Sains Malaysiana 55(2)(2026): 283-292

http://doi.org/10.17576/jsm-2026-5502-08

 

Telomere Shortening and Its Association with Oxidative Stress and Telomere Maintenance Genes in Schizophrenia

(Pemendekan Telomer dan Hubungannya dengan Tekanan Oksidatif dan Gen Penyelenggaraan Telomer dalam Skizofrenia)

 

GOH XUE XIN¹, TEE SHIAU FOON^1,*, TANG PEK YEE², CHEE KOK YOON³ & TAN YIN QING²

 

¹Department of Chemical Engineering, Lee Kong Chian Faculty of Engineering and Science, Universiti Tunku Abdul Rahman, Bandar Sungai Long, Cheras 43000 Kajang, Selangor, Malaysia

²Department of Mechatronics and Biomedical Engineering, Lee Kong Chian Faculty of Engineering and Science, Universiti Tunku Abdul Rahman, Bandar Sungai Long, Cheras 43000 Kajang, Selangor, Malaysia

³Department of Psychiatry and Mental Health, Hospital Kuala Lumpur, Jalan Pahang, 50586 Kuala Lumpur, Malaysia

 

Received: 26 March 2025/Accepted: 26 January 2026

 

Abstract

Schizophrenia is known to be associated with premature mortality. Oxidative stress and telomere maintenance gene polymorphisms are assumed to be the possible trait markers. Hence, the present study aimed to explore the relationship between leukocyte telomere length (LTL) with oxidative stress status and single nucleotide polymorphisms (SNPs) of TERT, TERC, and MYNN genes in patients suffering from schizophrenia. A total of 150 schizophrenia patients and 139 healthy volunteers were recruited. The participants had their LTL measured and TERT rs33954691, TERC rs2293607, and MYNN rs10936599 were genotyped. Oxidative stress index (OSI) based on the ratio of total oxidant status (TOS) to total antioxidant capacity (TAC) was calculated. We found that patients had significantly decreased relative LTL (p = 0.006), but there were no significant effects of oxidative stress level (p = 0.496 for TOS; p = 0.216 for TAC; p = 0.905 for OSI) on relative LTL in schizophrenia. We also confirmed the association between rs33954691 CC (p = 0.007), rs2293607 AG (p = 0.042), and rs10936599 CC (p = 0.001) genotypes and shortened relative LTL in patients with schizophrenia. Thus, the findings suggested the presence of accelerated biological aging in patients with schizophrenia, despite their chronological ages and oxidative stress status. In conclusion, gene polymorphisms may have varying effects on LTL. To further understand the telomere shortening in schizophrenia, baseline and repeated LTL should be investigated.

Keywords: Leukocyte telomere length; oxidative stress; schizophrenia; single nucleotide polymorphism

 

Abstrak

Skizofrenia diketahui dikaitkan dengan kematian pramatang. Tekanan oksidatif dan polimorfisme gen penyelenggaraan telomer dianggap sebagai penanda ciri yang berpotensi. Oleh itu, penyelidikan ini bertujuan untuk meneroka hubungan antara panjang telomer leukosit (LTL) dengan tekanan oksidatif dan polimorfisme nukleotida tunggal (SNP) dalam gen TERT, TERC dan MYNN dalam kalangan pesakit skizofrenia. Seramai 150 pesakit skizofrenia dan 139 sukarelawan sihat telah direkrut. Panjang relatif LTL peserta diukur, manakala genotip TERT rs33954691, TERC rs2293607 dan MYNN rs10936599 telah dianalisis. Indeks tekanan oksidatif (OSI) dikira berdasarkan nisbah jumlah status oksidan (TOS) kepada kapasiti antioksidan total (TAC). Kami mendapati bahawa pesakit mempunyai LTL relatif yang berkurangan secara signifikan (p = 0.006), tetapi tiada kesan signifikan tahap tekanan oksidatif terhadap LTL relatif dalam skizofrenia (p = 0.496 untuk TOS; p = 0.216 untuk TAC; p = 0.905 untuk OSI). Kami juga mengesahkan hubungan antara genotip rs33954691 CC (p = 0.007), rs2293607 AG (p = 0.042) dan rs10936599 CC (p = 0.001) dengan pemendekan LTL relatif dalam pesakit skizofrenia. Oleh itu, penemuan ini mencadangkan adanya penuaan biologi yang dipercepatkan dalam pesakit skizofrenia, tanpa mengira usia kronologi mereka dan tekanan oksidatif. Kesimpulannya, polimorfisme gen mungkin mempunyai kesan yang berbeza terhadap LTL. Untuk memahami dengan lebih lanjut pemendekan telomer dalam skizofrenia, kajian asas dan pengukuran berulang terhadap LTL harus dilakukan.

