POLYMORPHIC VARIANTS OF GENES OF PROINFLAMMATORY CYTOKINES IN AFFECTIVE DISORDERS AND IN THE CASE OF THEIR COMORBIDITY WITH ALCOHOL DEPENDENCE



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Abstract

Abstract

Affective disorders and alcohol dependence are among the most frequent disorders in the general population and in general medical practice. Clinical manifestations in comorbidity of affective and addictive disorders are characterized by polymorphism and a major degree of severity. They are due to complex biological mechanisms associated with dysregulation of various neuromediator systems. The role of immunoinflammation in the development of affective disorders and alcohol dependence is recognized widely, while the participation of cytokines in the pathophysiology of these disorders is still not extensively studied. The objective of the present study was to investigate polymorphic variants of genes of proinflammatory cytokines of interleukin-6 (IL6) and the gene of tumor necrosis factor α (TNFA) in patients with affective disorder and a comorbid course of affective disorder and alcohol dependence. Materials and Methods. The study included 239 patients with current depressive episode within bipolar disorder, single depressive episode, recurrent depressive disorder and with dysthymia (F31, F32, F33, F34.1, ICD-10; group F3), 69 patients with comorbid course of alcohol dependence (F10, ICD-10) and affective disorder (group F3+F10) and 205 mentally healthy individuals. The assessment of the severity of the condition and mental state of a patient was conducted in the dynamic of the therapy using the SIGH-SAD, SHAPS and SASS scales. Genotyping of DNA samples on the polymorphic variants of genes markers of the immunoinflammation IL6 (rs2069840) and TNFA (rs361525, rs1799964) was conducted using the Real-time PCR method on the amplifier QuantStudio™ 5 Real-Time PCR System (Applied Biosystems, USA) with use of kits Biomaster UDG HS-qPCR Lo-ROX (2x) (Biolabmix, Russia) and primers of the company DNA-synthesis (Russia). Results. The analysis of polymorphic variants of gene IL6 (rs2069840) and gene TNFA (rs361525, rs1799964) is evidence of the contribution of the allele Т of polymorphic variant rs1799964 of the gene of TNFA into the development of alcohol dependence and the association of polymorphism rs2069840 of gene of IL6 with clinical degree of symptoms of depressive disorders. Our findings confirm the hypothesis about the participation of genetically caused alterations in the regulation of cytokines in the pathogenesis of affective disorders.

About the authors

Lyudmila A. Levchuk

Mental Health Research Institute, Tomsk National Research Medical Center of the Russian Academy of Sciences, Tomsk, Russia

Email: levchukniipz@mail.ru
ORCID iD: 0000-0003-1982-8492
SPIN-code: 7609-2051
Scopus Author ID: 55386990200
ResearcherId: R-8201-2016

PhD, Scientific Secretary, Senior Researcher of the Laboratory of Molecular Genetics and Biochemistry

Russian Federation, 634014, Tomsk, Aleutskaya, 4

Natalia M. Vyalova

Mental Health Research Institute, Tomsk National Research Medical Center of the Russian Academy of Sciences, Tomsk, Russia

Email: natarakitina@yandex.ru
ORCID iD: 0000-0001-6464-6474
SPIN-code: 3214-2623
Scopus Author ID: 36169533900
ResearcherId: F-4046-2017

PhD, Senior Researcher of the Laboratory of Molecular Genetics and Biochemistry, Research Institute of Mental Health, Tomsk National Research Medical Center, Russian Academy of Sciences

Russian Federation, 634014, Tomsk, Aleutskaya, 4

Ekaterina V. Mikhalitskaya

Mental Health Research Institute, Tomsk National Research Medical Center of the Russian Academy of Sciences, Tomsk, Russia

Email: uzen63@mail.ru
SPIN-code: 3375-2141
Scopus Author ID: 57201483055
ResearcherId: AAT-8376-2020

PhD, Researcher of the Department of Affective States, Research Institute of Mental Health, Tomsk National Research Medical Center, Russian Academy of Sciences

