, Yokoi T, Nagashima K, Inoue K et al. Characterization of CYP2A6 involved in 3′-hydroxylation of cotinine in human liver microsomes. J Pharmacol Exp Ther 1996; 277: 1010–1015.

    CAS  PubMed  Google Scholar 

  174. Kwon JT, Nakajima M, Chai S, Yom YK, Kim HK, Yamazaki H et al. Nicotine metabolism and CYP2A6 allele frequencies in Koreans. Pharmacogenetics 2001; 11: 317–323.

    Article  CAS  PubMed  Google Scholar 

  175. Schoedel KA, Hoffmann EB, Rao Y, Sellers EM, Tyndale RF . Ethnic variation in CYP2A6 and association of genetically slow nicotine metabolism and smoking in adult Caucasians. Pharmacogenetics 2004; 14: 615–626.

    Article  CAS  PubMed  Google Scholar 

  176. Dempsey D, Tutka P, Jacob III P, Allen F, Schoedel K, Tyndale RF et al. Nicotine metabolite ratio as an index of cytochrome P450 2A6 metabolic activity. Clin Pharmacol Therapeut 2004; 76: 64.

    Article  CAS  Google Scholar 

  177. Nakajima M, Yokoi T . Interindividual variability in nicotine metabolism: C-oxidation and glucuronidation. Drug Metab Pharmacokinetics 2005; 20: 227–235.

    Article  CAS  Google Scholar 

  178. Nakajima M, Kwon J-T, Tanaka N, Zenta T, Yamamoto Y, Yamamoto H et al. Relationship between interindividual differences in nicotine metabolism and CYP2A6 genetic polymorphism in humans. Clin Pharmacol Therapeut 2001; 69: 72.

    Article  CAS  Google Scholar 

  179. Nakajima M, Yamagishi S-i, Yamamoto H, Yamamoto T, Kuroiwa Y, Yokoi T . Deficient cotinine formation from nicotine is attributed to the whole deletion of the CYP2A6 gene in humans. Clin Pharmacol Therapeut 2000; 67: 57.

    Article  CAS  Google Scholar 

  180. Tyndale RF, Sellers EM . Variable CYP2A6-mediated nicotine metabolism alters smoking behavior and risk. Drug Metab Dispos 2001; 29: 548–552.

    CAS  PubMed  Google Scholar 

  181. Pianezza ML, Sellers EM, Tyndale RF . Nicotine metabolism defect reduces smoking. Nature 1998; 393: 750.

    Article  CAS  PubMed  Google Scholar 

  182. Minematsu N, Nakamura H, Furuuchi M, Nakajima T, Takahashi S, Tateno H et al. Limitation of cigarette consumption by CYP2A6*4, *7 and *9 polymorphisms. Eur Resp J 2006; 27: 289–292.

    Article  CAS  Google Scholar 

  183. Malaiyandi V, Lerman C, Benowitz NL, Jepson C, Patterson F, Tyndale RF . Impact of CYP2A6 genotype on pretreatment smoking behaviour and nicotine levels from and usage of nicotine replacement therapy. Mol Psychiatry 2006; 11: 400.

    Article  CAS  PubMed  Google Scholar 

  184. Fujieda M, Yamazaki H, Saito T, Kiyotani K, Gyamfi MA, Sakurai M et al. Evaluation of CYP2A6 genetic polymorphisms as determinants of smoking behavior and tobacco-related lung cancer risk in male Japanese smokers. Carcinogenesis 2004; 25: 2451–2458.

    Article  CAS  PubMed  Google Scholar 

  185. Rao Y, Hoffmann E, Zia M, Bodin L, Zeman M, Sellers EM et al. Duplications and defects in the CYP2A6 gene: identification, genotyping, and in vivo effects on smoking. Mol Pharmacol 2000; 58: 747–755.

    Article  CAS  PubMed  Google Scholar 

  186. O’Loughlin J, Paradis G, Kim W, DiFranza J, Meshefedjian G, McMillan-Davey E et al. Genetically decreased CYP2A6 and the risk of tobacco dependence: a prospective study of novice smokers. Tob Control 2004; 13: 422–428.

    Article  PubMed  PubMed Central  Google Scholar 

  187. Strasser AA, Malaiyandi V, Hoffmann E, Tyndale RF, Lerman C . An association of CYP2A6 genotype and smoking topography. Nicotine Tobacco Res 2007 (in press).

  188. Kubota T, Nakajima-Taniguchi C, Fukuda T, Funamoto M, Maeda M, Tange E et al. CYP2A6 polymorphisms are associated with nicotine dependence and influence withdrawal symptoms in smoking cessation. Pharmacogenomics J 2006; 6: 115.

