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Genetics of Tobacco Use

By Nancy Nairi Maserejian and Athanasios I Zavras


The worldwide prevalence of tobacco use is widespread, resulting in nearly 4.5 million deaths every year. Nicotine is addictive and has psychopharmacological effects that maintain the use of tobacco products. Several studies have documented a strong hereditary component to tobacco use. The present article reviews results from twin and adoption studies and proceeds to present association studies of specific genes that may be involved in tobacco use. Cholinergic receptor nicotinic beta polypeptide 2, serotonin receptor and transporter genes, dopamine receptor and transporter genes, and the cytochrome P450A6 gene are reviewed. Linkage studies help to identify regions of the genome that may be worth further investigation. The paper concludes with a discussion of the limitations of genetic research and the future of genetic epidemiology in this domain

Topics: Review
Publisher: BioMed Central
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Provided by: PubMed Central

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  1. (1997). 5-HT2C (HTR2C) serotonin receptor gene polymorphism associated with the human personality trait of reward dependence: interaction with dopamine D4 receptor (D4DR) and dopamine D3 receptor (D3DR) polymorphisms.
  2. (1999). A genetic association for cigarette smoking behavior. Health Psychology
  3. (1999). A genome-wide search for loci contributing to smoking and alcoholism. Genetic Epidemiology
  4. (1997). A major role for CYP2A6 in nicotine C-oxidation by human liver microsomes.
  5. (1999). A population-based twin study in women of smoking initiation and nicotine dependence. Psychological Medicine
  6. (1999). A twin study of drinking and smoking onset and latencies from first use to regular use. Behavior Genetics
  7. (1993). Abnormal behavior associated with a point mutation in the structural gene for monoamine oxidase A. Science
  8. (1999). Aggression and angerrelated traits associated with a polymorphism of the tryptophan hydroxylase gene. Biological Psychiatry
  9. (1991). Allelic association of the D2 dopamine receptor gene with receptor- binding characteristics in alcoholism. Archives of General Psychiatry
  10. (2002). Annual Smoking-Attributable Mortality, Years of Potential Life Lost, and Economic Costs – United States, 1995-1999. Centers for Disease Control and Prevention. Morbidity and Mortality Weekly Report
  11. (2002). Applying genetic approaches to the treatment of nicotine dependence. Oncogene
  12. (2000). Association between polymorphisms in dopamine metabolic enzymes and tobacco consumption in smokers. Pharmacogenetics
  13. (1999). Association between serotonin transporter gene polymorphism and smoking among Japanese males. Cancer Cancer Epidemiolgy, Biomarkers & Prevention
  14. (2001). Association between the dopamine D2 receptor A2/A2 genotype and smoking behavior in the Japanese. Cancer Epidemiolgy, Biomarkers & Prevention
  15. (1996). Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region. Science
  16. (2001). Association of the tryptophan hydroxylase gene with smoking initiation but not progression to nicotine dependence.
  17. (2002). Attenuation of nicotine-induced antinociception, rewarding effects, and dependence in mu-opioid receptor knock-out mice.
  18. (1997). Behavior of boys in kindergarten and the onset of substance use during adolescence. Archives of General Psychiatry
  19. (1999). Benefits and pitfalls encountered in psychiatric genetic association studies. Biological Psychiatry
  20. (1996). Brain monoamine oxidase A inhibition in cigarette smokers.
  21. (2004). Candidate genes for nicotine dependence via linkage, epistasis, and bioinformatics.
  22. (1998). Case-control study of the D2 dopamine receptor gene and smoking status in lung cancer patients.
  23. (2001). Changes in brain activation associated with reward processing in smokers and nonsmokers. A positron emission tomography study. Experimental Brain Research.
  24. (2003). Characterisation of genetic variation in the human dopamine transporter gene and its relevance to smoking behavior. Abstract presented at Society for Research on Nicotine and Tobacco
  25. (2001). Characterization of the genomic structure of the human neuronal nicotinic acetylcholine receptor CHRNA5/A3/B4 gene cluster and identification of novel intragenic polymorphisms.
