The Role of Genetics in Nicotine Dependence: Mapping the Pathways from Genome to Syndrome
Tóm tắt
Nicotine dependence continues to be a major public health problem worldwide and there is unequivocal evidence that genetics play a substantial role in its etiology. This review provides an overview of the evidence for genetic influences and recent advances in the field. Traditional quantitative genetics studies have revealed nicotine dependence is heritable and molecular genetics studies are providing increasing evidence that the genes responsible for nicotine’s pharmacokinetics and pharmacodynamics are particularly important. Despite considerable progress, a number of significant complexities and challenges remain. These include determining the specificity of genetic influences and clarifying the role of interactive contributions. One promising strategy for addressing these issues is an intermediate phenotype approach that attempts to identify the intervening proximal mechanisms that confer differential genetic risk. Understanding these mechanisms may permit more precision in understanding genetic influences and may also identify novel targets for intervention or prevention.
Tài liệu tham khảo
World Health Organization: World Health Organization Statistics Report - 2008. Geneva, Switzerland: World Health Organization Press; 2008.
Center for Disease Control: Smoking-attributable mortality, years of potential life lost, and productivity losses—United States, 2000–2004. MMWR Morb Mortal Wkly Rep 2008, 57:1226–1228.
Henningfield JE, Miyasato K, Jasinski DR: Abuse liability and pharmacodynamic characteristics of intravenous and inhaled nicotine. J Pharmacol Exp Ther 1985, 234:1–12.
•• Rose RJ, et al.: Genetics of smoking behavior. In Handbook of Behavior Genetics. Edited by Kim YK. New York: Springer; 2009:411–442. This chapter provides a full review of the quantitative genetic findings using twin methodologies.
Li MD, et al.: A meta-analysis of estimated genetic and environmental effects on smoking behavior in male and female adult twins. Addiction 2003, 98:23–31.
Morley KI, et al.: Exploring the inter-relationship of smoking age-at-onset, cigarette consumption and smoking persistence: genes or environment? Psychol Med 2007, 37:1357–1367.
Hamilton AS, et al.: Gender differences in determinants of smoking initiation and persistence in California twins. Cancer Epidemiol Biomarkers Prev 2006, 15:1189–1197.
Mwenifumbo JC, Tyndale RF: Molecular genetics of nicotine metabolism. Handbook Exp Pharmacol 2009, 192:235–259.
Swan GE, et al.: Nicotine metabolism: the impact of CYP2A6 on estimates of additive genetic influence. Pharmacogenet Genomics 2005, 15:115–125.
Mwenifumbo JC, Sellers EM, Tyndale RF: Nicotine metabolism and CYP2A6 activity in a population of black African descent: impact of gender and light smoking. Drug Alcohol Depend 2007, 89:24–33.
Malaiyandi V, et al.: CYP2A6 genotype, phenotype, and the use of nicotine metabolites as biomarkers during ad libitum smoking. Cancer Epidemiol Biomarkers Prev 2006, 15:1812–1819.
Schoedel KA, et al.: Ethnic variation in CYP2A6 and association of genetically slow nicotine metabolism and smoking in adult Caucasians. Pharmacogenetics 2004, 14:615–626.
Strasser AA, et al.: An association of CYP2A6 genotype and smoking topography. Nicotine Tob Res 2007, 9:511–518.
Munafò M, et al.: The genetic basis for smoking behavior: a systematic review and meta-analysis. Nicotine Tob Res 2004, 6:583–597.
Lee AM, et al.: CYP2B6 genotype alters abstinence rates in a bupropion smoking cessation trial. Biol Psychiatry 2007, 62:635–641.
Lee AM, et al.: CYP2B6 genotype does not alter nicotine metabolism, plasma levels, or abstinence with nicotine replacement therapy. Cancer Epidemiol Biomarkers Prev 2007, 16:1312–1314.
Ring HZ, et al.: Gene-gene interactions between CYP2B6 and CYP2A6 in nicotine metabolism. Pharmacogenet Genomics 2007, 17:1007–1015.
Yamanaka H, et al.: Metabolic profile of nicotine in subjects whose CYP2A6 gene is deleted. Eur J Pharm Sci 2004, 22:419–425.
Chen G, et al.: Glucuronidation of nicotine and cotinine by UGT2B10: loss of function by the UGT2B10 Codon 67 (Asp>Tyr) polymorphism. Cancer Res 2007, 67:9024–9029.
Benowitz NL: Neurobiology of nicotine addiction: implications for smoking cessation treatment. Am J Med 2008, 121(4 Suppl 1):S3–S10.
Berridge KC: The debate over dopamine’s role in reward: the case for incentive salience. Psychopharmacology (Berl) 2007, 191:391–431.
Tapper AR, et al.: Nicotine activation of alpha4* receptors: sufficient for reward, tolerance, and sensitization. Science 2004, 306:1029–1032.