    Article  CAS  PubMed  Google Scholar 

  189. Gu DF, Hinks LJ, Morton NE, Day INM . The use of long PCR to confirm three common alleles at the CYP2A6 locus and the relationship between genotype and smoking habit. Ann Hum Genet 2000; 64: 383–390.

    Article  CAS  PubMed  Google Scholar 

  190. Sellers EM, Kaplan HL, Tyndale RF . Inhibition of cytochrome P450 2A6 increases nicotine's oral bioavailability and decreases smoking. Clin Pharmacol Therapeut 2000; 68: 35.

    Article  CAS  Google Scholar 

  191. Duescher RJ, Elfarra AA . Human liver microsomes are efficient catalysts of 1,3-butadiene oxidation: evidence for major roles by cytochromes P450 2A6 and 2E1. Arch Biochem Biophys 1994; 311: 342.

    Article  CAS  PubMed  Google Scholar 

  192. Hecht SS, Hoffmann D . The relevance of tobacco-specific nitrosamines to human cancer. Cancer Surv 1989; 8: 273–294.

    CAS  PubMed  Google Scholar 

  193. Sellers E, Ramamoorthy Y, Zeman M, Djordjevic M, Tyndale R . The effect of methoxsalen on nicotine and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) metabolism in vivo. Nicotine Tobacco Res 2003; 5: 891.

    Article  CAS  Google Scholar 

  194. Kamataki T, Fujieda M, Kiyotani K, Iwano S, Kunitoh H . Genetic polymorphism of CYP2A6 as one of the potential determinants of tobacco-related cancer risk. Biochem Biophys Res Commun 2005; 338: 306.

    Article  CAS  PubMed  Google Scholar 

  195. Tan W, Chen GF, Xing DY, Song CY, Kadlubar FF, Lin DX . Frequency of CYP2A6 gene deletion and its relation to risk of lung and esophageal cancer in the Chinese population. Int J Cancer 2001; 95: 96–101.

    Article  CAS  PubMed  Google Scholar 

  196. Ariyoshi N, Miyamoto M, Umetsu Y, Kunitoh H, Dosaka-Akita H, Sawamura Y-i et al. Genetic polymorphism of CYP2A6 gene and tobacco-induced lung cancer risk in male smokers. Cancer Epidemiol Biomarkers Prev 2002; 11: 890–894.

    CAS  PubMed  Google Scholar 

  197. Zhang X, Amemo K, Ameno S, Iwahashi K, Kinoshita H, Kubota T et al. Lack of association between smoking and CYP2A6 gene polymorphisms in A Japanese population. Nihon Arukoru Yakubutsu Igakkai Zasshi 2001; 36: 486–490.

    CAS  PubMed  Google Scholar 

  198. Ando M, Hamajima N, Ariyoshi N, Kamataki T, Matsuo K, Ohno Y . Association of CYP2A6 gene deletion with cigarette smoking status in Japanese adults. J Epidemiol 2003; 13: 176–181.

    Article  PubMed  Google Scholar 

  199. Loriot MA, Rebuissou S, Oscarson M, Cenee S, Miyamoto M, Ariyoshi N et al. Genetic polymorphisms of cytochrome P450 2A6 in a case–control study on lung cancer in a French population. Pharmacogenetics 2001; 11: 39–44.

    Article  CAS  PubMed  Google Scholar 

  200. London SJ, Idle JR, Daly AK, Coetzee GA . Genetic variation of CYP2A6, smoking, and risk of cancer. Lancet 1999; 353: 898.

    Article  CAS  PubMed  Google Scholar 

  201. Carter B, Long T, Cinciripini P . A meta-analytic review of the CYP2A6 genotype and smoking behavior. Nicotine Tobacco Res 2004; 6: 221.

    Article  CAS  Google Scholar 

  202. Munafo M, Clark T, Johnstone E, Murphy M, Walton R . The genetic basis for smoking behavior: a systematic review and meta-analysis. Nicotine Tobacco Res 2004; 6: 583.

    Article  CAS  Google Scholar 

  203. Vandenbergh DJ, Bennett CJ, Grant MD, Strasser AA, O’Connor R, Stauffer RL et al. DAT's not all, but it may be more than we realize. Nicotine Tobacco Res 2002; 4: 251.

    Article  Google Scholar 

  204. Lerman C, Swan GE . Non-replication of genetic association studies: is DAT all, folks? Nicotine Tobacco Res 2002; 4: 247–249.

