ymjЯкутский медицинский журналYakut Medical Journal1813-19052312-1017ЯНЦ КМП10.25789/YMJ.2023.83.03ymj-39Research ArticleОРИГИНАЛЬНЫЕ ИССЛЕДОВАНИЯORIGINAL RESEARCHГены над-зависимых деацетилаз семейства сиртуинов и риск развития различных фенотипов хронической обструктивной болезни легкихNad-dependent deacetylase genes of sirtuin family and risk of developing various phenotypes of chronic obstructive pulmonary diseasehttps://orcid.org/0000-0002-1695-5173КорытинаГ. Ф.KorytinaG. F.

КОРЫТИНА Гульназ Фаритовна – д.б.н., доцент, гл.н.с. ИБГ УФИЦ РАН, проф. Башкирского ГМУ Минздрава России

Уфа

KORYTINA Gulnaz Faritovna – MD in Biology, Associate Professor, Head of Scientific Research, Prof. Bashkir State Medical University of the Ministry of Health of Russia

Ufa

guly_kory@mail.ruhttps://orcid.org/0000-0002-0663-7219МаркеловВ. А.MarkelovV. A.

МАРКЕЛОВ Виталий Андреевич – очный аспирант ИБГ УФИЦ РАН, м.н.с. Ин-та фундам. медицины Башкирского ГМУ Минздрава России

Уфа

MARKELOV Vitaly Andreevich – full-time postgraduate student, junior researcher of the Bashkir State Medical University of the Ministry of Health of Russia

Ufa

marckelow.vitalick2017@yandex.ruhttps://orcid.org/0000-0003-0043-5090АхмадишинаЛ. З.AkhmadishinaL. Z.

ХМАДИШИНА Лейсан Зинуровна – к.б.н., н.с.

Уфа

AKHMADISHINA Leysan Zinurovna – PhD in Biology, research asocciate

Ufa

l.akhmadishina@gmail.orghttps://orcid.org/0000-0002-1518-774XАзнабаеваЮ. Г.AznabaevaYu. G.

АЗНАБАЕВА Юлия Геннадиевна – к.м.н., доцент, завуч кафедры

Уфа

AZNABAYEVA Yulia Gennadievna – Candidate of Medical Sciences, Associate Professor, Head Teacher of the Bashkir State Medical University of the Ministry of Health of Russia

Ufa

3251251@gmail.comhttps://orcid.org/0000-0002-2944-4428КочетоваО. В.KochetovaO. V.

КОЧЕТОВА Ольга Владимировна – к.б.н., с.н.с.

Уфа

KOCHETOVA Olga Vladimirovna – PhD in Biology, Senior Researcher, IBG UFRC RAS

Ufa

olga_mk78@mail.ruЛаркинаА. П.LarkinaA. P.

ЛАРКИНА Анастасия Павловна – м.н.с.

Уфа

LARKINA Anastasia Pavlovna – junior researcher, IBG UFRC RAS

Ufa

arina030300@gmail.comhttps://orcid.org/0000-0003-4127-078XХуснутдиноваН. Н.KhusnutdinovaN. N.

ХУСНУТДИНОВА Наталья Николаевна – к.б.н., н.с.

Уфа

KHUSNUTDINOVA Natalia Nikolaevna – PhD in Biology, research associate IBG UFRC RAS

Ufa

natalia.smirnova17@mail.ruhttps://orcid.org/0009-0004-0130-9410ИзмайловаС. М.IzmailovaS. M.

ИЗМАЙЛОВА Светлана Михайловна – к.б.н., доцент

Уфа

ZMAILOVA Svetlana Mikhailovna – PhD in Biology, Associate Professor of Bashkir State Medical University of the Ministry of Health of Russia

Ufa

izmailovas73@mail.ruhttps://orcid.org/0000-0003-2386-6707ЗагидуллинН. Ш.ZagidullinN. Sh.

ЗАГИДУЛЛИН Науфаль Шамилевич – д.м.н., проф., зав. кафедрой

Уфа

ZAGIDULLIN Naufal Shamilevich – MD, Professor, Head of the Department of Bashkir State Medical University of the Ministry of Health of Russia

Ufa

znaufal@mail.ruhttps://orcid.org/0000-0001-8900-2480ВиктороваТ. В.ViktorovaT. V.