Kata kunci: Panjang telomer leukosit; polimorfisme nukleotida tunggal; skizofrenia; tekanan oksidatif

 

REFERENCES

Ali, S., Santomauro, D., Ferrari, A.J. & Charlson, F. 2022. Excess mortality in severe mental disorders: A systematic review and meta-regression. Journal of Psychiatric Research 149: 97-105.

Antwi, S.O., Bamlet, W.R., Rabe, K.G., Cawthon, R.M., Umudi, I., Druliner, B.R., Sicotte, H., Oberg, A.L., Jatoi, A., Boardman, L.A. & Petersen, G.M. 2020. Leukocyte telomere length and its interaction with germline variation in telomere-related genes in relation to pancreatic adenocarcinoma risk. Cancer Epidemiology, Biomarkers & Prevention 29(7): 1492-1500.

Armanios, M. & Blackburn, E.H. 2012. The telomere syndromes. Nature Reviews Genetics 13(10): 693-704.

Atzmon, G., Cho, M., Cawthon, R.M., Budagov, T., Katz, M., Yang, X., Siegel, G., Bergman, A., Huffman, D.M., Schechter, C.B. & Wright, W.E. 2010. Genetic variation in human telomerase is associated with telomere length in Ashkenazi centenarians. Proceedings of the National Academy of Sciences 107(suppl_1): 1710-1717.

Bertuch, A.A. 2016. The molecular genetics of the telomere biology disorders. RNA Biology 13(8): 696-706.

Cawthon, R.M. 2002. Telomere measurement by quantitative PCR. Nucleic Acids Research 30(10): e47.

Czepielewski, L.S., Massuda, R., Panizzutti, B., Grun, L.K., Barbé-Tuana, F.M., Teixeira, A.L., Barch, D.M. & Gama, C.S. 2018. Telomere length and CCL11 levels are associated with gray matter volume and episodic memory performance in schizophrenia: Evidence of pathological accelerated aging. Schizophrenia Bulletin 44(1): 158-167.

Do, S.K., Yoo, S.S., Choi, Y.Y., Choi, J.E., Jeon, H.S., Lee, W.K., Lee, S.Y., Lee, J., Cha, S.I., Kim, C.H. & Park, J.Y. 2015. Replication of the results of genome-wide and candidate gene association studies on telomere length in a Korean population. The Korean Journal of Internal Medicine 30(5): 719-726.

Erel, O. 2005. A new automated colorimetric method for measuring total oxidant status. Clinical Biochemistry 38(12): 1103-1111.

Erel, O. 2004. A novel automated direct measurement method for total antioxidant capacity using a new generation, more stable ABTS radical cation. Clinical Biochemistry 37(4): 277-285.

Farrukh, S., Baig, S., Hussain, R., Imad, R., Kulsoom, O. & Yousaf Rana, M. 2024. Identification of polymorphic alleles in TERC and TERT gene reprogramming the telomeres of newborn and legacy with parental health. Saudi Journal of Biological Sciences 31(2): 103897.

