Polymorphic variant of NQO1 rs1800566 and antipsychotic-induced metabolic disorders in patients with schizophrenia

Aim. To conduct an associative analysis between antipsychotic-induced metabolic disorders and the polymorphic variant NQO1 rs1800566.
Materials and methods. The study included 603 patients with schizophrenia, who underwent a comprehensive clinical, anthropometric and laboratory examination. Metabolic syndrome (MetS) was established based on the 2005 International Diabetes Federation criteria. Genotyping of the polymorphic variant NQO1 rs1800566 was performed in the studied sample of patients. Statistical processing of the results was performed using Statistica 12.0 software package (StatSoft, Russia).
Results. Among patients receiving basic therapy with atypical antipsychotics, the T allele had an effect predisposing to the development of MetS (odds ratio: 1.63, 95% confidence interval: 1.01–2.62), while the C allele was statistically significantly more common among patients without metabolic syndrome (odds ratio: 0.61, 95% confidence interval: 0.38–0.99). In carriers of the TT genotype, serum triglyceride levels are statistically significantly higher than in carriers of the CC or CT genotypes (p = 0.049).
Conclusion. The results of the study for the first time revealed associations of the polymorphic variant NQO1 rs1800566 with MetS and hypertriglyceridemia in patients with schizophrenia receiving pharmacotherapy with second-generation antipsychotics. The results of this study confirm the contribution of the genetic component to the development of metabolic disorders in patients with schizophrenia and open up prospects for further search for genetic markers for the prevention and correction of this undesirable phenomenon.

1. Ceraso A., Lin J.J., Schneider-Thoma J., Siafis S., Tardy M., Komossa K. et al. Maintenance treatment with antipsychotic drugs for schizophrenia. Cochrane Database Syst. Rev. 2020;8(8):CD008016. DOI: 10.1002/14651858.CD008016.pub3.

2. Leucht S., Priller J., Davis J.M. Antipsychotic Drugs: A Concise Review of History, Classification, Indications, Mechanism, Efficacy, Side Effects, Dosing, and Clinical Application. Am J. Psychiatry. 2024;181(10):865–878. DOI: 10.1176/appi.ajp.20240738.

3. Галкин С.А., Корнетова Е.Г., Меднова И.А., Тигунцев В.В., Корнетов А.Н. Распространенность и факторы риска синдрома удлинения интервала QT у пациентов с шизофренией на фоне приема антипсихотиков. Современная терапия психических расстройств. 2024;2:32–39. DOI: 10.21265/PSYPH.2024.31.31.004.

4. Вайман Е.Э., Шнайдер Н.А., Насырова Р.Ф. Лечение антипсихотик-индуцированной тардивной дискинезии у пациентов с шизофренией. Социальная и клиническая психиатрия. 2020;30(2):62–70.

5. Евсегнеев Р.А. Гиперпролактинемия, вызванная антипсихотиками. Психиатрия, психотерапия и клиническая психология. 2020;11(2):297–307. DOI; 10.34883/PI.2020.11.2.007.

6. Куртмамбетова С.Э., Андрух Я.В., Куртмамбетов Р.Э., Примышева Е.Н., Репинская И.Н. Влияние атипичных антипсихотиков на развитие сахарного диабета 2-го типа. Клинический разбор в общей медицине. 2024;5(4):9–14. DOI: 10.47407/kr2024.5.4.00414.

7. Абдуллозода С.М., Усманова Г.М., Гулбекова З.А. Маркеры окислительного стресса и антиоксидантной защиты при ожирении. Вестник последипломного образования в сфере здравоохранения. 2023;3:5–13.

8. Reddy R., Yao J.K. Free radical pathology in schizophrenia: A review. PLEFA. 1996;55(1–2):33–43. DOI: 10.1016/s0952-3278(96)90143-x.

9. Li X.F., Zheng Y.L., Xiu M.H., da Chen C., Kosten T.R., Zhang X.Y. Reduced plasma total antioxidant status in first-episode drug-naive patients with schizophrenia. Prog. Neuropsychopharmacol. Biol. Psychiatry. 2011;35(4):1064–1067. DOI: 10.1016/j.pnpbp.2011.03.001.