  26. Cigarette smoking among adults –
  27. (1986). Cigarette withdrawal symptoms in adolescent smokers. Psychopharmacology
  28. (1991). Cloning of the gene for a human dopamine D4 receptor with high affinity for the antipsychotic clozapine. Nature
  29. (1992). Comparison of a novel thin-layer chromatographic-fluorescence detection method with a spectrofluorometric method for the determination of 7- hydroxycoumarin in human urine.
  30. (2001). Countries to Prevent a Tobacco Epidemic Among Women and Girls. World Health Organization Press Release
  31. (1999). CYP2A6 gene deletion reduces susceptibility to lung cancer.
  32. (1997). D2 dopamine receptor gene (DRD2) Taq1 A polymorphism: reduced dopamine D2 receptor binding in the human striatum associated with the A1 allele. Pharmacogenetics
  33. (1994). D2 dopamine receptor gene and cigarette smoking: a reward gene? Medical Hypotheses
  34. (2003). D2 dopamine receptor gene in psychiatric and neurologic disorders and its phenotypes.
  35. (2000). D2 dopamine receptor gene polymorphisms among African-Americans and MexicanGenetics of Tobacco Use 99Americans: a lung cancer case-control study. Cancer Epidemiolgy, Biomarkers & Prevention
  36. (1984). Daily intake of nicotine during cigarette smoking. Clinical Pharmacology and Therapeutics
  37. (2002). DAT's not all, but it may be more than we realize.
  38. (1998). Depression and self-medication with nicotine: the modifying influence of the dopamine D4 receptor gene. Health Psychology
  39. (1990). Depression and the dynamics of smoking. A national perspective.
  40. (2002). Disease Control and Prevention. Morbidity and Mortality Weekly Report
  41. (2003). Does the DRD2-Taq1 A polymorphism influence treatment response to bupropion hydrochloride for reduction of the nicotine withdrawal syndrome? Nicotine & Tobacco Research
  42. (1998). Dopamine D4 receptors and the risk of cigarette smoking in African-Americans and Caucasians. Cancer Epidemiology, Biomarkers and Prevention
  43. (2003). Dopamine receptor DRD2 genotype and smoking cessation outcome following treatment with bupropion SR.
  44. (2003). Down-regulation of hepatic nicotine metabolism and a CYP2A6-like enzyme in African green monkeys after long-term nicotine administration. Molecular Pharmacology
  45. (2000). Duplications and defects in the CYP2A6 gene: identification, genotyping, and in vivo effects on smoking. Molecular Pharmacology
  46. (2004). Effects of dopamine receptor D4 variation on alcohol and tobacco use and on novelty seeking: multivariate linkage and association analysis.
  47. (1998). Effects of nicotine and mecamylamine on rat dorsal raphe neurons.
  48. (1993). Effects of systemic nicotine on serotonin release in rat brain.
  49. (2003). Elucidating the role of genetic factors in smoking behavior and nicotine dependence.
  50. (2003). Epidemiology of cigarette smoking and cessation.
  51. (1997). Estrogen differentially modulates nicotine-evoked dopamine release from the striatum of male and female rats. Neuroscience Letters
  52. (1999). Ethnic differences in Nglucuronidation of nicotine and cotinine.
  53. (1996). Ethnicrelated differences in coumarin 7-hydroxylation activities catalyzed by cytochrome P4502A6 in liver microsomes of Japanese and Caucasian populations. Xenobiotica
  54. (2001). Evaluation of methoxsalen, tranylcypromine, and tryptamine as specific and selective CYP2A6 inhibitors in vitro. Drug Metabolism and Disposition
  55. (1999). Evidence suggesting the role of specific genetic factors in cigarette smoking. Health Psychology
  56. (2000). Familybased study of the association of the dopamine D2 receptor gene (DRD2) with habitual smoking.