Jones, A.M., Beggs, A.D., Carvajal-Carmona, L., Farrington, S., Tenesa, A., Walker, M., Howarth, K., Ballereau, S., Hodgson, S.V., Zauber, A. & Bertagnolli, M. 2012. TERC polymorphisms are associated both with susceptibility to colorectal cancer and with longer telomeres. Gut 61(2): 248-254.

Katerji, M., Filippova, M. & Duerksen-Hughes, P. 2019. Approaches and methods to measure oxidative stress in clinical samples: Research applications in the cancer field. Oxidative Medicine and Cellular Longevity 2019: 1279250.

Lin, J. & Epel, E. 2022. Stress and telomere shortening: Insights from cellular mechanisms. Ageing Research Reviews 73: 101507.

Lindqvist, D., Epel, E.S., Mellon, S.H., Penninx, B.W., Révész, D., Verhoeven, J.E., Reus, V.I., Lin, J., Mahan, L., Hough, C.M. & Rosser, R. 2015. Psychiatric disorders and leukocyte telomere length: Underlying mechanisms linking mental illness with cellular aging. Neuroscience & Biobehavioral Reviews 55: 333-364.

Michalek, J.E., Kepa, A., Vincent, J., Frissa, S., Goodwin, L., Hotopf, M., Hatch, S.L., Breen, G. & Powell, T.R. 2017. Genetic predisposition to advanced biological ageing increases risk for childhood-onset recurrent major depressive disorder in a large UK sample. Journal of Affective Disorders 213: 207-213.

Morera-Fumero, A.L., Diaz-Mesa, E., Abreu-Gonzalez, P., Fernandez-Lopez, L. & Guillen-Pino, F. 2017. A three-month longitudinal study of changes in day/night serum total antioxidant capacity in paranoid schizophrenia. PLoS ONE 12(12): e0189348.

Müezzinler, A., Zaineddin, A.K. & Brenner, H. 2013. A systematic review of leukocyte telomere length and age in adults. Ageing Research Reviews 12(2): 509-519.

Njajou, O.T., Blackburn, E.H., Pawlikowska, L., Mangino, M., Damcott, C.M., Kwok, P.Y., Spector, T.D., Newman, A.B., Harris, T.B., Cummings, S.R. & Cawthon, R.M. 2010. A common variant in the telomerase RNA component is associated with short telomere length. PLoS ONE 5(9): e13048.

Okusaga, O.O. 2014. Accelerated aging in schizophrenia patients: The potential role of oxidative stress. Aging and Disease 5(4): 256-262.

Puhlmann, L.M., Valk, S.L., Engert, V., Bernhardt, B.C., Lin, J., Epel, E.S., Vrtička, P. & Singer, T. 2019. Association of short-term change in leukocyte telomere length with cortical thickness and outcomes of mental training among healthy adults: A randomized clinical trial. JAMA Network Open 2(9): e199687.

Rambaud, V., Marzo, A. & Chaumette, B. 2022. Oxidative stress and emergence of psychosis. Antioxidants 11(10): 1870.

Rao, S., Ye, N., Hu, H., Shen, Y. & Xu, Q. 2016. Variants in TERT influencing telomere length are associated with paranoid schizophrenia risk. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics 171(3): 317-324.

Reichert, S. & Stier, A. 2017. Does oxidative stress shorten telomeres in vivo? A review. Biology Letters 13(12): 20170463.

Russo, P., Prinzi, G., Proietti, S., Lamonaca, P., Frustaci, A., Boccia, S., Amore, R., Lorenzi, M., Onder, G., Marzetti, E. & Valdiglesias, V. 2018. Shorter telomere length in schizophrenia: Evidence from a real-world population and meta-analysis of most recent literature. Schizophrenia Research 202: 37-45.

