Molecular Biology Reports

, Volume 46, Issue 4, pp 3929–3936 | Cite as

Chronic tinnitus and BDNF/GDNF CpG promoter methylations: a case–control study

  • Seda Orenay-BoyaciogluEmail author
  • Metin Caliskan
  • Olcay Boyacioglu
  • Aysun Coskunoglu
  • Gokay Bozkurt
  • F. Sirri Cam
Original Article


Brain-derived neurotrophic factor (BDNF) and Glial-derived neurotrophic factor (GDNF) are neurotrophic factors that play key roles in the auditory pathway. While the relationship between serum levels and polymorphisms of BDNF/GDNF and chronic tinnitus is emphasized in the literature, there is no study showing the link between the promoter methylations of these genes and tinnitus. For this purpose, the relationship between chronic tinnitus and peripheral blood derived BDNF/GDNF promoter methylations was investigated to identify their role in the pathophysiology of tinnitus. In this case–control study, we examined the possible effects of BDNF/GDNF methylations in the blood samples of patients with tinnitus complaints for more than 3 months. Sixty tinnitus subjects between the ages of 18–55 and 50 healthy control subjects in the same age group who were free of any otorhinolaryngology and systemic disease were selected for examination. Methylation of total 12 CpG sites in BDNF and GDNF promoter regions were determined by the bisulfite-pyrosequencing method. Statistically significant differences were detected between BDNF CpG6 and GDNF CpG3-5-6 methylation ratios in the comparison of control group and the chronic tinnitus patients (P = 0.002, 0.0005, 0.00003, and 0.0029, respectively). To our knowledge, this is the first study in the literature investigating the relationship between chronic tinnitus and peripheral blood derived BDNF/GDNF promoter methylations. It is believed that the current results might be supported by investigating the relationships between BDNF/GDNF methylations and genotypes in future research using higher sample sizes.


BDNF GDNF Chronic tinnitus Promoter methylation Bisulfite-pyrosequencing 



This study was conducted without funding.

Compliance with ethical standards

Conflict of interest

The authors have not declared any conflicts of interest.


