Barış YILBAŞ, Neslihan AKKISI KUMSAR, Nesrin DİLBAZ

Eroin bağımlılarında dopamin 2 reseptör (DRD2) TaqIA gen polimorfizmi ile bağımlılık ilişkisi

Amaç: Eroin bağımlılığının etiyolojik nedenlerinin anlaşılması, bu hastalığın önlenmesinde ve tedavisinde önemli bir katkı sağlayacaktır. Son yıllarda yapılan çalışmalar, bağımlılık gelişiminde ödül yolaklarının ve dopaminerjik sisteminin önemini vurgulamaktadır. DRD2 TaqIA gen polimorfizminin hipodopaminerjik aktiviteye neden olarak ödül sistemini etkilediği ve madde bağımlılığı gelişimine neden olabileceği düşünülmektedir. Bu çalışmada, TaqIA polimorfizminin eroin bağımlılığı ile olası ilişkisinin incelenmesi amaçlanmıştır. Yöntem: Bu çalışmaya Ankara Numune Hastanesi Alkol Madde Tedavi ve Eğitim Merkezi'ne tedavi için başvuran, DSM-IV ölçütlerine göre yapılan klinik değerlendirme sonucu eroin bağımlılığı tanısı alan 100 hasta alındı. Kontrol grubu olarak çalışmaya katılmayı kabul eden, hasta grubuyla yaş ve cinsiyet bakımından eşleştirilmiş 100 sağlıklı gönüllü alındı. Bulgular: Hasta grubu ve kontroller arasında A1 aleli taşıyıcılığı açısından istatistiksel olarak anlamlı fark yoktu. Hasta grubunun A1 aleli taşıyıcılığına göre iki gruba ayrılmasıyla yapılan değerlendirmede madde kullanım özellikleriyle A1 aleli arasında istatiksel olarak anlamlı bir ilişki saptanmamıştır. Sonuçlar: Çalışmamızın sonuçları, ödül yolaklarıyla ilişkili olduğu bilinen TaqIA polimorfizminin tek başına eroin bağımlılığı gelişimi ile ilişkili olmadığını göstermektedir. Bu çalışma, karmaşık bir yapıya sahip olan eroin bağımlılığının tek bir genetik faktörle açıklanamayacağını, genetik faktörler kadar başka faktörlerin de eroin bağımlılığı gelişiminde rol oynayabileceğini, bağımlılığa neden olan genetik etkenlerin bulunabilmesi için çok daha geniş örneklemlerde, farklı genlere ve gen-gen etkileşimlerine bakılması gerektiğini düşündürmektedir.

Relation of addiction with dopamine 2 receptor (DRD2) TaqIA polymorphism in heroin addicts

Objective: To understand the etiologic reasons of heroin addiction will make an important contribution to the prevention and treatment of this disease. It is thought that DRD2 TaqIA gene polymorphism affects the reward system by causing hyperdopaminergic activity and thereby might also lead to the development of substance addiction. The purpose of this study is to examine the possible relation between TaqIA polymorphism and heroin addiction. Methods: One hundred patients, who applied to Ankara Numune Hospital Alcohol and Substance Treatment and Training Centre for treatment and were diagnosed with heroin addiction as a result of the clinical evaluation that was conducted in accordance with DSM-IV were included in this study. One hundred healthy volunteers, who accepted to participate in the study as the control group and were matched with the patient group in terms of age and gender, were involved. Results: There was no statistically significant difference between the patient and control groups in terms of A1 allele carrier. As a result of the evaluation that was performed by dividing the patient group into two groups according to A1 allele carrier, no statistically significant relation was determined between the substance-use features and A1 allele. Conclusion: DRD2 TaqIA polymorphism, which is known to be associated with reward pathways, cannot be a genetic factor that is effective on the development of heroin addiction alone and it is required to consider different genes and gene-gene interactions in broader sample groups in order to determine the genetic factors causing the addiction.

