Comparative analysis of COMT expression levels in blood and exosome-derived samples of patients with schizophrenia

Yıl 2025, Cilt: 50 Sayı: 3, 624 - 634, 30.09.2025

Nuray Altıntaş , Şebnem Ciddi , Demet Bulut , Onur Tonk , Özge Sarıca , Pervin Elvan Tokgün , Cihan Gül , Ayşen Esen Danacı

https://doi.org/10.17826/cumj.1658381

Öz

Purpose: The objective of this study was to analyse the variability of COMT expression in peripheral blood and exosome samples from individuals diagnosed with schizophrenia and to establish its correlation with the drugs employed in the treatment of schizophrenia.
Materials and Methods: 45 subjects diagnosed with chronic schizophrenia were included in the patient group and 45 healthy volunteers with no family history of chronic schizophrenia were included in the control group. RNA isolation from exosome and peripheral blood was performed for each individual in the sample group. Real-time polymerase chain reaction was used to determine COMT expression levels obtained from peripheral blood and exosome samples and their association with drugs used in antipsychotic therapy was evaluated.
Results: Differential gene expression analysis was performed using the 2-ΔΔCT method. The analysis revealed an increase in COMT gene expression levels in exosome samples. Similarly, an increase in COMT expression levels was detected in peripheral blood samples. In peripheral blood samples, 31 patients exhibited an increase and 14 patients exhibited a decrease. In the exosome samples, a decrease in COMT gene expression was observed in 25 subjects, while an increase was observed in 20 subjects. A statistically significant difference was found between COMT expression levels in peripheral blood and exosome samples.
Conclusion: Investigation of alterations in COMT expression levels in schizophrenia and its treatment may provide a valuable framework for future studies to elucidate the mechanisms of this psychiatric disorder.

Anahtar Kelimeler

Schizophrenia , COMT , Exosome , RNA , Real-Time PCR

Destekleyen Kurum

Manisa Celal Bayar University

Proje Numarası

BAP 2017-218 BAP 2018-184

Şizofreni tanılı hastalarda kan ve eksozom kaynaklı örneklerde COMT ekspresyon düzeylerinin karşılaştırmalı analizi

Öz

Amaç: Bu çalışmanın amacı, şizofreni tanısı almış bireylerden elde edilen periferik kan ve eksozom örneklerinde COMT ekspresyonundaki değişkenliği analiz etmek ve bu ekspresyon seviyelerinin şizofreni tedavisinde kullanılan ilaçlarla olan korelasyonunu belirlemektir.
Gereç ve Yöntem: Çalışmaya, kronik şizofreni tanılı 45 hasta ile ailesinde kronik şizofreni öyküsü bulunmayan 45 sağlıklı gönüllü kontrol grubu olarak dahil edilmiştir. Tüm bireylerden periferik kan ve eksozom örnekleri alınarak RNA izolasyonu gerçekleştirilmiştir. Periferik kan ve eksozom örneklerinden elde edilen COMT ekspresyon seviyeleri, gerçek zamanlı polimeraz zincir reaksiyonu yöntemi ile belirlenmiş ve antipsikotik tedavide kullanılan ilaçlarla olan ilişkisi değerlendirilmiştir.
Bulgular: Diferensiyal gen ekspresyon analizi 2-ΔΔCT yöntemi kullanılarak gerçekleştirilmiştir. Yapılan analizde, eksozom örneklerinde COMT gen ekspresyon seviyelerinde artış tespit edilmiştir. Periferik kan örneklerinde 31 hastada COMT ifadesinde artış, 14 hastada düşüş saptanmıştır. Eksozom örneklerinde 25 hastada COMT ifadesi azalırken 20 hastada artmıştır. Periferik kan ile eksozom örneklerindeki COMT ekspresyon seviyeleri arasında istatistiksel olarak anlamlı bir farklılık saptanmıştır.
Sonuç: Şizofreni hastalarında COMT ekspresyon seviyelerindeki değişimlerin ve bu değişimlerin şizofreni tedavisinde kullanılan ilaçlarla olan ilişkilerinin incelenmesi, bu psikiyatrik bozukluğun altında yatan mekanizmaların aydınlatılmasına yönelik gelecekteki çalışmalara önemli bir çerçeve sağlayabilir.

