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. Şule Akçay

Baskent University, Pulmonary Diseases

26.04.2008

Genetic link to smoking addiction

Cigarettes may interact with our genes

Scientists have identified genetic variations that raise the risk of lung cancer for smokers and former smokers

BBC NEWS

2 April 2008

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

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?

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

Smoking behaviour

Nonsmoker

Nondependent

Dependent

These two groups are under genetic researchs

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

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

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

NDSS

Nicotine Dependence Syndrome Scale

5 phenotypic factors: Drive, priority, tolerance, continuity, stereotypy

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)

WISDM 68

Wisconsin Inventory of Smoking Dependence Motives

13 factors: Similar to other questionnaires

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

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

α4β2nAcRs: Stimulates mesocorticolimbic system

Activation of reward pathway

SSS- Nikotin ilişkisi

• N. Accumbens (Dopamin)• Kişinin kendini iyi hissetmesini sağlayan hormon

• Locus coeruleus (Noradrenalin)• Yoksunluk semptomlarından sorumlu hormon

.

Beyindeki‘ödüllendirme’

yolu (mesolimbic

system)

‘yoksunluksemptomları’yolu (locus coeruleus)

Relationship Between CNS and Nicotine

N accumbens (Dopamine) Reward pathway

Locus coeruleus (Noradrenaline) Abstinence symptoms

(mesolimbic system)

(locus coeruleus)

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.

Univariate investigations

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

Adult Heritability Studies

FTND and heritability 40-75 %

Heaviness of smoking index (HSI) 59-71%

Diagnostic nicotine dependence 33-77%

Adolescent heritability studies

Nicotine dependence is also heritable in adolescents (44%),

37% of the variance was explained by environmental factors

FTND components

There are strong genetic influences, including;

Time to first cigarette in the morning: 55-68%

Daily cigarette quantity: 45-70%

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

Questinnaires

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

Interesting findings

There appear to be greater genetic influences on women’s 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%)

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

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

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

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

Linkage studies

Chromosome 1

Chromosome 2

Chromosome 4: tobacco and alcohol abuse

Genomewide studies

Alcohol and tobacco dependence;

Described 8 genes : 1, 3, 7, 9, 10, 12 ve X chromosomes

Acetylcholine receptor genes

α4β2nAcR genes: CHRNA4 and CHNRB2: Chromosome 1

CHNRB2 SNP to both alcohol and cigarettes in both Caucasians and Hispanic samples

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

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

Nicotine withdrawal symptoms

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

Dopamine receptor genes

DRD2

ANKK1

NCAM1

TTC12

Chromosome 11q23

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

Mid-South Tobacco Family Study (MSTF)

CHRNA4 (nAChR) chromosome 20q13,

CHRNB2 1q21

GABA-A receptor: chromosome 17p13

µ-opioid receptor 6q24-25

OPRM1: 4 SNP anormalities

Genetic researchesDisadvantages

Slow progression

Low quantity of samples

High cost

Different phenotypes

Unsufficient interpretation of markers (SNP, polymorphism, deletion or insertion etc)

Genetic researchesAdvantages

To determine pharmocotherapy candidates

To invent gene therapies

Smoking addiction is an organic disease

DSM V

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

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

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

THANK YOU FOR YOUR ATTENTION