Genetikten epigenetiğe alkol bağımlılığı

Alkol bağımlılığı büyük toplumsal etkileri olan kronik, yineleyici bir hastalıktır. Kişilerin sahip oldukları bireysel bağımlılık risklerini saptamak, etkili tedavi ve önleme programları geliştirmek için alkol bağımlılığının genetik temellerini anlamak gereklidir. Yeni çalışmalarda alkol bağımlılığının epigenetiği ve moleküler düzenekleri üzerin- de durulmaktadır. Beynin ödüllendirme düzeneğinde yer alan bölgelerde gözlenen gen ekspresyonu değişiklikleri- nin alkol bağımlılığı oluşmasında ve sürmesinde etkili olduğu düşünülmektedir. Klasik genetik çalışmalardan ve yeni epigenetik çalışmalardan elde edilen veriler, bize alkol bağımlılığının yeni boyutlarını gösterebilir. Genetik çalışmalardan elde edilen veriler alkol bağımlılığı için uygun farmakolojik tedaviyi seçmede yol gösterici olabilir. Bu gözden geçirme yazısında alkol bağımlılığı, genetik, epigenetik ve polimorfizm anahtar sözcüklerini kullanarak PubMed veri tabanını inceledik ve elde ettiğimiz verileri tartıştık.

From genetics to epigenetics: Alcohol addiction

Alcohol addiction is a chronic, relapsing disorder with a huge societal impact. Understanding the genetic basis of alcohol addiction is crucial to characterize individuals’ risk and to develop efficacious prevention and treatment strategies. Recent studies have also begun to focus on the molecular mechanisms and epigenetics of alcohol addiction. Changes in gene expression in brain reward regions are thought to contribute to the pathogenesis and persistence of drug addiction. Data from classical genetic studies to new epigenetic studies could show us new dimensions of alcohol addiction. Data from genetic studies also guide pharmacotherapeutic agent choice for optimum treatment of alcohol addiction. In this review, we examined the Pubmed database, using alcoholism, genetics, epigenetics and polymorphism key words and than discussed results of studies.

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1. Köhnke MD. Approach to the genetics of alcoholism: A review based on pathophysiology. Biochem Pharmacol 2008; 75:160-177.
2. Nestler EJ. Transcriptional mechanisms of addiction: role of DeltaFosB. Philos Trans R Soc Lond B Biol Sci 2008; 363:3245-3255.
3. Yüncü Z, Savaş HA. Madde kullanım bozukluklarında genetik: Bir gözden geçirme. Bağımlılık Dergisi 2007; 8:146-152.
4. Herken H. MSS ve Genler. İstanbul, Okuyanus Yayınları, 2003.
5. Herken H. Depresyonun etiyolojisinde genetik kanıtlar. Klinik Psikiyatri 2002(Suppl.4):5-10.
6. Schmidt LG, Harms H, Kuhn S, Rommelspacher H, Sander T. Modification of alcohol withdrawal by the A9 allele of the dopamine transporter gene. Am J Psychiatry 1998; 155:474-478.
7. Gemma S, Vichi S, Testai E. Individual susceptibility and alcohol effects: biochemical and genetic aspects. Ann Ist Super Sanita 2006; 42:8-16.
8. Mayfield RD, Harris RA, Schuckit MA. Genetic factors influencing alcohol dependence. Br J Pharmacol 2008; 154:275-287.
9. Coşkunol H, Altıntoprak E. Alkol kullanımının genetik yönleri. Klinik Psikiyatri 1999; 2:222-229.
10. Agarwal DP. Genetic polymorphisms of alcohol metabolizing enzymes. Pathol Biol 2001; 49:703-709.
11. Neumark YD, Friedlander Y, Thomasson HR, Li TK. Association of the ADH2*2 allele with reduced ethanol consumption in Jewish men in Israel: a pilot study. J Stud Alcohol 1998; 59:133-139.
12. Edenberg HJ, Foroud T. The genetics of alcoholism: identifying specific genes through family studies. Addict Biol 2006; 11:386-396.
13. Chen WJ, Loh EW, Hsu YP, Chen CC, Yu JM, Cheng AT. Alcohol-metabolising genes and alcoholism among Taiwanese Han men: independent effect of ADH2, ADH3 and ALDH2. Br J Psychiatry 1996; 168:762-767.
