Kamuran Karakülah, Cem Şengül, Ceyhan Balcı Şengül

Genetics of Smoking Addiction

Sigara birçok hastalığın sebepleri arasındadır ve her yıl 5 milyon insanın ölümüne neden olarak, en önemli ölüm nedenleri arasında yer almaktadır. Bağımlılık, sigara kullanımının yol açtığı en önemli sendromlardandır ve içerdiği nikotin ile ilişkilendirilmiştir. Sigara bağımlılığının nedenleri farklı bileşenleri ile yoğun bir şekilde araştırılmıştır. Epidemiyolojik, farmakolojik, nörobiyolojik ve genetik çalışmalar başlıca çalışma alanlarıdır. Sigara ve nikotin bağımlılığının genetiği 50 yıldır çalışılmaktadır. Öncelikle, İkiz, aile ve evlat edinme çalışmaları sigara bağımlılığında genetik geçişin olduğunu göstermiştir. Moleküler genetik çalışmalar ile, içilen sigara miktarı ve nikotin ile aday genler arasında ilişkili olduğu gösterilmiştir. Bağımlılığın yüksek derecede kalıtsal bir hastalık olması, pozisyonel genetiği kullanarak şüphelenilen genlerin aydınlatılmasına çalışılması için birçok çalışmanın yapılmasını tetiklemiştir. Sigara bağımlılığı genetik diseksiyonu için aday gen çalışmaları da ayrıca kullanılmaktadır. Bu iki yaklaşımın son 20 yılda hastalık patofizyolojisini anlamamızda önemli etkisi olmuştur. Sigara bağımlılığında tüm genomun incelendiği ilişkilendirme çalışmaları ve kopya sayısı değişikliklerinin tespiti de yakın gelecekte önemli katkı sağlayabilecektir. Yeni çalışmalar, epigenetik mekanizmaların veya DNA'nın kimyasal belirteçlerinin ve onu çevreleyen histon proteinlerinin yaşam boyu değişken olduğunu ve çevresel faktörler tarafından değiştirilebileceğini göstermiştir. Epigenetik mekanizmalar, çevresel koşulların şizofreniye etkisini açıklayan cazip bir moleküler hipotez olmuştur. Bu yazıda, klasik genetik çalışmalardan yeni epigenetik yaklaşımlara kadar sigara bağımlılığındaki genetik çalışmaların gelişimini gözden geçirilmiştir.

Anahtar Kelimeler:

Sigara, bağımlılık, genetik, epigenetik

Sigara Bağımlılığının Genetiği

Tobacco smoking is associated with many diseases causing 5 million deaths per year worldwide and is regarded as one of the leading causes of death. Addiction is of the most notorious tobacco-related syndrome and is mainly attributed to nicotine. The causes of tobacco smoking addiction were intensively investigated with several components. Epidemiologic, pharmacologic, neurobiological and genetic studies were main study topics. Genetic studies of smoking and nicotine dependence has been studied for 50 years. Twin, family and adoption studies show evidence for genetic effects on smoking and nicotine dependence. Molecular genetic analyses have identified genes associated with the amount smoked and nicotine dependence. The high heritability of addiction has stimulated much work aimed at identifying susceptibility genes using positional genetics. Candidate gene approaches are also being used for the genetic dissection of smoking addiction. These two approaches had a major impact on our understanding of disease pathophysiology in last 2 decades. Recent work indicates that epigenetic mechanisms or the chemical markings of the DNA and the surrounding histone proteins remain labile through the lifespan and can be altered by environmental factors. Thus, epigenetic mechanisms are an attractive molecular hypothesis for environmental contributions to tobacco smoking addiction. Genome wide association and copy number variation studies are new genetic techniques and they would probably provide us important information in the near future. In this report we aimed to review progress of genetic studies in smoking addiction from classical genetic studies to new epigenetic approaches.

Keywords:

