Majör depresyon hastalarında BDNF gen polimorfizmi (rs6265) ile BDNF gen ekspresyon düzeylerinin araştırılması

Öz

Amaç: Beyin kaynaklı nörotrofik faktörün (BDNF) genetik, moleküler ve hücresel mekanizmalarının ve bunun nöroplastisite ile ilişkisinin daha iyi anlaşılması, majör depresyonda (MD) yeni ilaçlar için gelecekteki terapötik hedeflerin bulunmasında çok önemli bir rol oynayabilir. Bu çalışma, BDNF polimorfizmlerinin MD'deki kesin rolüne ilişkin hala çelişkili sonuçlar olduğundan, MD'de BDNF ile ilişkili polimorfizm (rs6265) ve ekspresyon ilişkisini anlamak amacıyla planlandı. Yöntem: Bu olgu-kontrol çalışmasında, DSM-5 ölçütlerine göre MD’li 51 hasta ve 75 sağlıklı kontrole ait kanlardan BDNF gen Val66Met (rs6265) polimorfizmleri için dizayn edilmiş primerler ile Real-Time PCR ile tek nükleotid polimorfizm çalışmaları yapıldı. Gen ekspresyon analizleri için total RNA kullanıldı. Kantitatif Real-Time PCR yöntemi ile saptanan, MD ve kontrol gruplarındaki BDNF genine ait ekspresyon düzeyleri ile polimorfizmler arasındaki ilişki istatistiksel yöntemlerle incelendi. Bulgular: Erkek ve kadınlarda, genotip ile grup ve alel frekansı ile grup arasında istatistiksel olarak anlamlı bir ilişki gözlenmemiştir. Alel ile MD arasındaki ilişkide ve genotip ile MD arasında anlamlı bir ilişki olmadığı görülmüştür. Genotip grupları arasında BDNF ekspresyon düzeyleri bakımından istatistiksel olarak anlamlı bir farklılık yoktur. Hem MD grubu hem de kontrol grubu için BDNF’nin polimorfik genotipleri arasında ekspresyon düzeyleri bakımından fark gözlenmemiştir. Sonuç: Çalışma bulguları istatistiksel olarak önemli olmamasına rağmen rapor edilmiş önceki çalışmaların da ışığında BDNF varyantlarının daha derinlemesine analizlerinin, gelecekte farmasötik müdahale ve majör depresyonun hassas tıbbı için olası yeni hedeflere işaret edebileceğini düşünmekteyiz. Ayrıca kişiselleştirilmiş tıp çağında, klinik müdahalelerin etkinliğini etkileyebilecek hem küresel hem de spesifik faktörlerin anlaşılması, tıp alanında önemli ilerlemeler sağlayabilir

Anahtar Kelimeler

• Beyin kaynaklı nörotrofik faktör
• ekspresyon
• majör depresyon
• polimorfizm
• rs6265

Association study of BDNF gene polymorphism (rs6265) and BDNF gene expression levels in patients with major depression

Öz

Aim: A better understanding of the genetic, molecular, and cellular mechanisms of brain-derived neurotrophic factor (BDNF) and its relationship with neuroplasticity could be pivotal in finding future therapeutic targets for new drugs in major depression (MD). This study was planned to understand the relationship between BDNF-related polymorphism (rs6265) and expression in MD. There are still conflicting results regarding the precise role of BDNF polymorphisms in MD. Method: In this case-control study, single nucleotide amplification studies were performed by Real-Time PCR with primers designed for BDNF gene Val66Met (rs6265) polymorphisms from the blood of 51 patients with MD and 75 healthy controls according to DSM-5 criteria. The total RNA obtained was used for gene expression analyses. The relationship between the expression levels of the BDNF gene in the MD and control groups, which were determined by the quantitative Real-Time PCR method, and the polymorphisms were analyzed by statistical methods. Results: No statistically significant correlation was observed between the genotype and the group also between the allele frequency and the group in males and females. It was observed that there was no significant relationship between allele and MD and between genotype and MD. There is no statistically significant difference between genotype groups regarding BDNF expression levels. No difference was observed between the polymorphic genotypes of BDNF in terms of expression levels for the MD and the control groups. Conclusion: Although the study findings were not statistically significant, we think that in the light of previous studies reported, more in-depth analyzes of BDNF variants may point to possible new targets for future pharmaceutical intervention and precision medicine for major depression. In addition, in the age of personalized medicine, understanding global and specific factors that can affect the effectiveness of clinical interventions can lead to significant advances in medicine.