  57. (2002). Gender differences in tobacco smoking: higher relative exposure to smoke than nicotine in women.
  58. (2003). Gender-specific molecular heterosis and association studies: Dopamine D2 receptor gene and smoking.
  59. (1999). Genetic and social determinants of initiation and age at onset of smoking in Australian twins. Behavior Genetics
  60. (2001). Genetic association studies of alcoholism–problems with the candidate gene approach. Alcohol and Alcoholism
  61. (1995). Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results. Nature Genetics
  62. (2000). Genetic Influences in Drug Abuse.
  63. (2001). Genetic polymorphisms in the cytochrome P450 2A6 (CYP2A6) gene: implications for interindividual differences in nicotine metabolism. Drug Metabolism and Disposition
  64. (2002). Genetic variation in CYP2A6-mediated nicotine metabolism alters smoking behavior. Therapeutic Drug Monitoring
  65. (1992). Genetic vulnerability to drug abuse. The D2 dopamine receptor Taq I B1 restriction fragment length polymorphism appears more frequently in polysubstance abusers. Archives of General Psychiatry
  66. (1998). Genomic organization and partial duplication of the human alpha7 neuronal nicotinic acetylcholine receptor gene (CHRNA7). Genomics
  67. (1998). Genomic screening.
  68. (2000). Genotype influences in vivo dopamine transporter availability in human striatum. Neuropsychopharmacology
  69. (1999). Global variation of a 40-bp VNTR in the 3'-untranslated region of the dopamine transporter gene (SLC6A3). Biological Psychiatry
  70. (2000). Haplotypes of four novel single nucleotide polymorphisms in the nicotinic acetylcholine receptor beta2-subunit (CHRNB2) gene show no association with smoking initiation or nicotine dependence.
  71. (2000). High levels of dopamine activity in the basal ganglia of cigarette smokers.
  72. (1993). High variability of nitrosamine metabolism among individuals: role of cytochromes P450 2A6 and 2E1 in the dealkylation of N- nitrosodimethylamine and N-nitrosodiethylamine in mice and humans. Molecular Carcinogenesis
  73. (1999). Identification and characterisation of novel polymorphisms in the CYP2A locus: implications for nicotine metabolism. FEBS Letters
  74. (1990). Identification of the human liver cytochrome P-450 responsible for coumarin 7-hydroxylase activity.
  75. (1999). Imaging the neurochemistry of nicotine actions: studies with positron emission tomography.
  76. (1996). Indicators of genetic and environmental influences in drug abusing individuals. Drug and Alcohol Dependence
  77. (2001). Influence of genes and family environment on adult smoking behavior assessed in an adoption study. Genetic Epidemiology
  78. (2000). Inhibition of cytochrome P450 2A6 increases nicotine's oral bioavailability and decreases smoking. Clinical Pharmacology and Therapeutics
  79. (1996). Inhibition of monoamine oxidase B in the brains of smokers. Nature
  80. (2000). Interacting effects of the serotonin transporter gene and neuroticism in smoking practices and nicotine dependence. Molecular Psychiatry
  81. (2000). Interaction between the serotonin transporter gene and neuroticism in cigarette smoking behavior. Molecular Psychiatry
  82. (1994). Interindividual variability of coumarin 7-hydroxylation in a Turkish population.
  83. (1992). Interindividual variability of coumarin 7-hydroxylation in healthy volunteers. Pharmacogenetics
  84. (1999). KaGenetics of Tobacco Use 101wamoto T. The significance of the homozygous CYP2A6 deletion on nicotine metabolism: a new genotyping method of CYP2A6 using a single PCR-RFLP. Biochemical and Biophysical Research Communications
  85. (2001). Lack of dependence and rewarding effects of deltorphin II in mu-opioid receptor-deficient mice.
  86. (1958). Lung cancer and cigarettes.