    Article  Google Scholar 

  205. Balfour D . The neurobiology of tobacco dependence: a preclinical perspective on the role of the dopamine projections to the nucleus accumbens. Nicotine Tobacco Res 2004; 6: 899–912.

    Article  CAS  Google Scholar 

  206. Slemmer JE, Martin BR, Damaj MI . Bupropion is a nicotinic antagonist. J Pharmacol Exp Therapeut 2000; 295: 321.

    CAS  Google Scholar 

  207. Ascher JA, Cole JO, Colin JN, Feighner JP, Ferris RM, Fibiger HC et al. Bupropion: a review of its mechanism of antidepressant activity. J Clin Psychiatry 1995; 56 (Suppl 7): 395.

    CAS  PubMed  Google Scholar 

  208. Fryer JD, Lukas RJ . Noncompetitive functional inhibition at diverse, human nicotinic acetylcholine receptor subtypes by bupropion, phencyclidine, and ibogaine. J Pharmacol Exp Therapeut 1999; 288: 88.

    CAS  Google Scholar 

  209. Lee AM, Tyndale RF . Drugs and genotypes: how pharmacogenetic information could improve smoking cessation treatment. J Psychopharmacol 2006; 20 (Suppl 4): 7–14.

    Article  PubMed  Google Scholar 

  210. Munafo MR, Shields AE, Berrettini WH, Patterson F, Lerman C . Pharmacogenetics and nicotine addiction treatment. Pharmacogenomics 2005; 6: 211–223.

    Article  CAS  PubMed  Google Scholar 

  211. Johnstone EC, Yudkin PL, Hey K, Roberts SJ, Welch SJ, Murphy MF et al. Genetic variation in dopaminergic pathways and short-term effectiveness of the nicotine patch. Pharmacogenetics 2004; 14: 83–90.

    Article  CAS  PubMed  Google Scholar 

  212. Yudkin P, Munafo M, Hey K, Roberts S, Welch S, Johnstone E et al. Effectiveness of nicotine patches in relation to genotype in women versus men: randomised controlled trial. BMJ 2004; 328: 989–990.

    Article  PubMed  PubMed Central  Google Scholar 

  213. Swan GE, Valdes AM, Ring HZ, Khroyan TV, Jack LM, Ton CC et al. Dopamine receptor DRD2 genotype and smoking cessation outcome following treatment with bupropion SR. Pharmacogenomics J 2005; 5: 21–29.

    Article  CAS  PubMed  Google Scholar 

  214. David SP, Niaura R, Papandonatos GD, Shadel WG, Burkholder GJ, Britt DM et al. Does the DRD2-Taq1 A polymorphism influence treatment response to bupropion hydrochloride for reduction of the nicotine withdrawal syndrome? Nicotine Tobacco Res 2003; 5: 935–942.

    Article  CAS  Google Scholar 

  215. Arinami T, Gao M, Hamaguchi H, Toru M . A functional polymorphism in the promoter region of the dopamine D2 receptor gene is associated with schizophrenia. Hum Mol Genet 1997; 6: 577–582.

    Article  CAS  PubMed  Google Scholar 

  216. Lerman C, Jepson C, Wileyto EP, Epstein LH, Rukstalis M, Patterson F et al. Role of functional genetic variation in the dopamine D2 receptor (DRD2) in response to bupropion and nicotine replacement therapy for tobacco dependence: results of two randomized clinical trials. Neuropsychopharmacology 2006; 31: 231–242.

    Article  CAS  PubMed  Google Scholar 

  217. Munafo MR, Johnstone EC, Wileyto EP, Shields PG, Elliot KM, Lerman C . Lack of association of 5-HTTLPR genotype with smoking cessation in a Nicotine Replacement Therapy Randomized Trial. Cancer Epidemiol Biomarkers Prev 2006; 15: 398–400.

    Article  CAS  PubMed  Google Scholar 

  218. Lerman C, Wileyto EP, Patterson F, Rukstalis M, Audrain-McGovern J, Restine S et al. The functional mu opioid receptor (OPRM1) Asn40Asp variant predicts short-term response to nicotine replacement therapy in a clinical trial. Pharmacogenomics J 2004; 4: 184–192.

    Article  CAS  PubMed  Google Scholar 

  219. Jefferson JW, Pradko JF, Muir KT . Bupropion for major depressive disorder: pharmacokinetic and formulation considerations. Clin Therapeut 2005; 27: 1685.

    Article  CAS  Google Scholar 

  220. Hesse LM, Venkatakrishnan K, Court MH, von Moltke LL, Duan SX, Shader RI et al. CYP2B6 mediates the in vitro hydroxylation of bupropion: potential drug interactions with other antidepressants. Drug Metab Dispos 2000; 28: 1176–1183.