Anahtar Kelimeler

Şizofreni , COMT , Eksozom , RNA , Gerçek Zamanlı PCR

Proje Numarası

BAP 2017-218 BAP 2018-184

Kaynakça

• Stepnicki P, Kondej M, Kaczor AA. Current concepts and treatments of schizophrenia. Molecules. 2018;20:23:2087.
• Bosun A, Albu-Kalinovic R, Neda-Stepan O, Bosun I, Farcas SS, Enatescu VR et al. Dopaminergic epistases in schizophrenia. Brain Sci. 2024;14:1089.
• Chana G, Bousman CA, Money TT, Gibbons A, Gillett P, Dean B et al. Biomarker investigations related to pathophysiological pathways in schizophrenia and psychosis. Front Cell Neurosci. 2013;7:95.
• Altıntas N, Sengöz S, Karamil S. Investigation of catechol-o-methyltransferase (COMT) Val158Met polymorphism in chronic schizophrenia diagnosed individuals in Manisa. Journal of Applied Biological Sciences. 2019;13:128-32.
• Wang Z, Xiao Z, Inslicht SS, Tong H, Jiang W, Wang X et al. Low expression of catecholamine-O-methyl-transferase gene in obsessive-compulsive disorder. J Anxiety Disord. 2009;23:660-64.
• Li Z, He Y, Han H, Zhou Y, Ma X, Wang D et al. COMT, 5-HTR2A, and SLC6A4 mRNA expressions in first-episode antipsychotic-naïve schizophrenia and association with treatment outcomes. Front Psychiatry. 2018;9:577.
• Sagud M, Tudor L, Uzun S, Perkovic MN, Zivkovic M, Konjevod M et al. Haplotypic and genotypic association of catechol-o-methyltransferase rs4680 and rs4818 polymorphisms and treatment resistance in schizophrenia. Front Pharmacol. 2018;9:705.
• Kirenskaya AV, Storozheva ZI, Gruden MA, Sewell RDE. COMT and GAD1 gene polymorphisms are associated with impaired antisaccade task performance in schizophrenic patients. Eur Arch Psychiatry Clin Neurosci. 2018;268:571-84.
• Chen J, Lipska BK, Halim N, Ma QD, Matsumoto M, Melhem S et al. Functional analysis of genetic variation in catechol-O-methyltransferase (COMT): effects on mRNA, protein, and enzyme activity in postmortem human brain. Am J Hum Genet. 2004;75:807-21.
• Bertolino A, Blasi G, Latorre V, Rubino V, Rampino A, Sinibaldi L et al. Additive effects of genetic variation in dopamine regulating genes on working memory cortical activity in human brain. J Neurosci. 2006;26:3918-22.
• Wang H, Zhang B, Zeng B, Tang Y, Zhang T, Zhao S et al. Association between catechol-O-methyltransferase genetic variation and functional connectivity in patients with first episode schizophrenia. Schizophr Res. 2018;199:214-20.
• Abdolmaleky HM, Cheng KH, Faraone SV, Wilcox M, Glatt SJ, Gao F et al. Hypomethylation of MB-COMT promoter is a major risk factor for schizophrenia and bipolar disorder. Hum Mol Genet. 2006;15:3132-45.
• Yavich L, Forsberg MM, Karayiorgou M, Gogos JA, Männistö PT. Site-specific role of catechol-O-methyltransferase in dopamine overflow within prefrontal cortex and dorsal striatum. J Neurosci. 2007;27:10196-209.
• Fekih-Romdhane F, Kerbage G, Hachem N, El Murr M, Haddad G, Loch AA et al. The moderating role of COMT gene rs4680 polymorphism between maladaptive metacognitive beliefs and negative symptoms in patients with schizophrenia. BMC Psychiatry. 2024;24:831.