Smoking, addiction, genetics, epigenetics,

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Vink JM, Willemsen G, Boomsma DI. Heritability of smoking initiation and nicotine dependence. Behav Genet 2005; 35:397–406.
Sullivan PF, Kendler KS. The genetic epidemiology of smoking. Nicotine Tob Res 1999; 1:51–57.
Bierut LJ. Genetic vulnerability and susceptibility to substance dependence. Neuron 2011; 69:618–627.
Akgün GA, Tufan AE, Yurteri N, Erdoğan A. Dikkat eksikliği hiperaktivite bozukluğunun genetik boyutu. Psikiyatride Güncel Yaklaşımlar-Current Approaches in Psychiatry 2011; 3:15-48.
Fisher RA. Cancer and smoking. Nature 1958; 182:596.
True WR, Heath AC, Scherrer JF, Waterman B, Goldberg J, Lin N et al. Genetic and environmental contributions to smoking. Addiction 1997; 92:1277–1287
Carmelli D, Swan GE, Robinette D, Fabsitz R. Genetic in fluence on smoking–a study of male twins. N Engl J Med 1992; 327:829–833.
Edwards KL, Austin MA, Jarvik GP. Evidence for genetic influences on smoking in adult women twins. Clin Genet 1995; 47:236–244.
Tyndale RF, Sellers EM. Variable CYP2A6-mediated nicotine metabolism alters smoking behavior and risk. Drug Metab Dispos 2001; 29:548–552.
Lovlie R, Daly AK, Molven A, Molven A, Idle JR, Steen VM. Ultrarapid metabolizers of debrisoquine: characterization and PCR-based detection of alleles with duplication of the CYP2D6 gene. FEBS Lett 1996; 392:30–34.
Cholerton S, Boustead C, Taber H, Arpanahi A, Idle JR. CYP2D6 genotypes in cigarette smokers and non-tobacco users. Pharmacogenetics 1996; 6:261–263
Saarikoski ST, Sata F, Husgafvel-Pursiainen K, Rautalahti M, Haukka J, Impivaara O et al. CYP2D6 ultrarapid metabolizer genotype as a potential modifier of smoking behaviour. Pharmacogenetics 2000; 10:5–10.
Toker Uğurlu T, Balcı Şengül C, Şengül C. Bağımlılık psikofarmakolojisi. Psikiyatride Güncel Yaklaşımlar-Current Approaches in Psychiatry 2012; 4:37-50.
Şengül C, Herken H. Dopaminerjik sistem ve bağımlılık. Bağımlılık Dergisi, 2009; 10:155-161.
Gelernter J, Liu X, Hesselbrock V, Page GP, Goddard A, Zhang H. Results of a genomewide linkage scan: support for chromosomes 9 and 11 loci increasing risk for cigarette smoking. Am J Med Genet B Neuropsychiatr Genet 2004; 128B:94–
Ohmoto M, Sakaishi K, Hama A, Morita A, Nomura M, Mitsumoto Y. Association between dopamine receptor 2 TaqIA polymorphisms and smoking behavior with an influence of ethnicity: a systematic review and meta-analysis update. Nicotine Tob Res 2013; 15:633-642.
Munafo MR, Timpson NJ, David SP, Ebrahim S, Lawlor DA. Association of the DRD2 gene Taq1A polymorphism and smoking behavior: a meta-analysis and new data. Nicotine Tob Res 2009; 11:64–76.
Wu X, Hudmon KS, Detry MA, Chamberlain RM, Spitz MR. D2 dopamine receptor gene polymorphisms among AfricanAmericans and Mexican-Americans: a lung cancer case-control study. Cancer Epidemiol Biomarkers Prev 2000; 9:1021– 10
Stapleton JA, Sutherland G, O'Gara C, Spirling LI, Ball D. Association between DRD2/ANKK1 Taq1A genotypes, depression and smoking cessation with nicotine replacement therapy. Pharmacogenet Genomics 2011; 21:447–453.
Singleton AB, Thomson JH, Morris CM, Court JA, Lloyd S, Cholerton S. Lack of association between the dopamine D2 receptor gene allele DRD2*A1 and cigarette smoking in a United Kingdom population. Pharmacogenetics 1998; 8:125– 1
Vandenbergh DJ, O'Connor RJ, Grant MD, Jefferson AL. Dopamine receptor genes (DRD2, DRD3 and DRD4) and gene–gene interactions associated with smoking-related behaviors. Addict Biol 2007; 12:106–116.
Lerman C, Jepson C, Wileyto EP, Epstein LH. Role of functional genetic variation in the dopamine D2 receptor (DRD2) in response to bupropion and nicotine replacement therapy for tobacco dependence: results of two randomized clinical trials. Neuropsychopharmacology 2006; 31:231–242.
Oak JN, Oldenhof J, Van Tol HH. The dopamine D(4) receptor: one decade of research. Eur J Pharmacol 2000; 405:303-327. Shields PG, Lerman C, Audrain J, Bowman ED, Main D, Boyd NR et al. Dopamine D4 receptors and the risk of cigarette smoking in African- Americans and Caucasians. Cancer Epidemiol Biomarkers Prev 1998; 7:453–458.