    CAS  PubMed  Google Scholar 

  221. Lerman C, Shields PG, Wileyto EP, Audrain J, Pinto A, Hawk L et al. Pharmacogenetic investigation of smoking cessation treatment. Pharmacogenetics 2002; 12: 627–634.

    Article  CAS  PubMed  Google Scholar 

  222. Lang T, Klein K, Fischer J, Nussler AK, Neuhaus P, Hofmann U et al. Extensive genetic polymorphism in the human CYP2B6 gene with impact on expression and function in human liver. Pharmacogenetics 2001; 11: 399–415.

    Article  CAS  PubMed  Google Scholar 

  223. Collins B, Wileyto P, Patterson F, Rukstalis M, Audrain-McGovern J, Kaufmann V et al. Gender differences in smoking cessation in a placebo-controlled trial of bupropion with behavioral counseling. Nicotine Tobacco Res 2004; 6: 27.

    Article  CAS  Google Scholar 

  224. Yamazaki H, Inoue K, Hashimoto M, Shimada T . Roles of CYP2A6 and CYP2B6 in nicotine C-oxidation by human liver microsomes. Arch Toxicol 1999; 73: 65.

    Article  CAS  PubMed  Google Scholar 

  225. Miksys S, Lerman C, Shields PG, Mash DC, Tyndale RF . Smoking, alcoholism and genetic polymorphisms alter CYP2B6 levels in human brain. Neuropharmacology 2003; 45: 122.

    Article  CAS  PubMed  Google Scholar 

  226. Yamanaka H, Nakajima M, Fukami T, Sakai H, Nakamura A, Katoh M et al. CYP2A6 and CYP2B6 are involved in nornicotine formation from nicotine in humans: interindividual differences in these contributions. Drug Metab Dispos 2005; 33: 1811–1818.

    CAS  PubMed  Google Scholar 

  227. Lerman C, Tyndale R, Patterson F, Wileyto EP, Shields PG, Pinto A et al. Nicotine metabolite ratio predicts efficacy of transdermal nicotine for smoking cessation. Clin Pharmacol Ther 2006; 79: 600–608.

    Article  CAS  PubMed  Google Scholar 

  228. World Health Organization. The World Health Report 2002 – Reducing Risks, Promoting Healthy Life, Chapter 4: Substance Abuse. 2002 [cited June 19, 2006]; Available from: http://www.who.int/whr/2002/chapter4/en/index6.html.

  229. Snedecor SM, Mehringer AM, Marks JL, Pomerleau CS . Development and validation of a self-rated DSM-based scale for assessing nicotine dependence. In: Annual Meeeting of the Society for Research on Nicotine and Tobacco. Scottsdale, Arizona, 2004.

    Google Scholar 

  230. Bergen AW, Korczak JF, Weissbecker KA, Goldstein A . A genome-wide search for loci contributing to smoking and alcoholism. Genet Epidemiol 1999; 17 (Suppl 1): S55–S60.

    Article  PubMed  Google Scholar 

  231. Lander E, Kruglyak L . Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results. Nat Genet 1995; 11: 241–247.

    Article  CAS  PubMed  Google Scholar 

  232. Wang D, Ma JZ, Li MD . Mapping and verification of susceptibility loci for smoking quantity using permutation linkage analysis. Pharmacogenomics J 2005; 5: 166–172.

    Article  CAS  PubMed  Google Scholar 

  233. Audrain-McGovern J, Lerman C, Wileyto EP, Rodriguez D, Shields PG . Interacting effects of genetic predisposition and depression on adolescent smoking progression. Am J Psychiatry 2004; 161: 1224–1230.

    Article  PubMed  Google Scholar 

  234. Costa-Mallen P, Costa LG, Checkoway H . Genotype combinations for monoamine oxidase-B intron 13 polymorphism and dopamine D2 receptor TaqIB polymorphism are associated with ever-smoking status among men. Neurosci Lett 2005; 385: 158.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by CIHR Grant MOP 53248, an NSERC CGS-M Scholarship (MKH) and a Canada Research Chair in Pharmacogenetics (RFT).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to R F Tyndale.

Additional information

Duality of Interest

RFT is a shareholder in Nicogen, a company focused on novel smoking cessation treatments.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ho, M., Tyndale, R. Overview of the pharmacogenomics of cigarette smoking. Pharmacogenomics J 7, 81–98 (2007). https://doi.org/10.1038/sj.tpj.6500436

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.tpj.6500436

Keywords

This article is cited by

Search

Quick links