Genetics of Nicotine Dependence and Pharmacotherapy

1
Genetics of Nicotine Dependence and
Pharmacotherapy

• Lessov- Schlaggar C, Pergardia ML, Khroyan TV,
  Swan GE, USA
• Biochem Pharmacol 2008 75 178-195
• TTS Tobacco Control Assembly
• Clinical Year in Review
• Assoc. Prof. Dr. Sule Akçay
• Baskent University, Pulmonary Diseases
• 26.04.2008

2
Scientists have identified genetic variations
that raise the risk of lung cancer for smokers
and former smokers
Genetic link to smoking addiction
Cigarettes may interact with our genes
BBC NEWS 2 April 2008
3
Components of Tobacco Control

• Decrease the number of active smokers (if
  possible, total eradication)
• To avoid passive smoking (laws no 4207, 5727)
• To prevent initiation of smoking

4

• 21 of American adults, 45 of Turkish adults
  continue to smoke cigarettes
• Long term abstinence rates of 6 months are
  averaging 5-10 in nonpharmacotherapy group
• Average quit rates increase with pharmacological
  treatment to 19-37 (NRT, bupropion,
  varenicline)
• Is there any association between low success
  rates and high heritability?

5
AIM

• Genetic research on smoking behavior shows that
  individuals differences in smoking can be
  attributed to hundred (if not thousands) genetic
  and environmental factors,
• The goal of this review is to analyse basic
  genetic researchs on smoking behavior in the
  literature

6
Smoking behaviour

• Nonsmoker
• Nondependent
• Dependent

These two groups are under genetic researchs
7
Instruments Used For Assessment of Nicotine
Dependence

• Fagerström Tolerance Questionnaire (FTQ)
• DSM-III and DSM-IV criteria
• Nicotine Dependence Syndrome Scale (NDSS)
• Modified Reasons for Smoking Scale (MRSS)
• Wisconsin Inventory of Smoking Dependence Motives
  (WISDM 68)
• European Medical Association Smoking or Health

Currently, there are no measures of nicotine
dependence that incorporate measurement of
underlying neuropathological processes
8
FTQ

• The earliest and the most used test
• 8 items survey FTQ
• 6 items survey FTND (time to first cigarettes
  after waking, difficulty refraining from smoking
  in place where it is forbidden, would most hate
  to give up first cigarette in the morning versus
  all others, number of cigarettes smoked per day,
  smoking more frequently during the first hours
  after waking than during the rest of the day,
  smoking when so ill that you are in bed most of
  the day)
• FTQ results are well-matched with objective
  measurements

9
DSM

• DSM-III Diagnostic and Statistical Manual for
  Mental disorders
• DSM-IV Revised DSM-III
• 6 items that comprise nicotine dependence
  tolerance, withdrawal, using more of the
  substance than intended, persistent desire to
  quit or unsuccessful efforts to cut down, great
  deal of time spent obtaining the substance,
  important activities given up or reduced because
  of substance use

10
NDSS

• Nicotine Dependence Syndrome Scale
• 5 phenotypic factors Drive, priority, tolerance,
  continuity, stereotypy

11
MRSS

• Modified Reasons for Smoking Scale
• 7 factors Addictive smoking, smoking because of
  the pleasurable effects, smoking for tension
  reduction/relaxation, social smoking, stimulation
  smoking, habit/automatism, handling (smoking for
  the ritualized behaviors)

12
WISDM 68

• Wisconsin Inventory of Smoking Dependence Motives
• 13 factors Similar to other questionnaires

13
European Medical Association Smoking or Health

• EMASH very simple and effective
• 2 items time to first cigarettes after waking,
  number of cigarettes smoked per day

14
Neurobiology of Nicotine Dependence

• Upon inhalation of cigarette smoke, nicotine
  quickly crosses the blood-brain barrier and binds
  nicotinic acetylcholine receptors (nAChRs) in the
  brain
• a4ß2nAcRs Stimulates mesocorticolimbic system
• Activation of reward pathway

15
Relationship Between CNS and Nicotine

• N accumbens (Dopamine)
• Reward pathway
• Locus coeruleus (Noradrenaline)
• Abstinence symptoms

(mesolimbic system)
(locus coeruleus)
16
Nicotine dependence levels in humans are different

• To know is necessary
• Neurobiology of nicotine,
• Variation in the genes that code for the drug
  receptor proteins,
• Code for metabolic and catabolic enzymes that
  influence neurotransmitter levels, represent
  candidate genes for measured genetic studies of
  nicotine dependence and treatment.