Russian Federation, 634014, Tomsk, Aleutskaya, 4

Diana Z. Paderina

Mental Health Research Institute, Tomsk National Research Medical Center of the Russian Academy of Sciences, Tomsk, Russia

Email: osmanovadiana@mail.ru
ORCID iD: 0000-0002-5546-7316
SPIN-code: 4118-1155
Scopus Author ID: 57188558197
ResearcherId: P-1482-2017

PhD, Researcher of the Laboratory of Molecular Genetics and Biochemistry, Research Institute of Mental Health, Tomsk National Research Medical Center, Russian Academy of Sciences

Russian Federation, 634014, Tomsk, Aleutskaya, 4

Olga V. Roschina

Mental Health Research Institute, Tomsk National Research Medical Center of the Russian Academy of Sciences, Tomsk, Russia

Email: roshchinaov@yandex.ru
ORCID iD: 0000-0002-2246-7045
SPIN-code: 3379-6963
Scopus Author ID: 57211884523
ResearcherId: J-1725-2017

PhD, Researcher of the Department of Affective States, Research Institute of Mental Health, Tomsk National Research Medical Center, Russian Academy of Sciences

Russian Federation, 634014, Tomsk, Aleutskaya, 4

German G. Simutkin

Mental Health Research Institute, Tomsk National Research Medical Center of the Russian Academy of Sciences, Tomsk, Russia

Email: ggsimutkin@gmail.com
ORCID iD: 0000-0002-9813-3789
SPIN-code: 4372-4950
Scopus Author ID: 14028858600
ResearcherId: I-9405-2017

MD, Leading Researcher of the Department of Affective States, Research Institute of Mental Health, Tomsk National Research Medical Center, Russian Academy of Sciences

Russian Federation, 634014, Tomsk, Aleutskaya, 4

Nikolay A. Bokhan

Mental Health Research Institute, Tomsk National Research Medical Center of the Russian Academy of Sciences, Tomsk, Russia;
Psychiatry, Addictology and Psychotherapy Department, Siberian State Medical University, Tomsk, Russia

Email: bna909@gmail.com
ORCID iD: 0000-0002-1052-855X
SPIN-code: 2419-1263
Scopus Author ID: 6506895310
ResearcherId: P-1720-2014

Academician of the Russian Academy of Sciences, Professor, MD, Honored Scientist of the Russian Federation, Director of the Research Institute of Mental Health, Tomsk National Research Medical Center of the Russian Academy of Sciences

Russian Federation, 634014, Tomsk, Aleutskaya, 4; 634050, Tomsk, Moskovsky trakt 2

Svetlana A. Ivanova

Mental Health Research Institute, Tomsk National Research Medical Center of the Russian Academy of Sciences, Tomsk, Russia;
Psychiatry, Addictology and Psychotherapy Department, Siberian State Medical University, Tomsk, Russia

Author for correspondence.
Email: ivanovaniipz@gmail.com
ORCID iD: 0000-0001-7078-323X
SPIN-code: 5776-1365
Scopus Author ID: 36113599800
ResearcherId: С-5333-2012

Professor, MD, Deputy director for scientific work of the Research Institute of Mental Health, Head of the Laboratory of Molecular Genetics and Biochemistry, Research Institute of Mental Health, Tomsk National Research Medical Center, Russian Academy of Sciences

Russian Federation, 634014, Tomsk, Aleutskaya, 4; 634050, Tomsk, Moskovsky trakt 2

