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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


Genes and tobacco use

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


Genes and tobacco use

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.