17
Univariate investigations

• Twin studies show that significant proportion of
  the phenotypic variance in nicotine dependence is
  attributable to additive genetic effects
  (heritability)

18
Adult Heritability Studies

• FTND and heritability 40-75
• Heaviness of smoking index (HSI) 59-71
• Diagnostic nicotine dependence 33-77

19
Adolescent heritability studies

• Nicotine dependence is also heritable in
  adolescents (44),
• 37 of the variance was explained by
  environmental factors

20
FTND components

• There are strong genetic influences, including
• Time to first cigarette in the morning 55-68
• Daily cigarette quantity 45-70

21

• In one study The results are conflicting the
  other genetic studies
• The clear definition of smoking groups in
  publications is vital to furthering our
  understanding of the etiology of nicotine
  dependence

22
Questinnaires

• Each of all diagnostic nicotine dependence
  criteria have been shown to be heritable, as well
  as individual nicotine withdrawal symptoms

23
Interesting findings

• There appear to be greater genetic influences on
  womens risk in difficulty quitting smoking (68)
  compared to men (54) for whom shared
  environmental factors (26)
• Experiencing depressed mood upon nicotine
  withdrawal has been found to be more genetically
  influenced in women compared to men (53 vs 29)

24

• There are two published reports on the
  heritability of multidimensional dependence
  constructs
• Twin study Total NDSS score was moderately
  heritable (30),
• Tolerance scores 39,
• Stereotypy/continuity 44,
• There was no evidence for a significant
  contribution from genetic sources on the scores
  from the drive/priority factor

25
The second study

• Examined the heritability of four smoking motives
  considered to capture a pharmacological dimension
  of smoking
• Smoking for sedative effects,
• For stimulatory effects,
• For the addictive properties,
• Automatic smoking strong genetic relationship

26
Studies that compared genetic and environmental
influences on smoking

• Australian, Finnish and Swedish twins
• No significant differences in genetic influences
  on either phenotype by country, despite
  prevalence differences in both smoking across
  countries
• In Chinese male twins, heritability estimates for
  current and heavy smoking were within the range
  of those reported for twins of European origin
• These studies suggest genetic risks for smoking
  are important, despite cultural variation among
  countries

27
Multivariate Investigation

• Nicotine dependence and comorbid substance use
  can be overlapped
• Using twins and families, it is possible to
  understand the extent to which genetic factors
  underlie this covariation

28
Linkage studies

• Chromosome 1
• Chromosome 2
• Chromosome 4 tobacco and alcohol abuse

29
Genomewide studies

• Alcohol and tobacco dependence
• Described 8 genes 1, 3, 7, 9, 10, 12 ve X
  chromosomes

30
Acetylcholine receptor genes

• a4ß2nAcR genes CHRNA4 and CHNRB2 Chromosome 1
• CHNRB2 SNP to both alcohol and cigarettes in
  both Caucasians and Hispanic samples

31
Other comorbidities

• Some studies found common genetic liability to
  smoking and cannabis use
• The strong relationship between schizophrenia and
  smoking can be attributable to common familial
  vulnerability,
• A significant association between nicotine
  dependence and eating disorders

32
Linkage studies

• Significant linkage for the FTND on chromosomes
  2,5,6 SNP,
• Quantity smoked has been more commonly examined
  in linkage studies with significant linkage
  reported for chromosome 1,4,6,9,10,11, and 22

33
Nicotine withdrawal symptoms

• Lifetime short term quit attempt (more than 1
  month but less than 1 year) showed chromosome 6
  defect

34
Dopamine receptor genes

• DRD2
• ANKK1
• NCAM1
• TTC12
• Chromosome 11q23

35

• Dopa decarboxylase (DDC) gene variation on
  chromosome 7p11 DSM IV and FTQ correlation
• PPP1R1B (in dopamine signaling) 17q12
• Catechol-o-methyl transpherase (in dopamine
  degradation) 22q11

36
Mid-South Tobacco Family Study (MSTF)

• CHRNA4 (nAChR) chromosome 20q13,
• CHRNB2 1q21
• GABA-A receptor chromosome 17p13

37

• µ-opioid receptor 6q24-25
• OPRM1 4 SNP anormalities

38
Genetic researchesDisadvantages

• Slow progression
• Low quantity of samples
• High cost
• Different phenotypes
• Unsufficient interpretation of markers (SNP,
  polymorphism, deletion or insertion etc)

39
Genetic researchesAdvantages

• To determine pharmocotherapy candidates
• To invent gene therapies
• Smoking addiction is an organic disease

40
DSM V

• An association between smoking and genes should
  be emphasized in light of literature

41
NIH Transdisciplinarity in Tobacco Research

• Understanding the mechanisms of treatment
  efficacy
• The risk factors for treatment failure
• Testing novel approaches to treatment
• Research on tobacco control policy
• Harm reduction
• The interplay of genes and prevention in
  multi-cultural settings
• Identification of more precise and informative
  measures for lifetime tobacco use patterns

42
Conclusions

• Nicotine dependence is a complex disorder
• It includes a variety of disciplines ethics,
  policy, public health, epidemiology, sociology,
  psychology, pharmacology, neuroscience,
  psychiatry, molecular genetics, medicine
  (pulmonology, cardiology etc.)
• Active smokers are difficult cases,
• Pasif smoking and initiation of smoking should
  be prevented by effective measures

43
THANK YOU FOR YOUR ATTENTION