Association of BDNF Val66Met polymorphism with Amphetamine and Opioid dependency in Azeri population of Iran: A case- control study

Document Type : Original Article

Authors

1 Professor of Child and Adolescent Psychiatry, Research Center of Psychiatry and Behavioral Sciences, Tabriz University of Medical Sciences, Tabriz, Iran

2 Resident of Psychiatry, Research Center of Psychiatry and Behavioral Sciences, Tabriz University of Medical Sciences, Tabriz, Iran

3 Assistance Professor of Molecular Genetics, Department of Animal Biology, Faculty of Natural Science, University of Tabriz, Tabriz, Iran

4 Assistant professor of Psychiatry, Research Center of Psychiatry and Behavioral Sciences, Tabriz University of Medical Sciences, Tabriz, Iran

5 Health psychology, Research Center of Psychiatry and Behavioral Sciences, Tabriz University of Medical Sciences, Tabriz, Iran

6 Associate Professor of Cognitive Neuroscience, Department of Cognitive Neuroscience, Faculty of Education and Psychology, University of Tabriz, Tabriz, Iran

Abstract

Background: Emerging evidence suggests a link between the Val66Met polymorphism of brain-derived neurotrophic factor (BDNF) and an increased risk of neurobehavioral disorders (reference here). The present study aims to elucidate the potential relationship between this genotype and the predisposition to amphetamine and opiate dependencies among the Iranian Azeri population. Through rigorous analysis and comprehensive genetic profiling, this research endeavors to contribute valuable insights into the complex interplay between genetic factors and substance dependency in this specific ethnic group.
 
Methods: A cohort of 150 participants was recruited for this study, consisting of 133 males and 17 females in the treatment group, alongside 100 controls, comprising 74 males and 26 females. Genotyping procedures utilized PCR-RFLP genotyping.
 
Results: Comprehensive analysis revealed no statistically significant differences in the distribution of genotypes and alleles of the BDNF gene polymorphism (rs6265) between the case and control cohorts. The control group’s GG and AA genotypes were higher than the case group’s, while the control group’s AG genotype was lower than the case group’s, but statistically significant difference was not showed (p > 0.05).
 
Conclusion: The outcomes of this rigorously designed study fail to substantiate a significant correlation between the Val66Met polymorphism of the BDNF gene and the susceptibility to amphetamine and opiate dependency. This finding adds a new piece of the puzzle to our understanding of genetic predispositions in substance dependence.

Keywords


Acknowledgements: The authors express their sincere gratitude to all the participants who generously volunteered their time and effort for this study.

 

Availability of data and materials: The data supporting the findings of this research is available upon request from the corresponding author.

 

Conflicts of interests: The authors declare that there are no competing interests.

 

Consent for publication: Not applicable.

 

Ethics approval and consent to participate: This study was conducted according to the principles of the Helsinki declaration. The information of all participants remained completely anonymous. This research protocol was approved by the ethics committee of Tabriz University of Medical sciences (code no. 5/4/12152).The study was conducted in accordance with the principles of the Declaration of Helsinki.

 

Financial disclosure: This research was financially supported by the Research Centre of Psychiatry and Behavioral Sciences of Tabriz University of Medical Sciences.

 

Author contributions: LMF, NZ, SD contributed to the study design and lab experiments. SA, HB & SD performed statistical analyses of data, interpretation of data. SA & AM supervised the study and contributed to all parts of the paper. LMF wrote the paper and all authors read and approved the final version of the paper.

 

 

Open Access Policy: This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. To view a copy of this licence, visit https://creativecommons.org/licenses/by/4.0/

1. Kreek, M.J., Nielsen, D.A., Butelman, E.R. & LaForge, K.S. Genetic influences onimpulsivity, risk taking, stress responsivity and vulnerability to drug abuse and addiction. Nat Neurosci 2005:8,1450-1457.
https://doi.org/10.1038/nn1583
PMid:16251987
 
2. Bolanos CA, Nestler EJ. Neurotrophic mechanisms in drug addiction. Neuromol Med 2004;5:69-83.
https://doi.org/10.1385/NMM:5:1:069
PMid:15001814  
 
3. Autry AE, Monteggia LM. Brain-derived neurotrophic factor and neuropsychiatric disorders. Pharmacol Rev 2012:64:238-58.
https://doi.org/10.1124/pr.111.005108
PMid:22407616 PMCid:PMC3310485  
 