  1. 1.
    Nondahl DK, Cruickshanks KJ, Wiley TL, Klein R, Klein BE, Tweed TS (2002) Prevalence and 5-year incidence of tinnitus among older adults: the epidemiology of hearing loss study. J Am Acad Audiol 13(6):323–331Google Scholar
  2. 2.
    Nondahl DM, Cruickshanks KJ, Wiley TL et al (2010) The 10-year incidence of tinnitus among older adults. Int J Audol 49(8):580–585CrossRefGoogle Scholar
  3. 3.
    Sand PG, Langguth B, Kleinjung T, Eichhammer P (2007) Genetics of chronic tinnitus. Prog Brain Res 166:159–168CrossRefGoogle Scholar
  4. 4.
    Jastreboff PJ, Hazell JWP (2004) Tinnitus retraining therapy. Cambridge University Press, CambridgeCrossRefGoogle Scholar
  5. 5.
    Kotan Z, Sarandöl A, Eker SS, Akkaya C (2009) Depresyon, Nöroplastisite ve Nörotrofik Faktörler. Curr Approaches Psychiatry 1:22–26Google Scholar
  6. 6.
    Goto F, Saruta J, Kanzaki S, To M, Tsutsumi T, Tsukinoki K, Ogawa K (2012) Various levels of plasma brain-derived neurotrophic factor in patients with tinnitus. Neurosci Lett 510(2):73–77CrossRefGoogle Scholar
  7. 7.
    Eker C, Kitis O, Ozan E, Okur H, Donat Eker O, Ersoy MA et al (2005) BDNF gene Val66met polymorphism associated grey matter changes in human brain. BCF 15:104Google Scholar
  8. 8.
    Stöver T, Nam Y, Gong TL, Lomax MI, Altschuler RA (2001) Glial cell line-derived neurotrophic factor (GDNF) and its receptor complex are expressed in the auditory nerve of the mature rat cochlea. Hear Res 155:143–151CrossRefGoogle Scholar
  9. 9.
    Sand PG, Langguth B, Schecklmann M, Kleinjung T (2012) GDNF and BDNF gene interplay in chronic tinnitus. Int J Mol Epidemiol Genet 3(3):245–251Google Scholar
  10. 10.
    Juckkel G, Schumacher C, Giegling I, Assion HJ, Mavrogiorgou P, Pogarell O et al (2010) Serotonergic functioning as measured by the loudness dependence of auditory evoked potentials is related to a haplotype in the brain-derived neurotrophic factor (BDNF) gene. J Psychiatr Res 44:541–546CrossRefGoogle Scholar
  11. 11.
    Karege F, Perret G, Bondolfi G et al (2002) Decreased serum brain-derived neurotrophic factor levels in Major depressed patients. Psychiatry Res 109(2):143–148CrossRefGoogle Scholar
  12. 12.
    Tsai SJ, Cheng CY, Yu YWY, Chen TJ, Hong CJ (2003) Association study of a brain-derived neurotrophic-factor genetic polymorphism and major depressive disorders, symptomatology, and antidepressant response. Am J M Genet Part B Neuropsychiatric Genetics 123(1):19–22CrossRefGoogle Scholar
  13. 13.
    Langguth B, Landgrebe M, Kleinjung T et al (2011) Tinnitus and depression. World J Biol Psychiatry 12(7):489–500CrossRefGoogle Scholar
  14. 14.
    Coskunoglu A, Orenay-Boyacioglu S, Deveci A, Bayam M, Onur E, Onan A, Cam FS (2017) Evidence of associations between brain-derived neurotrophic factor (BDNF) serum levels and gene polymorphisms with tinnitus. Noise Health 19(88):140CrossRefGoogle Scholar
  15. 15.
    Orenay-Boyacioglu S, Coskunoglu A, Caki Z, Cam FS (2016) Relationship between chronic tinnitus and glial cell line-derived neurotrophic factor gene rs3812047, rs1110149, and rs884344 polymorphisms in a Turkish Population. Biochem Genet 54(4):552–563CrossRefGoogle Scholar
  16. 16.
    Leon A, Buriani A, Dal Toso R, Fabris M, Romanello S, Aloe L et al (1994) Mast cells synthesize, store, and release nerve growth factor. Proc Natl Acad Sci USA 91(9):3739–3743CrossRefGoogle Scholar
  17. 17.
    Cedar H, Bergman Y (2012) Programming of DNA methylation patterns. Annu Rev Biochem 81:97–117CrossRefGoogle Scholar
  18. 18.
    Stenz L, Zewdie S, Laforge-Escarra T, Prados J, La Harpe R, Dayer A et al (2015) BDNF promoter I methylation correlates between post-mortem human peripheral and brain tissues. Neurosci Res 91:1–7CrossRefGoogle Scholar
  19. 19.
    Guidotti A, Auta J, Davis JM, Dong E, Gavin DP, Grayson DR et al (2014) The identification of peripheral epigenetic biomarkers of schizophrenia. J Neurogenet 28:41–52CrossRefGoogle Scholar
  20. 20.
    Yi B, Wu C, Shi R, Han K, Sheng H, Li B et al (2018) Long-term administration of salicylate-induced changes in BDNF expression and CREB phosphorylation in the auditory cortex of rats. Otol Neurotol 39(3):e173CrossRefGoogle Scholar
  21. 21.
    Mulders WH, Vooys V, Makowiecki K, Tang AD, Rodger J (2016) The effects of repetitive transcranial magnetic stimulation in an animal model of tinnitus. Sci Rep 6:38234CrossRefGoogle Scholar
  22. 22.
    Yang H, Xiong H, Ou Y, Xu Y, Pang J, Lai L, Zheng Y (2016) Effect of repetitive transcranial magnetic stimulation on auditory function following acoustic trauma. Neurol Sci 37(9):1511–1516CrossRefGoogle Scholar
  23. 23.
    Tan J, Rüttiger L, Panford-Walsh R, Singer W, Schulze H, Kilian SB et al (2007) Tinnitus behavior and hearing function correlate with the reciprocal expression patterns of BDNF and Arg3. 1/arc in auditory neurons following acoustic trauma. Neuroscience 145(2):715–726CrossRefGoogle Scholar
  24. 24.
    Xiong H, Yang H, Liang M, Ou Y, Huang X, Cai Y et al (2016) Plasma brain-derived neurotrophic factor levels are increased in patients with tinnitus and correlated with therapeutic effects. Neuroscilett 622:15–18Google Scholar
  25. 25.
    Park YM, Lee SH, Lee HJ, Kang SG, Min JA, Chae JH (2013) Association between BDNF gene polymorphisms and serotonergic activity using loudness dependence of auditory evoked potentials in healthy subjects. PLoS ONE 8:e60340CrossRefGoogle Scholar

Copyright information

© Springer Nature B.V. 2019

Authors and Affiliations

  1. 1.Department of Medical Genetics, Faculty of MedicineAydin Adnan Menderes UniversityAydinTurkey
  2. 2.Faculty of EngineeringAydin Adnan Menderes UniversityAydinTurkey
  3. 3.Department of Medical GeneticsState Hospital of SivasSivasTurkey
  4. 4.Department of Medical Genetics, Faculty of MedicineManisa Celal Bayar UniversityManisaTurkey

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