  87. (1994). Metabolism of nicotine to cotinine studied by a dual stable isotope method. Clinical Pharmacology and Therapeutics
  88. (1997). Minority women and tobacco: implications for smoking cessation interventions. Annals of Behavioral Medicine
  89. (2002). Modulating tobacco smoking rates by dopaminergic stimulation and blockade.
  90. (1995). Modulation of intracellular cyclic AMP levels by different human dopamine D4 receptor variants.
  91. (1999). Molecular heterosis as the explanation for the controversy about the effect of the DRD2 gene on dopamine D2 receptor density. Molecular Psychiatry
  92. (1999). Monoamine oxidase: from genes to behavior. Annual Review of Neuroscience
  93. (2002). Motivational effects of cannabinoids are mediated by mu-opioid and kappa-opioid receptors.
  94. (2000). mu-Opioid receptor knockout mice do not self-administer alcohol.
  95. (1992). Multiple dopamine D4 receptor variants in the human population. Nature
  96. (1999). nicotine and psychiatric disorders: evidence for therapeutic role, controversies and implications for future research. Medical Hypotheses
  97. (1991). Nicotine dependence, major depression, and anxiety in young adults.
  98. (1997). Nicotine intake and its regulation by smokers: Tobacco smoking and nicotine. In:
  99. (2001). Nicotine metabolism and CYP2D6 phenotype in smokers.
  100. (1998). Nicotine metabolism defect reduces smoking.
  101. (1983). Nicotine's role in smoking: an analysis of nicotine regulation. Psychological Bulletin
  102. (1999). No association between D2 dopamine receptor (DRD2) "A" system alleles, or DRD2 haplotypes, and posttraumatic stress disorder. Biological Psychiatry
  103. (1994). Novelty seeking, risk taking, and related constructs as predictors of adolescent substance use: an application of Cloninger's theory.
  104. (2003). PET studies of the influences of nicotine on neural systems in cigarette smokers.
  105. (2000). Polymor98 Maserejian NN, Zavras AI phisms in dopamine receptors: what do they tell us?
  106. (2000). Polymorphisms in genes involved in neurotransmission in relation to smoking.
  107. (1999). Polymorphisms in the dopamine D2 receptor gene and their relationships to striatal dopamine receptor density of healthy volunteers. Molecular Psychiatry
  108. (2003). Population stratification and spurious allelic association. Lancet
  109. (2000). Population stratification in epidemiologic studies of common genetic variants and cancer: quantification of bias.
  110. (2000). Prediction of dopamine transporter binding availability by genotype: a preliminary report.
  111. (2000). Presynaptic dopamine D(4) receptor localization in the rat nucleus accumbens shell. Synapse
  112. (1995). psychopathology, and nicotine response as mediators of the genetics of smoking. Behavior Genetics
  113. (1991). Purification and characterization of human liver microsomal cytochrome P-450 2A6. Molecular Pharmacology
  114. (2004). Reduced dopamine D3 receptor expression in blood lymphocytes of smokers is negatively correlated with daily number of smoked cigarettes: a peripheral correlate of dopaminergic alterations in smokers.
  115. (1991). Rehabilitating a genetic perspective in the study of tobacco and alcohol use.
  116. (1992). Relationship of Tridimensional Personality Questionnaire scores and smoking variables in female and male smokers.
  117. (2002). Results from the 2001 National Household Survey on Drug Abuse: Volume I. Summary of National Findings.
  118. (2000). Reward deficiency syndrome: a biogenetic model for the diagnosis and treatment of impulsive, addictive, and compulsive behaviors.
  119. (1999). Roles of CYP2A6 and CYP2B6 in nicotine Coxidation by human liver microsomes. Archives of Toxicology
  120. (1997). Safety of cotinine in humans: physiologic, subjective, and cognitive effects. Pharmacology, Biochemistry and Behavior
  121. (1999). Searching for interactive effects in the etiology of early-onset substance use. Behavior Genetics
  122. (2002). Sequence variations in the mu-opioid receptor gene (OPRM1) associated with human addiction to heroin. Human Mutation
  123. (1999). Smoking a single cigarette does not produce a measurable reduction in brain MAO B in non-smokers.