Anahtar Kelimeler

• Brain-derived neurotrophic factor
• expression
• major depression
• polymorphism
• rs6265

Kaynakça

1. Li W, Ali T, Zheng C, et al. Anti-depressive-like behaviors of APN KO mice involve Trkb/BDNF signaling related neuroinflammatory changes. Mol Psychiatry. 2022;27(2):1047-1058. doi:https://doi.org/10.1038/s41380-021-01327-3
2. Li XL, Liu H, Liu SH, Cheng Y, Xie GJ. Intranasal Administration of Brain-Derived Neurotrophic Factor Rescues Depressive-Like Phenotypes in Chronic Unpredictable Mild Stress Mice. Neuropsychiatr Dis Treat. Published online 2022:1885-1894.
3. Nguyen VT, Hill B, Sims N, et al. Brain-derived neurotrophic factor rs6265 (Val66Met) single nucleotide polymorphism as a master modifier of human pathophysiology. Neural Regen Res. 2023;18(1):102-106. doi:doi: 10.4103/1673-5374.343894
4. Szarowicz CA, Steece-Collier K, Caulfield ME. New Frontiers in Neurodegeneration and Regeneration Associated with Brain-Derived Neurotrophic Factor and the rs6265 Single Nucleotide Polymorphism. Int J Mol Sci. 2022;23(14):8011.
5. Miller SA, Dykes DD, Polesky HF. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res. 1988;16(3):1215. doi:doi: 10.1093/nar/16.3.1215
6. Chomczynski P, Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987;162(1):156-159.
7. Gene. National Library of Medicine. Accessed January 25, 2023. https://www.ncbi.nlm.nih.gov/gene/?term=NM_001143805.1
8. Chourbaji S, Brandwein C, Gass P. Altering BDNF expression by genetics and/or environment: impact for emotional and depression-like behaviour in laboratory mice. Neurosci Biobehav Rev. 2011;35(3):599-611.

9. Notaras M, van den Buuse M. Brain-derived neurotrophic factor (BDNF): novel insights into regulation and genetic variation. The Neuroscientist. 2019;25(5):434-454. doi:https://doi.org/10.1177/1073858418810142
10. Arosio B, Guerini FR, Voshaar RCO, Aprahamian I. Blood brain-derived neurotrophic factor (BDNF) and major depression: do we have a translational perspective? Front Behav Neurosci. 2021;15:626906.
11. Balim DY, Ay Öİ, Ay ME, Karakaş Ü, Kenar Aİ, Erdal ME. Beyin kökenli nörotrofik faktör, nörotrofin-3 ve nörotrofin-4 gen ekspresyon değişimleri majör depresyonun patogenezinde etkili midir? Anadolu Psikiyatri Derg. 2019;20(6):581-589.
12. Bao MH, Zhu SZ, Gao XZ, Sun HS, Feng ZP. Meta-analysis on the association between brain-derived neurotrophic factor polymorphism rs6265 and ischemic stroke, poststroke depression. J Stroke Cerebrovasc Dis. 2018;27(6):1599-1608.
13. Corponi F, Fabbri C, Serretti A. Pharmacogenetics in psychiatry. Adv Pharmacol. 2018;83:297-331.
14. Phan L, Jin Y, Zhang H, et al. ALFA: Allele Frequency Aggregator (National Center for Biotechnology Information, US National Library of Medicine). Google Sch. Published online 2020.
15. The National Center for Biotechnology Information. National Library of Medicine, The National Center for Biotechnology Information dbSNP. Accessed January 23, 2023. https://www.ncbi.nlm.nih.gov/snp/rs6265#frequency_tab
16. Bath KG, Chuang J, Spencer-Segal JL, et al. Variant BDNF (Val66Met) polymorphism contributes to developmental and estrous-stage-specific expression of anxiety-like behavior in female mice. Biol Psychiatry. 2012;72(6):499.
17. Hennings JM, Kohli MA, Uhr M, Holsboer F, Ising M, Lucae S. Polymorphisms in the BDNF and BDNFOS genes are associated with hypothalamus-pituitary axis regulation in major depression. Prog Neuropsychopharmacol Biol Psychiatry. 2019;95:109686.
18. Zhang E, Liao P. Brain‐derived neurotrophic factor and post‐stroke depression. J Neurosci Res. 2020;98(3):537-548.
19. Shimizu E, Hashimoto K, Okamura N, et al. Alterations of serum levels of brain-derived neurotrophic factor (BDNF) in depressed patients with or without antidepressants. Biol Psychiatry. 2003;54(1):70-75.