4. Ghitza UE, Zhai H, Wu P, Airavaara M, Shaham Y, Lu L. Role of BDNFand GDNF in drug reward and relapse: a review. Neurosci Biobehav Rev2010:35:157-71.
https://doi.org/10.1016/j.neubiorev.2009.11.009
PMid:19914287 PMCid:PMC2891859  
 
5. Lessmann V, Gottmann K, Malcangio M. Neurotrophin secretion: current facts and future prospects. Prog Neurobiol 2003:69:341-74.
https://doi.org/10.1016/S0301-0082(03)00019-4
PMid:12787574  
 
6. Mufson EJ, Kroin JS, Sendera TJ, Sobreviela T. Distribution and retrograde transport of trophic factors in the central nervous system: functional implications for the treatment ofneurodegenerative diseases. Prog Neurobiol 1999:57:451-84.
https://doi.org/10.1016/S0301-0082(98)00059-8
PMid:10080385  
 
7. Dluzen DE, McDermott JL. Neuroprotective roleof estrogen upon methamphetamine and related neurotoxins within the nigrostriatal dopaminergic system. Ann N Y Acad Sci. 2000:914:112-126.
https://doi.org/10.1111/j.1749-6632.2000.tb05189.x
PMid:11085314  
 
8. Lewis C, Dluzen DE. Testosterone enhances dopamine depletion by methamphetamine in male, but not female, mice. Neurosci Lett. 2008:448:130 -133.
https://doi.org/10.1016/j.neulet.2008.10.011
PMid:18852023  
 
9. Enoch MA, Hodgkinson CA, Yuan Q, Albaugh B, Virkkunen M,Goldman D GABRA1 and GABRA2 as independent predictors for alcoholism in two populations. Neuropsychopharmacology 2009:34:1245-1254.
https://doi.org/10.1038/npp.2008.171
PMid:18818659 PMCid:PMC2656604  
 
10. Saccone NL, Saccone SF, Hinrichs AL, Stitzel JA, Duan W, Pergadia ML, Agrawal A, et al. Multiple distinct risk loci for nicotine dependence identified by dense coverage of the complete family of nicotinic receptor subunit (CHRN) genes. Am J Med Genet B Neuropsychiatr Genet 2009:150B:453-466.
https://doi.org/10.1002/ajmg.b.30828
PMid:19259974 PMCid:PMC2693307  
 
11. Yuferov V, Levran O, Proudnikov D, Nielsen DA, Kreek MJ.Search for genetic markers and functional variants involved in the development of opiate and cocaine addictionand treatment. Ann N Y Acad Sci 2010: 1187:184-207.
https://doi.org/10.1111/j.1749-6632.2009.05275.x
PMid:20201854 PMCid:PMC3769182  
 
12. Li MD, Burmeister M. New insights into the genetics ofaddiction. Nat Rev Genet 2009:10:225-231.
https://doi.org/10.1038/nrg2536
PMid:19238175 PMCid:PMC2879628  
 
13. Khokhar JY, Ferguson CS, Zhu AZX, Tyndale RF Pharmacogenetics of drug dependence: role of gene variations in susceptibility andtreatment. Annu Rev PharmacolToxicol 2010:50:39-61.
https://doi.org/10.1146/annurev.pharmtox.010909.105826
PMid:20055697  
 
14. Itoh, K., Hashimoto, K., Shimizu, E., Sekine, Y., Ozaki, N., Inada, T.,Harano, M., et al. Association study betweenbrain-derived neurotrophic factor gene polymorphisms and methamphetamine abusers in Japan. Am. J. Med. Genet. B Neuropsychiatr. Genet. 2005:132B, 70-73.
https://doi.org/10.1002/ajmg.b.30097
PMid:15459944  
 
15. Flanagin, B.A., Cook Jr., E.H., de Wit, H. An association studyof the brain-derivedneurotrophic factor Val66Metpolymorphism and amphetamine response. Am. J. Med. Genet.B Neuropsychiatr. Genet2006:141B, 576-583.
https://doi.org/10.1002/ajmg.b.30327
PMid:16823800 PMCid:PMC2556402  
 
16. Dluzen, D.E., Story, G.M., Xu, K., Kucera, J., Walro, J.M.Alterations in nigrostriatal dopaminergic function within BDNF mutant mice. Exp. Neurol. 1999:160, 500-507.
https://doi.org/10.1006/exnr.1999.7225
PMid:10619567  
 