Babic M, Nedic G, Muck-Seler D, Borovecki F, Pivac N. Lack of association between dopamine receptor D4 variable numbers of tandem repeats gene polymorphism and smoking/ Neurosci Lett 2012; 520:67–50.
Sullivan PF, Neale MC, Silverman MA, Harris-Kerr C, Myakishev MV, Wormley B et al. An association study of DRD5 with smoking ınitiation and progression to nicotine dependence. Am J Med Genet 2001; 105:259-265.
Lerman C, Caporaso NE, Audrain J, Main D, Bowman ED, Lockshin B et al. Evidence suggesting the role of specific genetic factors in cigarette smoking. Health Psychol 1999; 18:14–20.
McKinney EF, Walton RT, Yudkin P, Fuller A, Haldar NA, Mant D et al. Association between polymorphisms in dopamine metabolic enzymes and tobacco consumption in smokers. Pharmacogenetics 2000; 10:483–491.
Lachman HM, Morrow B, Shprintzen R, Veit S, Parsia SS, Faedda G et al. Association of codon 108/158 catechol-Omethyltransferase gene polymorphism with the psychiatric manifestations of velo-cardio-facial syndrome. Am J Med Genet 1996; 67:468-472.
Johnstone EC, Elliot KM, David SP, Murphy MF, Walton RT, Munafò MR. Association of COMT Val108/158Met genotype with smoking cessation in a nicotine replacement therapy randomized trial. Cancer Epidemiol Biomarkers Prev 2007; 16:1065–1069.
Berrettini WH, Wileyto EP, Epstein L, Restine S, Hawk L. Catechol-O-methyltransferase (COMT) gene variants predict response to bupropion therapy for tobacco dependence. Biol Psychiatry 2007; 61:111-118.
Olsson C, Anney R, Forrest S, Patton G, Coffey C, Cameron T et al. Association between dependent smoking and a polymorphism in the tyrosine hydroksilase gene in a prospective population-based study of adolescent health. Behav Genet 2004; 34:85-91.
Lerman C, Shields PG, Main D, Audrain J, Roth J, Boyd NR et al. Lack of association of tyrosine hydroxylase genetic polymorphism with cigarette smoking. Pharmacogenetics 1997; 7:521–524.
McDougle CJ, Epperson CN, Price LH, Gelernter J. Evidence for linkage disequilibrium between serotonin transporter protein gene (SLC6A4) and obsessive compulsive disorder. Mol Psychiatry 1998; 3:270-273.
Enoch MA, Greenberg BD, Murphy DL, Goldman D. Sexually dimorphic relationship of a 5-HT2A promoter polymorphism with obsessive compulsive disorder. Biol Psychiatry 2001; 49:385-388.
Collier DA, Stöber G, Li T, Heils A, Catalano M, Di Bella D et al. A novel functional polymorphism within the promoter of the serotonin transporter gene: possible role in susceptibility to affective disorders. Mol Psychiatry 1996; 1:453–460.
Lerman C, Shields PG, Audrain J, Main D, Cobb B, Boyd NR et al. The role of the serotonin transporter gene in cigarette smoking. Cancer Epidemiol Biomarkers Prev 1998; 7:253–255.
Ishikawa H, Ohtsuki T, Ishiguro H, Yamakawa-Kobayashi K, Endo K, Lin YL et al. Association between serotonin transporter gene polymorphism and smoking among Japanese males. Cancer Epidemiol Biomarkers Prev 1999; 8:831–833.
Chu SL, Xiao D, Wang C, Jing H. Association between 5-hydroxytryptamine transporter gene-linked polymorphic region and smoking behavior in Chinese males. Chin Med J 2009; 122:1365–1368.
Daw J, Shanahan M, Harris KM, Smolen A, Haberstick B, Boardman JD. Genetic sensitivity to peer behaviors: 5HTTLPR, smoking, and alcohol consumption. J Health Soc Behav 2013; 54:92-108.
Gelernter J, Kranzler H, Cubells JF. Serotonin transporter protein (SLC6A4) allele and haplotype frequencies and linkage disequilibria in African and European American and Japanese populations and in alcohol dependent subjects. Hum Genet 1997; 101:243–246.
Ribeiro EB, Bettiker RL, Bogdanov M, Wurtman RJ. Effects of systemic nicotine on serotonin release in rat brain. Brain Res 1993; 621:311–318.
Hitsman B, Spring B, Pingitore R, Munafo MR, Hedeker D. Effect of tryptophan depletion on the attentional salience of smoking cues. Psychopharmacology 2007; 192:317–324.
Johnson B. Update on neuropharmacological treatments for alcoholism: scientific basis and clinical findings. Biochem Pharmacol 2008; 75:34–56.
Heils A, Mossner R, Lesch KP. The human serotonin transporter gene polymorphism: basic research and clinical implications. J Neural Transm 1997; 104:1005–1014.