14. Blum K, Noble EP, Sheridan PJ, Montgomery A, Ritchie T, Jagadeeswaran P, et al. Allelic association of human dopamine D2 receptor gene in alcoholism. J Am Med Assoc 1990; 263:2055-2060.
15. Edenberg HJ, Foroud T, Koller DL, Goate A, Rice J, Van Eerdewegh P, et al. A family-based analysis of the association of the dopamine D2 receptor (DRD2) with alcoholism. Alcohol Clin Exp Res 1998; 22:505-512.
16. Smith L, Watson M, Gates S, Ball D, Foxcroft D. Meta-Analysis of the association of the Taq1A polymorphism with the risk of alcohol dependency: A HuGE Gene-Disease Association Review. Am J Epidemiol 2008; 167:125-138.
17. Bau CH, Almeida S, Costa FT, Garcia CE, Elias EP, Ponso AC, et al. DRD4 and DAT1 as modifying genes in alcoholism: interaction with novelty seeking on level of alcohol consumption. Mol Psychiatry 2001; 6:7-9.
18. Sander T, Harms H, Podschus J, Finckh U, Nickel B, Rolfs A, et al. Allelic association of a dopamine transporter gene polymorphism in alcohol dependence with withdrawal seizures or delirium. Biol Psychiatry 1997; 41:299-304.
19. Schmidt LG, Harms H, Kuhn S, Rommelspacher H, Sander T. Modification of alcohol withdrawal by the A9 allele of the dopamine transporter gene. Am J Psychiatry 1998; 155:474-478.
20. Kohnke MD, Zabetian CP, Anderson GM, Kolb W, Gaertner I, Buchkremer G, et al. A genotypecontrolled analysis of plasma dopamine betahydroxylase in healthy and alcoholic subjects: evidence for alcohol-related differences in noradrenergic function. Biol Psychiatry 2002; 52:1151-1158.
21. Hallikainen T, Lachman H, Saito T, Volavka J, Kauhanen J, Salonen JT, et al. Lack of association between the functional variant of the catechol-o-methyltransferase (COMT) gene and early-onset alcoholism associated with severe antisocial behavior. Am J Med Genet 2000; 96:348-352.
22. Buck KJ. Molecular genetic analysis of the role of GABAergic systems in the behavioral and cellular actions of alcohol. Behav Genet 1996; 26:313-323.
23. Loh EW, Ball D. Role of the GABA(A)beta2, GABA(A)alpha6, GABA (A)alpha1 and GABA(A) gamma2 receptor subunit genes cluster in drug responses and the development of alcohol dependence. Neurochem Int 2000; 37:413-423.
24. Park CS, Park SY, Lee CS, Sohn JW, Hahn GH, Kim BJ. Association between alcoholism and the genetic polymorphisms of the GABAA receptor genes on chromosome 5q33-34 in Korean population. J Korean Med Sci 2006; 21:533-538.
25. Sander T, Samochowiec J, Ladehoff M, Smolka M, Peters C, Riess O, et al. Association analysis of exonic variants of the gene encoding the GABAB receptor and alcohol dependence. Psychiatr Genet 1999; 9:69-73.
26. Loh el-W, Lane HY, Chen CH, Chang PS, Ku LW, Wang KH, et al. Glutamate decarboxylase genes and alcoholism in Han Taiwanese men. Alcohol Clin Exp Res 2006; 30:1817-1823.
27. Tsai G, Coyle JY. The role of glutamatergic neurotransmission in the pathophysiology of alcoholism. Annu Rev Med 1998; 49:173-184.
28. Wernicke C, Samochowiec J, Schmidt LG, Winterer G, Smolka M, Kucharska-Mazur J, et al. Polymorphisms in the N-methyl-D-aspartate receptor 1 and 2B subunits are associated with alcoholism-related traits. Biol Psychiatry 2003; 54:922-928.
29. Pastor IJ, Laso FJ, Inés S, Marcos M, González- Sarmiento R. Genetic association between 93A/G polymorphism in the Fyn kinase gene and alcohol dependence in Spanish men. Eur Psychiatry 2008; doi:10.1016/j.eurpsy.2008.08.007
30. Tadic A, Dahmen N, Szegedi A, Rujescu D, Giegling I, Koller G, et al. Polymorphisms in the NMDA subunit 2B are not associated with alcohol dependence and alcohol withdrawal-induced seizures and delirium tremens. Eur Arch Psychiatry Clin Neurosci 2005; 255:29-35.