  124. (1999). Smoking behavior is under the influence of a major quantitative trait locus on human chromosome 5q. Genetic Epidemiology
  125. (2002). 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.
  126. (1992). Species differences and interindividual variation in liver microsomal cytochrome P450 2A enzymes: effects on coumarin, dicumarol, and testosterone oxidation.
  127. (1997). splice site and population frequency distribution analyses of the polymorphic human tryptophan hydroxylase intron 7. Brain Research. Molecular Brain Research
  128. (1997). Studies of the potential role of the dopamine D1 receptor gene in addictive behaviors. Molecular Psychiatry
  129. (1985). Subject characteristics as predictors of self-change in smoking. Addictive Behaviors
  130. (1999). Susceptibility genes for nicotine dependence: a genome scan and followup in an independent sample suggest that regions on chromosomes 2, 4, 10, 16, 17 and 18 merit further study. Molecular Psychiatry
  131. (2001). Symptoms of depression and survival experience among three samples of smokers trying to quit. Psychology of Addictive Behaviors
  132. (1997). The "race" concept in smoking: a review of the research on African Americans. Social Sciences and Medicine
  133. (2001). The A1 allele of the D2 dopamine receptor gene is associated with high dopamine transporter density in detoxified alcoholics. Alcohol and Alcoholism
  134. (1998). The A1 allele of the human D2 dopamine receptor gene predicts low D2 receptor availability in healthy volunteers. Molecular Psychiatry
  135. (1996). The dopamine D2 receptor (DRD2) gene: a genetic risk factor in smoking. Pharmacogenetics
  136. (2002). The DRD4 VNTR polymorphism influences reactivity to smoking cues.
  137. (2002). The DRD4 VNTR polymorphism moderates craving after alcohol consumption. Health Psychology
  138. (1971). The effect of smoking on nicotine metabolism in vivo in man.
  139. (2002). The epidemiology of attention-deficit/hyperactivity disorder (ADHD): a public health view.
  140. (2001). The future of genetic casecontrol studies.
  141. (1996). The future of genetic studies of complex human diseases. Science
  142. (2003). The genetic determinants of smoking. Chest
  143. (1999). The genetic epidemiology of smoking.
  144. (1999). The genetics of smoking initiation and quantity smoked in Dutch adolescent and young adult twins. Behavior Genetics
  145. (1999). The genetics of smoking persistence in men and women: a multicultural study. Behavior Genetics
  146. (2003). The heritability of failed smoking cessation and nicotine withdrawal in twins who smoked and attempted to quit.
  147. (1997). The human serotonin transporter gene polymorphism--basic research and clinical implications.
  148. (2003). The influence of dopamine receptor genes (DRD2, DRD3, & DRD4) on smoking status: smokers and non-smokers study (SANS). Abstract presented at Society for Research on Nicotine and Tobacco
  149. (2003). The potential role of cotinine in the cognitive and neuroprotective actions of nicotine. Life Sciences
  150. (2003). The psychopharmacology of tobacco dependence.
  151. (1998). The role of dopamine D4 receptor in the induction of behavioral sensitization to amphetamine and accompanying biochemical and molecular adaptations.
  152. (1998). The role of the serotonin transporter gene in cigarette smoking.
  153. (1998). Tobacco Use Among Young People. World Health Organization
  154. (1974). Trends in cigarette smoking among US adolescents,
  155. (2001). Tryptophan hydroxylase gene variant and smoking behavior.
  156. (2002). Tyndale RF. CYP2A6 genetic variation and potential consequences. Advanced Drug Delivery Reviews
  157. (1998). Variability of coumarin 7- and 3-hydroxylation in a Jordanian population is suggestive of a functional polymorphism in cytochrome P450 CYP2A6.
  158. (1998). Why different rules are required for polygenic inheritance: lessons from studies of the DRD2 gene. Alcohol
  159. (1999). World Health Organization Fact Sheet

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