Brody AL, et al.: Cigarette smoking saturates brain alpha 4 beta 2 nicotinic acetylcholine receptors. Arch Gen Psychiatry 2006, 63:907–915.
•• Hutchison KE, et al.: CHRNA4 and tobacco dependence: from gene regulation to treatment outcome. Arch Gen Psychiatry 2007, 64:1078–1086. This article uses an intermediate phenotype approach to clarify the role of CHRNA4 polymorphisms in nicotine dependence on multiple levels of analysis.
Bierut LJ, et al.: Variants in nicotinic receptors and risk for nicotine dependence. Am J Psychiatry 2008, 165:1163–1171.
Baker TB, et al.: Human neuronal acetylcholine receptor A5-A3-B4 haplotypes are associated with multiple nicotine dependence phenotypes. Nicotine Tob Res 2009, 11:785–796.
•• Saccone NL, et al.: Multiple independent loci at chromosome 15q25.1 affect smoking quantity: a meta-analysis and comparison with lung cancer and COPD. PLoS Genet 2010 (in press). This meta-analysis reveals a highly significant association of cholinergic loci with smoking in a sample of over 38,000 individuals.
Beuten J, et al.: 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.
McKinney EF, et al.: Association between polymorphisms in dopamine metabolic enzymes and tobacco consumption in smokers. Pharmacogenetics 2000, 10:483–491.
Huang W, et al.: Significant association of ANKK1 and detection of a functional polymorphism with nicotine dependence in an African-American sample. Neuropsychopharmacology 2009, 34:319–330.
Huang W, et al.: A functional polymorphism, rs6280, in DRD3 is significantly associated with nicotine dependence in European-American smokers. Am J Med Genet B Neuropsychiatr Genet 2008, 147B:1109–1115.
Hutchison KE, et al.: The DRD4 VNTR polymorphism influences reactivity to smoking cues. J Abnorm Psychol 2002, 111:134–143.
Vandenbergh DJ, et al.: Dopamine receptor genes (DRD2, DRD3 and DRD4) and gene-gene interactions associated with smoking-related behaviors. Addict Biol 2007, 12:106–116.
David SP, Munafò MR: Genetic variation in the dopamine pathway and smoking cessation. Pharmacogenomics 2008, 9:1307–1321.
Zhang L, Kendler KS, Chen X: The mu-opioid receptor gene and smoking initiation and nicotine dependence. Behav Brain Funct 2006, 2:28.
Ray R, et al.: Association of OPRM1 A118G variant with the relative reinforcing value of nicotine. Psychopharmacology (Berl) 2006, 188:355–363.
Munafò MR, et al.: Association of the mu-opioid receptor gene with smoking cessation. Pharmacogenomics J 2007, 7:353–361.
Uhl GR, et al.: Molecular genetics of successful smoking cessation: convergent genome-wide association study results. Arch Gen Psychiatry 2008, 65:683–693.
Hutchison KE, et al.: Population stratification in the candidate gene study: fatal threat or red herring? Psychol Bull 2004, 130:66–79.
Grant BF, et al.: Nicotine dependence and psychiatric disorders in the United States: results from the national epidemiologic survey on alcohol and related conditions. Arch Gen Psychiatry 2004, 61:1107–1115.
Kendler KS, et al.: The structure of genetic and environmental risk factors for common psychiatric and substance use disorders in men and women. Arch Gen Psychiatry 2003, 60:929–937.
Kendler KS, Myers J, Prescott CA: Specificity of genetic and environmental risk factors for symptoms of cannabis, cocaine, alcohol, caffeine, and nicotine dependence. Arch Gen Psychiatry 2007, 64:1313–1320.
Eisenberg DT, et al.: Examining impulsivity as an endophenotype using a behavioral approach: a DRD2 TaqI A and DRD4 48-bp VNTR association study. Behav Brain Funct 2007, 3:2.
Gelernter J, et al.: Haplotype spanning TTC12 and ANKK1, flanked by the DRD2 and NCAM1 loci, is strongly associated to nicotine dependence in two distinct American populations. Hum Mol Genet 2006, 15:3498–3507.
Schmid B, et al.: The interaction between the dopamine transporter gene and age at onset in relation to tobacco and alcohol use among 19-year-olds. Addict Biol 2009, 14: 489–499.
Perkins KA, et al.: Dopamine and opioid gene variants are associated with increased smoking reward and reinforcement owing to negative mood. Behav Pharmacol 2008, 19:641–649.
Renthal W, Nestler EJ: Epigenetic mechanisms in drug addiction. Trends Mol Med 2008, 14:341–350.
Launay JM, et al.: Smoking induces long-lasting effects through a monoamine-oxidase epigenetic regulation. PLoS One 2009, 4:e7959.
Pembrey ME, et al.: Sex-specific, male-line transgenerational responses in humans. Eur J Hum Genet 2006, 14:159–166.
Flint J, Munafò MR: The endophenotype concept in psychiatric genetics. Psychol Med 2007, 37:163–180.