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GENES and TOBACCO USE. CAN GENES PREDICT WHO WILL…. develop heart disease? develop lung cancer? become a smoker? be able to quit?. FACTORS CONTRIBUTING to TOBACCO USE. Environment Tobacco advertising Conditioned stimuli Social interactions. Physiology Genetic predisposition

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can genes predict who will
CAN GENES PREDICT WHO WILL…
  • develop heart disease?
  • develop lung cancer?
  • become a smoker?
  • be able to quit?
factors contributing to tobacco use
FACTORS CONTRIBUTING toTOBACCO USE

Environment

  • Tobacco advertising
  • Conditioned stimuli
  • Social interactions

Physiology

  • Genetic predisposition
  • Coexisting medical conditions

Tobacco Use

Pharmacology

  • Alleviation of withdrawal symptoms
  • Weight control
  • Pleasure
available evidence
AVAILABLE EVIDENCE
  • Adoption studies
  • Twin studies
  • Twins reared apart studies
  • Linkage (family) studies
adoption studies
ADOPTION STUDIES

Adoption studies compare the similarities between

  • Children who have been adopted and their biological parents versus children who have been adopted and their adoptive parents

- OR -

  • Adoptive sibling pairs versus biological sibling pairs
adoption studies cont d
ADOPTION STUDIES (cont’d)

Correlations between relatives for average

reported cigarette consumption

Biological

Nonbiological

Eysenck HJ, 1980.

twin studies
TWIN STUDIES

Twin studies compare the similarities between

  • Identical (monozygotic) twins and fraternal (dizygotic) twins

Concordant or discordant?

Higher concordance of tobacco use

for identical than for fraternal twins

Estimated heritability for smoking = 0.53

twins reared apart studies
TWINS REARED APART STUDIES
  • Combine aspects of adoption and twin studies
  • Separate the effects of genetics from the effects of environment
  • Have found that 60% of the variance in regular smoking in men and women born after 1940 is attributable to genetic factors (Kendler et al., 2000)
linkage studies
LINKAGE STUDIES
  • Use human genome mapping to enable researchers to identify genes associated with traits or disorders
  • Examine family pedigrees to determine modes of inheritance of disorders
  • Are more difficult when multiple genes have a role
linkage studies cont d
LINKAGE STUDIES (cont’d)

Linkage studies of smoking

  • Identify families with affected individuals (i.e., tobacco users)
  • Genotype two or more affected siblings and biological parents
  • Conduct linkage analysis to determine whether affected siblings are likely to share the same gene as the parents
candidate genes
“CANDIDATE” GENES
  • Candidate genes are genes hypothesized to contribute to the susceptibility for a trait or disorder.
  • Two current lines of research in the area of candidate genes for smoking:
    • Genes affecting nicotine pharmacodynamics
    • Genes affecting nicotine pharmacokinetics
slide12

P h a r m a c o l o g y

Pharmacodynamics

Pharmacokinetics

  • DOPAMINE
  • Synthesis
    • Tyrosine hydroxylase
  • Receptor activation
    • DRD1, DRD2, DRD3, DRD4, DRD5
  • Reuptake
    • Dopamine transporter (SLC6A3)
  • Metabolism
    • Catechol-O -methyltransferase
    • MAO A, MAO B
    • Dopamine ß-hydroxylase
  • SEROTONIN
  • Synthesis
    • Tryptophan hydroxylase (TPH)
  • Reuptake
    • Serotonin transporter (5-HTT)
  • Nicotine Metabolism
  • CYP2A6 enzyme
  • CYP2D6 enzyme
slide13

Genetic Effects on the

Dopamine Reward Pathway

genetic effects on nicotine metabolism
GENETIC EFFECTS on NICOTINE METABOLISM

4.4%

9.8%

Nicotine-1\'-

N-oxide

0.4%

Nicotine

Nornicotine

Nicotine

glucuronide

Nicotine

4.2%

Trans-3\'-

hydroxycotinine

~80%

33.6%

Trans-3\'-

hydroxycotinine

Cotinine

Cotinine

13.0%

Trans-3\'-

hydroxycotinine

glucuronide

Cotinine

glucuronide

7.4%

Norcotinine

12.6%

Cotinine-

N-oxide

2.0%

Reprinted with permission, Benowitz et al. (1994).

2.4%

genetic effects on nicotine metabolism cont d
GENETIC EFFECTS on NICOTINE METABOLISM (cont’d)

Nicotine

CYP2A6

Aldehyde oxidase

Cotinine

genes and tobacco use societal and policy implications
GENES AND TOBACCO USE:SOCIETAL AND POLICY IMPLICATIONS

If genetic tests become available, should society encourage genetic testing for tobacco dependence?

  • Single gene or multiple gene?
  • Prevalence of the gene(s) in the population?
  • Is there an effective intervention to prevent smoking in those who are susceptible?
  • Impact of positive tests, and negative tests?
genes and tobacco use societal and policy implications cont d
GENES AND TOBACCO USE:SOCIETAL AND POLICY IMPLICATIONS (cont’d)

Improved treatment for tobacco dependence?

  • Perhaps the most promising benefit of genetic research on smoking
  • Improved understanding of tobacco dependence might result in development of more effective medications
  • Pharmacotherapy treatment matching
genes and tobacco use summary
GENES and TOBACCO USE: SUMMARY
  • Research in the area of genetics and smoking is in its infancy; however, there appears to be a genetic component to tobacco use.
  • Tobacco use is a complex behavior, with many determinants.
  • More research is needed.
  • Genetic research and testing must proceed with caution because the societal stakes are high.
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