31. McBride W, Li T. Animal models of alcoholism: neurobiology of high alcohol-drinking behaviour in rodents. Crit Rev Neurobiol 1998; 12:339-369.
32. Arias A, Feinn R, Kranzler HR. Association of an Asn40Asp (A118G) polymorphism in the muopioid receptor gene with substance dependence: a meta-analysis. Drug Alcohol Depend 2006; 83:262-268.
33. Ray LA, Hutchison KE. Effects of naltrexone on alcohol sensitivity and genetic moderators of medication response: a double-blind placebocontrolled study. Arch Gen Psychiatry 2007; 64:1069-1077.
34. Anton RF, Oroszi G, O'Malley S, Couper D, Swift R, Pettinati H, et al. An evaluation of mu-opioid receptor (OPRM1) as a predictor of naltrexone response in the treatment of alcohol dependence: results from the Combined Pharmacotherapies and Behavioral Interventions for Alcohol Dependence (COMBINE) study. Arch Gen Psychiatry 2008; 65:135-144.
35. Grant K. The role of 5-HT3 receptors in drug dependence. Drug Alcohol Depend 1995; 38:155-171.
36. Feinn R, Nellissery M, Kranzler HR. Metaanalysis of the association of a functional serotonin transporter promoter polymorphism with alcohol dependence. Am J Med Genet B (Neuropsychiatr Genet) 2005; 133:79-84.
37. Limosin F, Lose YV, Boni C, Hamon M, Ades J, Rouillon F, et al. Male-specific association be- tween the 5-HTTLPR S allele and suicide attempts in alcohol-dependent subjects. J Psychiatric Res 2005; 39:179-182.
38. Kohnke MD, Kolb W, Lutz U, Maurer S, Batra A. The serotonin transporter promotor polymorphism 5-HTTLPR is not associated with alcoholism or severe forms of alcohol withdrawal in a German sample. Psychiatr Genet 2006; 16:227-228.
39. Gürel SC, Ayhan Y, Babaoğlu M, Yaşar Ü, Demir B, Uluğ B, ve ark. Türkiye’de alkol bağımlılarında serotonin taşıyıcısı gen polimorfizmi. 44. Ulusal Psikiyatri Kongresi, 2008, Antalya.
40. Altıntoprak E, Tezcanlı B, Özel R, Kosova B, Topçu N, Çoşkunol H, ve ark. Alkol bağımlılığında serotonin reseptörü 5-HTR2A ve serotonin transportörü 5-HTT gen polimorfizmlerinin araştırılması. 4. Ulusal Bağımlılık Kongresi, 2007, Çeşme- İzmir.
41. Van Munster BC, Korevaar JC, Rooij SE, Levi M, Zwinderman AH. Genetic polymorphisms related to delirium tremens: a systematic review. Alcohol Clin Exp Res 2007; 31:177-184.
42. Schmidt LG, Sander T. Genetics of alcohol withdrawal. Eur Psychiatry 2000; 15:135-139.
43. Haile CN, Kosten TA, Kosten TR. Pharmacogenetic treatments for drug addiction: alcohol and opiates. Am J Drug Alcohol Abuse 2008; 34:355-381.
44. Ducci F, Goldman D. Genetic approaches to addiction: genes and alcohol. Addiction 2008; 103:1414-1428.
45. Johnson C, Drgon T, Liu QR, Walther D, Edenberg H, Rice J. Pooled association genome scanning for alcohol dependence using 104 268 SNPs: validation and use to identify alcoholism vulnerability loci in unrelated individuals from the collaborative study on the genetics of alcoholism. Am J Med Genet B Neuropsychiatr Genet 2006; 141:844-853.
46. Ma Q, Yu Y, Meng Y, Farrell J, Farrer LA, Wilcox MA. Genome-wide linkage analysis for alcohol dependence: a comparison between singlenucleotide polymorphism and microsatellite marker assays. BMC Genetics 2005(Suppl.1):1-8.
47. Tsankova N, Renthal W, Kumar A, Nestler EJ. Epigenetic regulation in psychiatric disorders. Nat Rev Neurosci 2007; 8:355-367.
48. Gilbert SF. Ecological developmental biology: developmental biology meets the real world. Dev Biol 2001; 233:1-12.
49. Gluckman PD, Hanson MA. Developmental origins of disease paradigm: a mechanistic and evolutionary perspective. Pediatr Res 2004; 56:311-317.
50. Nestler EJ. Molecular mechanisms of drug addiction. Neuropharmacology 2004; 47:24-32.