References

  1. Иванова С.А., Лосенков И.С., Левчук Л.А., Бойко А.С., Вялова Н.М., Симуткин Г.Г., Бохан Н.А. Депрессивные расстройства: гипотезы патогенеза и потенциальные биологические маркеры. – Новосибирск, Изд-во СО РАН, 2018. – 199 с. / ISBN 978-5-7692-1590-2
  2. Миронова Н.В. Современная биопсихосоциальная модель алкоголизма // Академический журнал Западной Сибири. – 2015. – Т. 11, № 1. – С. 41–43.
  3. Незнанов Н.Г., Рукавишников Г.В., Касьянов Е.Д., Филиппов Д.С., Кибитов А.О., Мазо Г.Э. Биопсихосоциальная модель в психиатрии как оптимальная парадигма для современных биомедицинских исследований // Обозрение психиатрии и медицинской психологии имени В.М.Бехтерева. 2020;(2):3-15. https://doi.org/10.31363/2313-7053-2020-2-3-15
  4. Пуговкина О.Д., Попинако А.В. Склонность к алкоголизации в структуре депрессивных расстройств с позиций биопсихосоциального подхода // Современная терапия в психиатрии и неврологии. – 2012. – № 4. – С. 26–29.
  5. Barnes J., Mondelli V., Pariante C.M. Genetic Contributions of Inflammation to Depression. Neuropsychopharmacology. 2017 Jan;42(1):81-98. doi: 10.1038/npp.2016.169.
  6. Barr T., Helms C., Grant K., Messaoudi I. Opposing effects of alcohol on the immune system. Prog Neuropsychopharmacol Biol Psychiatry. 2016 Feb 4;65:242-51. doi: 10.1016/j.pnpbp.2015.09.001.
  7. Bialek K., Czarny P., Watala C., Synowiec E., Wigner P., Bijak M., Talarowska M., Galecki P., Szemraj J., Sliwinski T. Preliminary Study of the Impact of Single-Nucleotide Polymorphisms of IL-1α, IL-1β and TNF-α Genes on the Occurrence, Severity and Treatment Effectiveness of the Major Depressive Disorder. Cell. Mol. Neurobiol. 2020;40:1049–1056. doi: 10.1007/s10571-019-00782-5.
  8. Chakrabarty T., Torres I.J., Bond D.J., Yatham L.N. Inflammatory cytokines and cognitive functioning in early-stage bipolar I disorder. J Affect Disord. 2019 Feb 15;245:679-685. doi: 10.1016/j.jad.2018.11.018.
  9. Chen X.,. Yao T., Cai J., Fu X., Li H., Wu J. Systemic inflammatory regulators and 7 major psychiatric disorders: A two-sample Mendelian randomization study. Prog Neuropsychopharmacol Biol Psychiatry. 2022 Jun 8;116:110534. doi: 10.1016/j.pnpbp.2022.110534.
  10. Cui G., Wang H., Li R., Zhang L., Li Z., Wang Y., Hui R., Ding H., Wang D.W. Polymorphism of tumor necrosis factor alpha (TNF-alpha) gene promoter, circulating TNF-alpha level, and cardiovascular risk factor for ischemic stroke. J Neuroinflammation. 2012 Oct 10;9:235. doi: 10.1186/1742-2094-9-235.
  11. Dowlati Y., Herrmann N., Swardfager W., Liu H., Sham L., Reim E.K., Lanctôt K.L. A meta-analysis of cytokines in major depression. Biol Psychiatry. 2010 Mar 1;67(5):446-57. doi: 10.1016/j.biopsych.2009.09.033.
  12. Dunn G.A., Loftis J.M., Sullivan E.L. Neuroinflammation in psychiatric disorders: An introductory primer. Pharmacol Biochem Behav. 2020 Sep;196:172981. doi: 10.1016/j.pbb.2020.172981.
  13. Ghafouri-Fard S., Oskooei V.K., Omrani M.D., Taheri M. Dysregulation of cytokine coding genes in peripheral blood of bipolar patients. J Affect Disord. 2019 Sep 1;256:578-583. doi: 10.1016/j.jad.2019.06.028.
