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. Şule 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 • α4β2nAcRs: 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 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%)

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 • α4β2nAcR 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