17. Egan MF, Kojima M, Callicott JH, Goldberg TE, Kolachana BS, Bertolino A, et al.The BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function. Cell. 2003:112(2):257-69.
https://doi.org/10.1016/S0092-8674(03)00035-7
PMid:12553913  
 
18. Beuten J, Ma JZ, Payne TJ, Dupont RT, Quezada P, Huang W, et al. Significantassociation of BDNF haplotypes in European‐ American male smokers but not inEuropean‐ American female or African‐ American smokers. American Journal of MedicalGenetics Part B: Neuropsychiatric Genetics. 2005:139(1):73-80.
https://doi.org/10.1002/ajmg.b.30231
PMid:16152573  
 
19. Montag C, Basten U, Stelzel C, Fiebach CJ, Reuter M. The BDNF Val66Metpolymorphism and smoking. Neuroscience letters. 2008:442(1):30-3.
https://doi.org/10.1016/j.neulet.2008.06.064
PMid:18602452  
 
20. Lang UE, Sander T, Lohoff FW, Hellweg R, Bajbouj M, Winterer G, et al. Association of the met66 allele of brain-derived neurotrophic factor (BDNF) with smoking. Psychopharmacology. 2007:190(4):433-9.
https://doi.org/10.1007/s00213-006-0647-1
PMid:17186223  
 
21. Haile, C.N., Kosten, T.R., Kosten, T.A. Pharmacogenetic treatments for drug addiction: cocaine, amphetamine and methamphetamine. Am. J. Drug Alcohol Abuse 2009:35, 161-177.
https://doi.org/10.1080/00952990902825447
PMid:19462300 PMCid:PMC2754046  
 
22. Cheng, C.Y., Hong, C.J., Yu, Y.W., Chen, T.J., Wu, H.C., Tsai, S.J. Brain-derived neurotrophic factor (Val66Met) genetic polymorphism is associated with substance abuse in males. Brain Res. Mol. Brain Res. 2005: 140, 86-90.
https://doi.org/10.1016/j.molbrainres.2005.07.008
PMid:16109452  
 
23. Hyman C, Hofer M, Barde YA, Juhasz M, Yancopoulos GD, Squinto SP, Lindsay RM: BDNF is a neurotrophic factor for dopaminergic neurons of the substantia nigra. Nature 1991:350:230-232.
https://doi.org/10.1038/350230a0
PMid:2005978  
 
24. Cowansage KK, LeDoux JE, Monfils MH: Brain-derived neurotrophic factor: a dynamic gatekeeper of neural plasticity. Curr Mol Pharmacol 2010:3:12-29.
https://doi.org/10.2174/1874467211003010012
PMid:20030625  
 
25. Xie B, Wang B, Suo P, Kou C, Wang J, Meng X, Cheng L, Ma X, Yu Y: Genetic association between BDNF gene polymorphisms and phobic disorders: a case-control study among mainland Han Chinese. J Affect Disord 2011: 132:239-242.
https://doi.org/10.1016/j.jad.2010.12.017
PMid:21295349  
 
26. Ducray A, Krebs SH, Schaller B, Seiler RW, Meyer M, Widmer HR: GDNF family ligandsdisplay distinct action profiles on cultured GA BAergic and serotonergic neurons of rat ventralmesencephalon. Brain Res 2006:1069:104-112.
https://doi.org/10.1016/j.brainres.2005.11.056
PMid:16380100  
 
27. Leal G, Afonso PM, Salazar IL, Duarte CB: Regulation of hippocampal synaptic plasticity by BDNF. Brain Res 2015:1621:82-101.
https://doi.org/10.1016/j.brainres.2014.10.019
PMid:25451089  
 
28. Klein AB, Williamson R, Santini MA, Clemmensen C, Ettrup A, Rios M, Knudsen GM,Aznar S: Blood BDNF concentrations reflect brain-tissue BDNF levels across species. Int JNeuropsychopharmacol 2011:14:347-253.
https://doi.org/10.1017/S1461145710000738
PMid:20604989  
 
29. Pedersen LM, Jacobsen LM, Mollerup S, Gjerstad J: Spinal cord long-term potentiation(LTP) is associated with increased dorsal horn gene expression of IL-1beta, GDNF and iNOS. Eur J Pain 2010:14:255-260.
https://doi.org/10.1016/j.ejpain.2009.05.016
PMid:19596210  
 
30. Lu L, Dempsey J, Liu SY, Bossert JM, Shaham Y: A single infusion of brain-derived neurotrophic factor into the ventral tegmental area induces long-lasting potentiation of cocaine seeking after withdrawal. J Neurosci 2004:24: 1604-1611.
https://doi.org/10.1523/JNEUROSCI.5124-03.2004
PMid:14973246 PMCid:PMC6730465  
 