  14. Goldsmith D.R., Rapaport M.H., Miller B.J. A meta-analysis of blood cytokine network alterations in psychiatric patients: comparisons between schizophrenia, bipolar disorder and depression. Mol Psychiatry. 2016 Dec;21(12):1696-1709. doi: 10.1038/mp.2016.3.
  15. Hassamal S. Chronic stress, neuroinflammation, and depression: an over-view of pathophysiological mechanisms and emerging anti-inflammatories. Front Psychiatry. 2023. – Vol. 14. – P. 1130989. doi: 10.3389/fpsyt.2023.1130989.
  16. Jeleń A., Żebrowska-Nawrocka M., Szmajda-Krygier D., Mazur K., Gałecki P., Balcerczak E. Preliminary investigation of two promoter region polymorphisms of the TNFA gene in patients with recurrent depressive disorder. Biomed Rep. 2021 Dec;15(6):105. doi: 10.3892/br.2021.1481.
  17. Köhler C.A., Freitas T.H., Maes M., de Andrade N.Q., Liu C.S., Fernandes B.S., Stubbs B., Solmi M., Veronese N., Herrmann N., Raison C.L., Miller B.J., Lanctôt K.L., Carvalho A.F. Peripheral cytokine and chemokine alterations in depression: a meta-analysis of 82 studies. Acta Psychiatr Scand. 2017 May;135(5):373-387. doi: 10.1111/acps.12698.
  18. Kouba B.R., de Araujo Borba L., Borges de Souza P., Gil-Mohapel J., Rodrigues A.L.S. Role of Inflammatory Mechanisms in Major Depressive Disorder: From Etiology to Potential Pharmacological Targets. Cells. 2024 Feb 28;13(5):423. doi: 10.3390/cells13050423.
  19. Kovacs D., Eszlari N., Petschner P., Pap D., Vas S., Kovacs P., Gonda X., Bagdy G., Juhasz G. Interleukin-6 promoter polymorphism interacts with pain and life stress influencing depression phenotypes. J Neural Transm (Vienna). 2016 May;123(5):541-8. doi: 10.1007/s00702-016-1506-9.
  20. Leonard B.E., Wegener G. Inflammation, insulin resistance and neuroprogression in depression. Acta Neuropsychiatr. 2020 Feb;32(1):1-9. doi: 10.1017/neu.2019.17.
  21. Lu D., Wang M., Yang T., Wang J., Lin B., Liu G., Liang Q. Association of Interleukin-6 Polymorphisms with Schizophrenia and Depression: A Case-Control Study. Lab Med. 2023 May 2;54(3):250-255. doi: 10.1093/labmed/lmac099.
  22. Maes M., Meltzer H.Y., Scharpé S., Bosmans E., Suy E., De Meester I., Calabrese J., Cosyns P. Relationships between lower plasma L-tryptophan levels and immune-inflammatory variables in depression. Psychiatry Res. 1993 Nov;49(2):151-65. doi: 10.1016/0165-1781(93)90102-m.
  23. Mednova I.A., Levchuk L.A., Boiko A.S., Roschina O.V., Simutkin G.G., Bokhan N.A., Loonen A.J.M., Ivanova S.A. Cytokine level in patients with mood disorder, alcohol use disorder and their comorbidity. World J Biol Psychiatry. 2023 Mar;24(3):243-253. doi: 10.1080/15622975.2022.2095439.
  24. Mikhalitskaya E.V., Vyalova N.M., Bokhan N.A., Ivanova S.A. Alcohol-Induced Activation of Chemokine System and Neuroinflammation Development. Biochemistry. 2024 Nov;89(11):1889-1903. doi: 10.1134/S0006297924110038.
  25. Mikhalitskaya E.V., Vyalova N.M., Ermakov E.A., Levchuk L.A., Simutkin G.G., Bokhan N.A., Ivanova S.A. Association of Single Nucleotide Polymorphisms of Cytokine Genes with Depression, Schizophrenia and Bipolar Disorder. Genes (Basel). 2023 Jul 17;14(7):1460. doi: 10.3390/genes14071460.