Carlson JM, Gilbert DG, Riise H, Rabinovich NE, Sugai C. Froeliger B. Serotonin transporter genotype and depressive symptoms moderate effects of nicotine on spatial working memory. Exp Clin Psychopharmacol 2009; 17:173–180.
Gilbert DG, Zuo Y, Rabinovich NE, Riise H, Needham R. Huggenvik JI. Neurotransmission-related genetic polymorphisms, negative affectivity traits, and gender predict tobacco abstinence symptoms across 44 days with and without nicotine patch. J Abnorm Psychol 2009; 118:322–334.
David SP, Johnstone EC, Murphy MF, Aveyard P, Guo B, Lerman C et al. Genetic variation in the serotonin pathway and smoking cessation. Drug Alcohol Depend 2008; 98:77–85.
Gerra G, Garofano L, Zaimovic A, Moi G, Branchi B, Bussandri M et al. Association of the serotonin transporter promoter polymorphism with smoking behavior among adolescents. Am J Med Genet B Neuropsychiatr Genet 2005; 135:73–78.
Kremer I, Bachner-Melman R, Reshef A, Broude L, Nemanov L, Gritsenko I et al. Association of serotonin transporter gene with smoking behaviour. Am J Psychiatry 2005; 162:924-930.
Sieminska A, Buczkowski K, Jassem E. Tkacz E. Lack of association between serotonin transporter gene polymorphism 5HTTLPR and smoking among Polish population: a case-control study. BMC Med Genet 2008; 9:76.
Biala G, Weglinska B. Calcium channel antagonists attenuate cross- sensitization to the locomotor effects of nicotine and ethanol in mice. Pol J Pharmacol 2004; 56:391-397.
Tobacco and Genetics Consortium. Genome-wide meta-analyses identify multiple loci associated with smoking behavior. Nat Genet 2010; 42:441-447.
Bierut LJ, Madden PAF, Breslau N, JohnsonEO, Hatsukami D et al. Novel genes identified in a high-density genome wide association study for nicotine dependence. Hum Mol Genet 2007; 16:24–35.
Thorgeirsson TE, Stefansson K. Genetics of smoking behavior and its consequences: the role of nicotinic acetylcholine receptors. Biol Psychiatry 2008; 64:919–921.
Baker TB, Weiss RB, Bolt D, von Niederhausern A, Fiore MC, Dunn DM et al. Human neuronal acetylcholine receptor A5-A3B4 haplotypes are associated with multiple nicotine dependence phenotypes. Nicotine Tob Res 2009; 11:785–796.
Ray R, Mitra N, Baldwin D, Guo M, Patterson F, Heitjan DF et al. Convergent evidence that choline acetyltransferase gene variation is associated with prospective smoking cessation and nicotine dependence. Neuropsychopharmacology 2010; 35:1374–1382
Sarginson JE, Killen JD, Lazzeroni LC, Fortmann SP, Ryan HS, Schatzberg AF et al. Markers in the 15q24 nicotinic receptor subunit gene cluster (CHRNA5-A3-B4) predict severity of nicotine addiction and response to smoking cessation therapy. Am J Med Genet B Neuropsychiatr Genet 2011; 156B: 275–284.
Munafo MR, Johnstone EC, Walther D, Uhl GR, Murphy MF, Aveyard P. CHRNA3 rs1051730 genotype and short-term smoking cessation. Nicotine Tob Res 2011; 13:982–988.
King DP, Paciga S, Pickering E, Benowitz NL, Bierut LJ, Conti DV et al. Smoking cessation pharmacogenetics: Analysis of varenicline and bupropion in placebo-controlled clinical trials. Neuropsychopharmacology 2012; 37:641–650.
Hutchison KE, Allen DL, Filbey FM, Jepson C, Lerman C, Benowitz NL et al. CHRNA4 and tobacco dependence: From gene regulation to treatment outcome. Arch Gen Psychiatry 2007; 64:1078–1086.
Şengül C, Herken H. Genetikten epigenetiğe alkol bağımlılığı. Anadolu Psikiyatri Dergisi 2009; 10:239-245.
Taki FA, Pan X, Zhang B. Chronic nicotine exposure systemically alters microRNA expression profiles during post-embryonic stages in Caenorhabditiselegans J Cell Physiol 2014; 229:79-89. Kamuran Karakülah, Uzm.Dr., Pamukkale Üniversitesi Tıp Fakültesi Psikiyatri Anabilim Dalı, Denizli; Cem Şengül, Doç.Dr., Pamukkale Üniversitesi Tıp Fakültesi Psikiyatri Anabilim Dalı, Denizli; Ceyhan Balcı Şengül, Yrd.Doç.Dr., Pamukkale Üniversitesi Tıp Fakültesi Psikiyatri Anabilim Dalı, Denizli. Yazışma Adresi/Correspondence: Cem Şengül, Pamukkale Üniv. Tıp Fak. Psikiyatri ABD, Denizli, Turkey. E-mail: acemsen@gmail.com Yazarlar bu makale ile ilgili herhangi bir çıkar çatışması bildirmemiştir. The authors reported no conflict of interest related to this article. Çevrimiçi adresi / Available online at: www.cappsy.org/archives/vol6/no3/ Çevrimiçi yayım / Published online 16 Ocak/January 16, 2014; doi: 10.5455/cap.20140116011913