10. Zhang X.Y., Tan Y.L., Cao L.Y., Wu G.Y., Xu Q., Shen Y. et al. Antioxidant enzymes and lipid peroxidation in different forms of schizophrenia treated with typical and atypical antipsychotics. Schizophr. Res. 2006;81(2–3):291–300. DOI: 10.1016/j.schres.2005.10.011.

11. Caroff S.N., Campbell E.C. Drug-induced extrapyramidal syndromes: implications for contemporary practice. Psychiatr Clin. North. Am. 2016;39(3):391–411. DOI: 10.1016/j.psc.2016.04.003.

12. Жиляева Т.В., Швачкина Д.С., Пятойкина А.С., Жукова Е.С., Костина О.В., Щербатюк Т.Г. и др. Пилотное исследование связи окислительно-восстановительного дисбаланса, маркеров метаболизма птеринов и ранних экстрапирамидных побочных эффектов антипсихотиков при шизофрении. Неврология, нейропсихиатрия, психосоматика. 2022;14(2):18–25. DOI: 10.14412/2074-2711-2022-2-18-25.

13. Cardoso G.A., Ribeiro M.D., Ferreira A.P., de Oliveira Y., Medeiros T.O., de Sousa B.R. et al. Oxidative stress does not influence weight loss induced by aerobic training in adults: randomized clinical trials. J. Sports Med. Phys. Fitness. 2020;60(6):875882. DOI: 10.23736/s0022-4707.20.10528-0.

14. Jakubiak G.K., Osadnik K., Lejawa M., Kasperczyk S., Osadnik T., Pawlas N. Oxidative stress in association with metabolic health and obesity in young adults. Oxid. Med. Cell Longev. 2021;20:9987352. DOI: 10.1155/2021/9987352.

15. Gonzalez A., Simon F., Achiardi O., Vilos C., Cabrera D., Cabello-Verrugio C. The critical role of oxidative stress in sarcopenic obesity. Oxid. Med. Cell Longev. 2021;20:4493817. DOI: 10.1155/2021/4493817.

16. Siegel D., Gustafson D.L., Dehn D.L., Han J.Y., Boonchoong P., Berliner L.J. et al. NAD(P)H: quinone oxidoreductase 1: role as a superoxide scavenge. Molecular Pharmacology. 2004;65(5):1238–1247. DOI: 10.1124/mol.65.5.123.

17. Go J., Ryu Y.K., Park H.Y., Choi D.H., Choi Y.K., Hwang D.Y. et al. NQO1 regulates pharmaco-behavioral effects of D-amphetamine in striatal dopaminergic system in mice. Neuropharmacology. 2020;170:108039. DOI: 10.1016/j.neuropharm.2020.108039.

18. Duffy S., So A., Murphy T.H. Activation of endogenous antioxidant defenses in neuronal cells prevents free radicals-mediated damCTe. Journal of Neurochemistry. 1998;71(1):69–77. DOI: 10.1046/j.14714159.1998.71010069.x.

19. Федоренко О.Ю., Иванова С.А., Корнетова Е.Г. Роль полиморфизма генов дофаминовой и глутаматной систем в клинической гетерогенности шизофрении и развитии антипсихотик-индуцированных побочных эффектов. Сибирский вестник психиатрии и наркологии. 2023;1(118):5–13. DOI: 10.26617/1810-3111-2023-1(118)-5-13.

20. Stauffer E.M., Bethlehem R.A.I., Dorfschmidt L., Won H., Warrier V., Bullmore E.T. The genetic relationships between brain structure and schizophrenia. Nat. Commun. 2023;14(1):7820. DOI: 10.1038/s41467-023-43567-7.

21. Palming J., Sjöholm K., Jernås M., Lystig T.C., Gummesson A., Romeo S. et al. The expression of NAD (P) H: quinone oxidoreductase 1 is high in human adipose tissue, reduced by weight loss, and correlates with adiposity, insulin sensitivity, and markers of liver dysfunction. The Journal of Clinical Endocrinology & Metabolism. 2007;92(6):2346–2352. DOI: 10.1210/jc.2006-2476.

22. Корнетова Е.Г., Гончарова А.А., Корнетов А.Н., Давыдов А.А., Дубровская В.В., Семке А.В. и др. Связь суицидального поведения и безнадёжности с акатизией у больных шизофренией. Суицидология. 2018;3(32):63–70. DOI: 10.32878/suiciderus.18-09-03(32)-63-70.