PDF

___

1. Mc Lellan AT, Lewis DC, O'Brien CP, Kleber HD. Drug dependence, a chronic medical illness: implications for treatment, insurance, and outcomes evaluation. JAMA 2000; 284(13):1689-1695.
2. Kreek MJ, Borg L, Ducat E, Ray B. Pharmacotherapy in the treatment of addiction: methadone. J Addict Dis 2010; 29(2):200-216.
3. Xu K, Lichtermann D, Lipsky RH, Franke P, Liu X, Hu Y. Association of specific haplotypes of D2 dopamine receptor gene with vulnerability to heroin dependence in 2 distinct populations. Arch Gen Psychiatry 2004; 61(6):597-606.
4. Blum K, Braverman ER, Holder JM, Lubar JF, Monastra VJ, Miller D. Reward deficiency syndrome: a biogenetic model for the diagnosis and treatment of impulsive, addictive and compulsive behaviors. J Psychoactive Drugs 2000; 32(Suppl:i-iv):1-112.
5. Neville MJ, Johnstone EC, Walton RT. Identification and characterization of ANKK1: a novel kinase gene closely linked to DRD2 on chromosome band 11q23.1. Hum Mutat 2004; 23(6):540- 545.
6. Grandy DK, Zhang Y, Civelli O. PCR detection of the TaqI A RFLP at the DRD2 locus. Hum Mol Genet 1993; 2(12):2197.
7. Tupala E, Hall H, Mantere T, Rasanen P, Sarkioja T, Tilhonen J. Dopamine receptors and transporters in the brain reward circuits of type 1 and 2 alcoholics measured with human whole hemisphere autoradiography. Neuroimage 2003; 19(1):145-155.
8. Thompson J, Thomas N, Singleton A, Piggott M, Lloyd S, Perry EK, et al. D2 dopamine receptor gene (DRD2) TaqI A polymorphism: reduced dopamine D2 receptor binding in the human striatum associated with the A1 allele. Pharmacogenetics 1997; 7(6):479-484.
9. Jonsson EG, Nothen MM, Grunhage F, Farde L, Nakashima Y, Propping P, et al. Polymorphisms in the dopamine D2 receptor gene and their relationships to striatal dopamine receptor density of healthy volunteers. Mol Psychiatry 1999; 4(3):290-296.
10. Noble EP. D2 dopamine receptor gene in psychiatric and neurologic disorders and its phenotypes. Am J Med Genet 2003;116B(1):103-125.
11. Neiswanger K, Hill SY, Kaplan B. Association and linkage studies of the TAQI A1 allele at the dopamine D2 receptor gene in samples of female and male alcoholics. Am J Med Genet 1995; 60(4):267-271.
12. Hietala J, Pohjalainen T, Heikkila-Kallio U, West C, Salaspuro M, Syvalahti E. Allelic association between D2 but not D1 dopamine receptor gene and alcoholism in Finland. Psychiatr Genet 1997; 7(1):19-25.
13. Amadeo S, Abbar M, Fourcade ML, Waksman G, Leroux MG, Madec A, Selin M, Champiat JC, Brethome A, Leclaire Y. D2 dopamine receptor gene and alcoholism. J Psychiatr Res 1993; 27(2):173-179.
14. Heinz A, Sander T, Harms H, Finckh U, Kuhn S, Dufeu P, et al. Lack of allelic association of dopamine D1 and D2 (TaqIA) receptor gene polymorphisms with reduced dopaminergic sensitivity to alcoholism. Alcohol Clin Exp Res 1996; 20(6):1109-1113.
15. Chen WJ, Lu ML, Hsu YP, Chen CC, Yu JM, Cheng AT. Dopamine D2 receptor gene and alcoholism among four aboriginal groups and Han in Taiwan. Am J Med Genet 1997; 74(2):129-136.
16. Ball D. Genetic approaches to alcohol dependence. Br J Psychiatry 2004; 185:449-451.
17. Cruz C, Camarena B, Mejia JM, Paez F, ErozaV, Ramon De La Fuente J, et al. The dopamine D2 receptor gene TaqI A1 polymorphism and alcoholism in a Mexican population. Arch Med Res 1995; 26(4):421-426.