  26. Perry B.I., Upthegrove R., Kappelmann N., Jones P.B., Burgess S., Khandaker G.M. Associations of immunological proteins/traits with schizophrenia, major depression and bipolar disorder: A bi-directional two-sample mendelian randomization study. Brain Behav Immun. 2021 Oct;97:176-185. doi: 10.1016/j.bbi.2021.07.009.
  27. Saad S., Dunn L.B., Koetters T., Dhruva A., Langford D.J., Merriman J.D., West C., Paul S.M., Cooper B., Cataldo J., Hamolsky D., Elboim C., Aouizerat B.E., Miaskowski C. Cytokine gene variations associated with subsyndromal depressive symptoms in patients with breast cancer. Eur J Oncol Nurs. 2014 Aug;18(4):397-404. doi: 10.1016/j.ejon.2014.03.009.
  28. Sandoval-Carrillo A., Alvarado-Esquivel C., Salas-Martinez C., Mendez-Hernandez E.M., Sifuentes-Alvarez A., Martínez-Martinez A.L., Castillo-Orona J.M., Hernandez-Tinoco J., Antuna-Salcido E.I., Sanchez-Anguiano L.F., Velez Velez L.M., Salas-Pacheco S.M., Castellanos-Juarez F.X., Llave-Leon O., Arias-Carrion O., Salas-Pacheco J.M. TNF-α Polymorphisms and Maternal Depression in a Mexican Mestizo Population. CNS Neurol Disord Drug Targets. 2018 Apr 26;17(1):69-74. doi: 10.2174/1871527317666180207165238.
  29. Santos M., Carvalho S., Lima L., Mota-Pereira J., Pimentel P., Maia D., Correia D., Gomes S., Cruz A., Medeiros R. The role of IL18-607C>A and IL18-137G>C promoter polymorphisms in antidepressant treatment phenotypes: A preliminary report. Neurosci Lett. 2016 May 27;622:107-12. doi: 10.1016/j.neulet.2016.03.026.
  30. Snaith R.P., Hamilton M., Morley S., Humayan A., Hargreaves D., Trigwell P. A scale for the assessment of hedonic tone the Snaith-Hamilton Pleasure Scale. Br J Psychiatry. 1995 Jul;167(1):99-103. doi: 10.1192/bjp.167.1.99.
  31. Strawbridge R., Hodsoll J., Powell T.R., Hotopf M., Hatch S.L., Breen G., Cleare A.J. Inflammatory profiles of severe treatment-resistant depression. J Affect Disord. 2019 Mar 1;246:42-51. doi: 10.1016/j.jad.2018.12.037.
  32. Sunyer J., Forastiere F., Pekkanen J., Plana E., Kolz M., Pistelli R., Jacquemin B., Brüske-Hohlfeld I., Pitsavos Ch., Bellander T., Koenig W., Peters A. AIRGENE Study Group. Interaction between smoking and the interleukin-6 gene affects systemic levels of inflammatory biomarkers. Nicotine Tob Res. 2009 Nov;11(11):1347-53. doi: 10.1093/ntr/ntp144.
  33. Szabo G., Mandrekar P. A recent perspective on alcohol, immunity, and host defense. Alcohol Clin Exp Res. 2009 Feb;33(2):220-32. doi: 10.1111/j.1530-0277.2008.00842.x.
  34. Wilhelm C.J., Fuller B.E., Huckans M., Loftis J.M. Peripheral immune factors are elevated in women with current or recent alcohol dependence and associated with altered mood and memory. Drug Alcohol Depend. 2017 Jul 1;176:71-78. doi: 10.1016/j.drugalcdep.2017.02.023.
  35. Williams J.B.W., Link M.J., Rosenthal N.E., Amira L., Terman M. Structured Interview Guide for the Hamilton Depression Rating Scale—Seasonal Affective Disorder Version (SIGH-SAD) New York, NY: New York State Psychiatric Institute; 1992.
  36. Zhang C., Wu Z., Zhao G., Wang F., Fang Y. Identification of IL6 as a susceptibility gene for major depressive disorder. Sci Rep. 2016 Aug 9;6:31264. doi: 10.1038/srep31264.

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