31. Pitts EG, Taylor JR, Gourley SL: Prefrontal cortical BDNF: A regulatory key in cocaineand food-reinforced behaviors. Neurobiol Dis 2016:91:326-335.
https://doi.org/10.1016/j.nbd.2016.02.021
PMid:26923993 PMCid:PMC4913044  
 
32. Raivio N, Tiraboschi E, Saarikoski ST et al. Brain-derived neurotrophic factor expression after acute administration of ethanol. Eur.J. Pharmacol. 2012:687(1-3), 9-13.
https://doi.org/10.1016/j.ejphar.2012.04.021
PMid:22546227  
 
33. Sadri-Vakili G, Kumaresan V, Schmidt HD et al. Cocaine-induced chromatin remodeling increases brain-derived neurotrophic factor transcription in the rat medial prefrontal cortex, which alters the reinforcing efficacy of cocaine. J. Neurosci. 2010:30(35), 11735-11744.
https://doi.org/10.1523/JNEUROSCI.2328-10.2010
PMid:20810894 PMCid:PMC2943400  
 
34. Vargas-Perez H, Ting-A Kee R, Walton CH et al. Ventral tegmental area: BDNF induces an opiate-dependent-like reward state in naïve rats. Science 2009:324(5935), 1732-1734.
https://doi.org/10.1126/science.1168501
PMid:19478142 PMCid:PMC2913611  
 
35. Egan MF, Kojima M, Callicott JH et al. The BDNF Val66Met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function. Cell 2003:112(2), 257-269.
https://doi.org/10.1016/S0092-8674(03)00035-7
PMid:12553913  
 
36. Cheng, C. Y. et al. Brain-derived neurotrophic factor (Val66Met) genetic polymorphism is associated with substance abuse in males. Brain Res Mol Brain Res 2005:140, 86-90.
https://doi.org/10.1016/j.molbrainres.2005.07.008
PMid:16109452  
 
37. Gratacos, M. et al. Brain-derived neurotrophic factor Val66Met and psychiatric disorders: meta-analysis of case-control studies confirm association to substance related disorders, eating disorders, and schizophrenia. Biol Psychiatry 2007:61,911-922.
https://doi.org/10.1016/j.biopsych.2006.08.025
PMid:17217930  
 
38. Haerian, B. S. BDNF rs6265 polymorphism and drug addiction: a systematic review and meta-analysis. Pharmacogenomics 2013:14, 2055-2065.
https://doi.org/10.2217/pgs.13.217
PMid:24279859  
 
39. Jia W, Shi JG, Wu B, Ao L, Zhang R, Zhu YS. Polymorphisms of brain-derived neurotrophic factor associated with heroin dependence. Neurosci Lett 2011:495, 221-224
https://doi.org/10.1016/j.neulet.2011.03.072
PMid:21458533  
 
40. Meng, C., Lan, J., Wang, Y., Song, M., Gao, X., Ran, L., Moira, S., & Wang, W. Influence of brain-derived neurotrophic factor genetic polymorphisms on the ages of onset for heroin dependence in a Chinese population. Genetic testing and molecular biomarkers, 2012. 16(9), 1044-1050
https://doi.org/10.1089/gtmb.2012.0016
PMid:22856871  
 
41. He, L., Liao, Y., Wu, Q., & Liu, T. Association Between Brain-Derived Neurotrophic Factor Val66Met Polymorphism and Methamphetamine Use Disorder: A Meta-Analysis. Frontiers in psychiatry,2020. 11, 585852.
https://doi.org/10.3389/fpsyt.2020.585852
PMid:33329128 PMCid:PMC7716815  
 
42. Sim MS., Zahurin Mohamed Z., Hatim A., Rajagopal VL., Habil MH. Association of brain-derived neurotrophic factor (Val66Met) genetic polymorphism with methamphetamine dependence in a Malaysian population, Brain Research, 2010. Volume 1357, Pages 91-96, ISSN 0006-8993.
https://doi.org/10.1016/j.brainres.2010.08.053
PMid:20736000  
 
43. Wang L, McLeod HL, Weinshilboum RM. Genomics and drug response. N. Engl. J. Med.2011:364(12), 1144-1153
https://doi.org/10.1056/NEJMra1010600
PMid:21428770 PMCid:PMC3184612