Sánchez-Ortí, J.V., Correa-Ghisays, P., Balanzá-Martínez, V., Macías Saint-Gerons, D., Berenguer-Pascual, E., Romá-Mateo, C., Victor, V.M., Forés-Martos, J., San-Martin, C., Selva-Vera, G. & Tabarés-Seisdedos, R. 2024. Systemic inflammation, oxidative damage and neurocognition predict telomere length in a transdiagnostic sample stratified by global DNA methylation levels. Scientific Reports 14: 13159.

Sánchez-Rodríguez, M.A. & Mendoza-Núñez, V.M. 2019. Oxidative stress indexes for diagnosis of health or disease in humans. Oxid. Med. Cell. Longev. 2019: 4128152. 

Scarabino, D., Broggio, E., Gambina, G., Pelliccia, F. & Corbo, R.M. 2017. Common variants of human TERT and TERC genes and susceptibility to sporadic Alzheimers disease. Experimental Gerontology 88: 19-24.

Schnack, H.G., Van Haren, N.E., Nieuwenhuis, M., Hulshoff Pol, H.E., Cahn, W. & Kahn, R.S. 2016. Accelerated brain aging in schizophrenia: A longitudinal pattern recognition study. American Journal of Psychiatry 173(6): 607-616.

Schürhoff, F., Corfdir, C., Pignon, B., Lajnef, M., Richard, J.R., Marcos, E., Pelissolo, A., Leboyer, M., Adnot, S., Jamain, S. & Szöke, A. 2021. No alteration of leukocyte telomere length in first episode psychosis. Psychiatry Research 301: 113941.

Shi, Y.Y. & He, L. 2005. SHEsis, a powerful software platform for analyses of linkage disequilibrium, haplotype construction, and genetic association at polymorphism loci. Cell Research 15(2): 97-98.

Teoh, S.L., Chong, H.Y., Abdul Aziz, S., Chemi, N., Othman, A.R., Md Zaki, N., Vanichkulpitak, P. & Chaiyakunapruk, N. 2017. The economic burden of schizophrenia in Malaysia. Neuropsychiatric Disease and Treatment 13: 1979-1987.

Topiwala, A., Nichols, T.E., Williams, L.Z., Robinson, E.C., Alfaro-Almagro, F., Taschler, B., Wang, C., Nelson, C.P., Miller, K.L., Codd, V. & Samani, N.J. 2023. Telomere length and brain imaging phenotypes in UK Biobank. PLoS ONE 18(3): e0282363.

Van Haren, N.E., Schnack, H.G., Cahn, W., Van Den Heuvel, M.P., Lepage, C., Collins, L., Evans, A.C., Pol, H.E.H. & Kahn, R.S. 2011. Changes in cortical thickness during the course of illness in schizophrenia. Archives of General Psychiatry 68(9): 871-880.

Van Mierlo, H.C., Wichers, C.G., He, Y., Sneeboer, M.A., Radstake, T.R., Kahn, R.S., Broen, J.C. & de Witte, L.D. 2017. Telomere quantification in frontal and temporal brain tissue of patients with schizophrenia. Journal of Psychiatric Research 95: 231-234.

Wysoczanska, B., Dratwa, M., Gebura, K., Mizgala, J., Mazur, G., Wrobel, T. & Bogunia-Kubik, K. 2019. Variability within the human TERT gene, telomere length and predisposition to chronic lymphocytic leukemia. OncoTargets and Therapy 12: 4309-4320.

Yadav, S. & Maurya, P.K. 2022. Correlation between telomere length and biomarkers of oxidative stress in human aging. Rejuvenation Research 25(1): 25-29.

Zhang, Y., Hishimoto, A., Otsuka, I., Watanabe, Y., Numata, S., Yamamori, H., Boku, S., Horai, T., Someya, T., Ohmori, T. & Hashimoto, R. 2018. Longer telomeres in elderly schizophrenia are associated with long-term hospitalization in the Japanese population. Journal of Psychiatric Research 103: 161-166.

 

*Corresponding author; email: teesf@utar.edu.my