23. Kay S.R., Fiszbein A., Opler L.A. The Positive And Negative Syndrome Scale (PANSS) for schizophrenia. Schizophr. Bull. 1987;13(2):261–276.

24. Мосолов С.Н. Шкалы психометрической оценки симптоматики шизофрении и концепция позитивных и негативных расстройств. М.: Новый цвет, 2001:238.

25. International Diabetes Federation. Clinical Guidelines Task Force. Global guideline for type 2 diabetes. Brussels: International Diabetes Federation, 2005.

26. Han S.J., Kang E.S., Kim H.J., Kim S.H., Chum S.W., Ahn C.H.W. The C609T variant of NQO1 is associated with carotid artery plaques in patients with type 2 diabetes. Mol. Genet. Metab. 2009;97:85–90. DOI: 10.1016/j.ymgme.2009.01.012.

27. Yang S., Zhao J., Li L. NAD(P)H: quinone oxidoreductase 1 gene rs1800566 polymorphism increases the risk of cervical cancer in a Chinese Han sample: A STROBE-complaint case-control study.Medicine (Baltimore).2020;99(20):e19941. DOI: 10.1097/MD.0000000000019941.

28. Abedinzadeh M., Moghimi M., Dastgheib S.A., Maleki H., Salehi E., Zare M. et al. Association of NAD (P) H Quinine Oxidoreductase 1 rs1800566 Polymorphism with Bladder and Prostate Cancers - a Systematic Review and Meta-Analysis. Klin. Onkol. 2020;33(2):92–100. DOI: 10.14735/amko202092.

29. Cura Y., Pérez Ramírez C., Sánchez Martín A., Martínez Martínez F., Calleja Hernández M.Á., Ramírez Tortosa M.D.C. et al. Genetic polymorphisms on the effectiveness or safety of breast cancer treatment: Clinical relevance and future perspectives. Mutat. Res. Rev. Mutat. Res. 2021;788:108391. DOI: 10.1016/j.mrrev.2021.108391.

30. Martínez-Hernández A., Córdova E.J., Rosillo-Salazar O., García-Ortíz H., Contreras-Cubas C., Islas-Andrade S. et al. Association of HMOX1 and NQO1 polymorphisms with metabolic syndrome components. PLoS One. 2015;10(5):e0123313. DOI: 10.1371/journal.pone.0123313.

31. Ramprasath T., Murugan P.S., Kalaiarasan E., Gomathi P., Rathinavel A., Selvam G.S. Genetic association of glutathione peroxidase-1 (GPx-1) and NAD(P)H:quinone oxidoreductase 1 (NQO1) variants and their association of CAD in patients with type-2 diabetes. Mol. Cell Biochem. 2012;361:143–50. DOI: 10.1007/s11010-011-1098-5.

32. Gaikwad A., Long D.J., Stringer J.L., Jaiswal A.K. In vivo role of NAD(P)H:quinone oxidoreductase 1 (NQO1) in the regulation of intracellular redox state and accumulation of abdominal adipose tissue. J. Biol. Chem. 2001;276:22559–22564. DOI: 10.1074/jbc.M101053200.

33. Hwang J.H., Kim D.W., Jo E.J., Kim Y.K., Jo Y.S., Park J.H. et al. Pharmacological stimulation of NADH oxidation ameliorates obesity and related phenotypes in mice. Diabetes. 2009;58:965–974. DOI: 10.2337/db08-1183.

34. Jiménez-Osorio A.S., González-Reyes S., García-Niño W.R., Moreno-Macías H., Rodríguez-Arellano M.E., Vargas-Alarcón G. et al. Association of nuclear factor-erythroid 2-related factor 2, thioredoxin interacting protein, and heme oxygenase-1 gene polymorphisms with diabetes and obesity in Mexican patients. Oxid. Med. Cell Longev. 2016;2016:7367641. DOI: 10.1155/2016/7367641.

35. Wang G., Zhang L., Li Q. Genetic polymorphisms of GSTT1, GSTM1, and NQO1 genes and diabetes mellitus risk in Chinese population. Biochemical and Biophysical Research Communications. 2006;341(2):310–313. DOI: 10.1016/j.bbrc.2005.12.195.