• Du Y, Tan WL, Chen L, Yang ZM, Li XS, Xue X et al. Exosome transplantation from patients with schizophrenia causes schizophrenia-relevant behaviors in mice: an integrative multi-omics data analysis. Schizophr Bull. 2021;47:1288-99.
• Xu CX, Huang W, Shi XJ, Du Y, Liang JQ, Fang X et al. Dysregulation of serum exosomal lipid metabolism in schizophrenia: a biomarker perspective. Mol Neurobiol. 2025;62:3556-67.
• Chulpanova DS, Kitaeva KV, James V, Rizvanov AA, Solovyeva VV. Therapeutic prospects of extracellular vesicles in cancer treatment. Front Immunol. 2018;9:1534.
• Hessvik NP, Llorente A. Current knowledge on exosome biogenesis and release. Cell Mol Life Sci. 2018;75:193-208.
• Galieva LR, James V, Mukhamedshina YO, Rizvanov AA. Therapeutic potential of extracellular vesicles for the treatment of nerve disorders. Front Neurosci. 2019;13:163.
• Kumar SR, Kimchi ET, Manjunath Y, Gajagowni S, Stuckel AJ, Kaifi JT. RNA cargos in extracellular vesicles derived from blood serum in pancreas associated conditions. Sci Rep. 2020;10:2800.
• Dai J, Zhang MZ, He QQ, Chen R. The emerging role of exosomes in schizophrenia. Psychiatry Res. 2023;327:115394.
• Arslan E, Altintas N, Ayer A, Danaci AE, Asci M, Orenay S. Manisa’da şizofren hastalarin sitogenetik analizi ve polimeraz zincir reaksiyonu ile COMT( 21q11.2 ) geninin teşhisi. Sağlık Bilimleri Dergisi. 2011;20:99-106.
• Regier DA, Kuhl EA, Kupfer D J. The DSM-5: Classification and criteria changes. World Psychiatry. 2013;12: 92–8.
• Funke B, Malhotra AK, Finn CT, Plocik AM, Lake SL, Lencz T et al. COMT genetic variation confers risk for psychotic and affective disorders: a case control study. Behav Brain Funct. 2005;1:19.
• Chan MK, Guest PC, Levin Y, Umrania Y, Schwarz E, Bahn S et al. Converging evidence of blood-based biomarkers for schizophrenia: an update. Int Rev Neurobiol. 2011;101:95-144.
• Zhu G, Lipsky RH, Xu K, Ali S, Hyde T, Kleinman J et al. Differential expression of human COMT alleles in brain and lymphoblasts detected by RT-coupled 5' nuclease assay. Psychopharmacology (Berl). 2004;177:178-84.
• Lago SG, Bahn S. The druggable schizophrenia genome: from repurposing opportunities to unexplored drug targets. NPJ Genom Med. 2022;7:25.
• Seeman P. Dopamine D2 receptors as treatment targets in schizophrenia. Clin Schizophr Relat Psychoses. 2010;4:56-73.
• Hewitt K, Huang XF. The role of microglial exosomes in clozapine treatment: effect on cognition in schizophrenia. J Neuroimmune Pharmacol. 2025;16:20:42.
• Ilgın C, Topuzoğlu A. Extracellular vesicles in psychiatry research in the context of rdoc criteria. Psychiatry Investig. 2018;15:1011-18.
• Li H, Yuan Y, Xie Q, Dong Z. Exosomes: potential targets for the diagnosis and treatment of neuropsychiatric disorders. J Transl Med. 2024:22,115.
• Zhang T, Fang Y, Wang L, Gu L, Tang J. Exosome and exosomal contents in schizophrenia. J Psychiatr Res. 2023;163:365-71.