18. 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(2):125-138.
19. Nacak M, Isir AB, Balci SO, Pehlivan S, Benlier N, Aynacioğlu S. Analysis of dopamine D2 receptor (DRD2) gene polymorphisms in cannabinoid addicts. J Forensic Sci 2012; 57(6):1621-1624.
20. Noble EP, Blum K, Khalsa ME, Ritchie T, Montgomery A, Wood RC. Allelic association of the D2 dopamine receptor gene with cocaine dependence. Drug Alcohol Depend 1993: 33(3):271- 285.
21. Shahmoradgoli NM, Ohadi M, Joghataie MT, Valaie F, Riazalhosseini Y, Mostafavi H, et al. Association between the DRD2 A1 allele and opium addiction in the Iranian population. Am J Med Genet 2005; 134B(1):39-41.
22. Hou QF, Li SB. Potential association of DRD2 and DAT1 genetic variation with heroin dependence. Neuroscience Letters 2009; 464(2):127-130.
23. Teh LK, Izuddin AF, Zakaria ZA, Salleh MZ. Tridimensional personalities and polymorphism of dopamine D2 receptor among and heroin addicts. Biol Res Nurs 2012; 14(2):188-196.
24. Barrat DT, Coller JK, Somogyi A. Association between the DRD2 A1 allele and response to methadone and buprenorphine maintenance treatments. Am J Med Genet B Neuropsychiatr Genet 2006; 141B:323-331.
25. Crettol S, Besson J, Croquette M, Hammig R, Gothuey I, Monat M. Association of dopamine and opioid receptor genetic polymorphisms with response to methadone maintenance treatment. Prog Neuropsychopharmacol Biol Psychiatry 2008; 32(7):1722-1727.
26. Fang YJ, Thomas GN, Xu ZL, Fang JQ, Critchley JA, Tomlinson B. An affected pedigree member analysis of linkage between the dopamine D2 receptor gene TaqIA polymorphism and obesity and hypertension. Int J Cardiol 2005; 102(1):111- 116.
27. Comings DE, Flanagan SD, Dietz G, Muhleman D, Knell E, Gysin R. The dopamine D2 receptor (DRD2) as a major gene in obesity and height. Biochem Med Metab Biol 1993; 50(2):176-185.
28. Noble EP, Noble ER, Ritchie T, Syndulko K, Bohlman NC, Noble LA. D2 dopamine receptor gene and obesity. Int J Eat Disord 1994; 15(3):205-217.
29. First MB, Gibbon M, Spitzer RL, Williams JBW. Structured Clinical Interview for DSM-IV(SCID). Washington: APA,1997.
30. Çorapçıoğlu A, Aydemir Ö, Yıldız M, Esen E, Köroğlu E. Structured Clinical Interview for Axis II Disorders for DSM-IV Clinical Version. Ankara: HYB, 2009. (In Turkish)
31. Roussotte FF, Jahanshad N, Hibar DP, Thompson PM. Altered regional brain volumes in elderly carriers of a risk variant for drug abuse in the dopamine D2 receptor gene (DRD2) Brain Imaging Behav 2015; 9(2):213-222.
32. Wang TY, Lee SY, Chen SL, Chang YH, Chen SH, Chu CH. The ADH1B and DRD2 gene polymorphism may modify the protective effect of the ALDH2 gene against heroin dependence. Prog Neuropsychopharmacol Biol Psychiatry 2013; 43:134-139.
33. Perez J, Baiget M, Trujols J, Sinol N, Volpini V, Banuls E. Allelic and genotypic associations of DRD2 TaqIA polymorphism with heroin dependence in Spanish subjects: a case control study. Behav Brain Funct 2007; 3:25.
34. Kaasinen V, Nagren K, Hietala J, Farde L, Rinne JO. Sex differences in extrastriatal dopamine D2- like receptors in the human brain. Am J Psychiatry 2001; 158:308-311.