ВИКТОРОВА Татьяна Викторовна – д.м.н., проф., зав. кафедрой

Уфа

VIKTOROVA Tatiana Viktorovna – MD, Prof., Head of the Department of Bashkir State Medical University of the Ministry of Health of Russia

Ufa

t_vict@mail.ruИБГ УФИЦ РАН; ГМУ Минздрава РоссииРоссияInstitute of Biochemistry and Genetics - Subdivision of the Ufa Federal Research Centre of the Russian Academy of ciences (IBG UFRC)Russian FederationИБГ УФИЦ РАН; Ин-т фундам. медицины Башкирского ГМУ Минздрава РоссииРоссияInstitute of Biochemistry and Genetics - Subdivision of the Ufa Federal Research Centre of the Russian Academy of ciences (IBG UFRC)Russian FederationИБГ УФИЦ РАНРоссияInstitute of Biochemistry and Genetics - Subdivision of the Ufa Federal Research Centre of the Russian Academy of ciences (IBG UFRC)Russian FederationБашкирский ГМУ Минздрава РоссииРоссияInstitute of Biochemistry and Genetics - Subdivision of the Ufa Federal Research Centre of the Russian Academy of ciences (IBG UFRC)Russian FederationХУСНУТДИНОВА Наталья Николаев- на – к.б.н., н.с. ИБГ УФИЦ РАН, ORCID 0000- 0003-4127-078X, natalia.smirnova17@mail. ruРоссияInstitute of Biochemistry and Genetics - Subdivision of the Ufa Federal Research Centre of the Russian Academy of ciences (IBG UFRC)Russian FederationБашкирский ГМУ Минздрава России,РоссияInstitute of Biochemistry and Genetics - Subdivision of the Ufa Federal Research Centre of the Russian Academy of ciences (IBG UFRC)Russian Federation202303022025031417Copyright © Корытина Г.Ф., Маркелов В.А., Ахмадишина Л.З., Азнабаева Ю.Г., Кочетова О.В., Ларкина А.П., Хуснутдинова Н.Н., Измайлова С.М., Загидуллин Н.Ш., Викторова Т.В., 20252025Корытина Г.Ф., Маркелов В.А., Ахмадишина Л.З., Азнабаева Ю.Г., Кочетова О.В., Ларкина А.П., Хуснутдинова Н.Н., Измайлова С.М., Загидуллин Н.Ш., Викторова Т.В.Korytina G.F., Markelov V.A., Akhmadishina L.Z., Aznabaeva Y.G., Kochetova O.V., Larkina A.P., Khusnutdinova N.N., Izmailova S.M., Zagidullin N.S., Viktorova T.V.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://ymj.elpub.ru/jour/article/view/39

Проведен анализ вклада генов сиртуинов (SIRT2, SIRT1, SIRT3, SIRT6) в риск развития различных фенотипов ХОБЛ. В результате проведенного исследования нами выявлены значимые ассоциации полиморфных вариантов генов SIRT1 (rs3818292), SIRT3 (rs536715) и SIRT6 (rs107251) с развитием обоих фенотипов ХОБЛ. Специфическим маркером развития фенотипа ХОБЛ с частыми обострениями является локус rs3782116 гена SIRT3. Полученные данные подтверждают гипотезу о существенной роли НАД-зависимых протеин-деацетилаз из семейства сиртуинов и механизмов клеточного старения в формировании наследственной предрасположенности к развитию ХОБЛ.

Chronic obstructive pulmonary disease (COPD) is one of the most common chronic respiratory diseases with high morbidity and mortality. The pathogenesis of COPD is closely related to oxidative stress, that is the main mechanism causes accelerated cell senescence. Published data suggest that the COPD pathogenesis may involve stress responses dysregulation that inhibit cellular senescence. We aimed to assess the contribution of sirtuin genes (SIRT2, SIRT1, SIRT3, SIRT6) to the various COPD phenotypes risk.

SNPs of SIRT2 (rs10410544), SIRT1 (rs3758391, rs3818292), SIRT3 (rs3782116, rs536715), SIRT6 (rs107251) genes were genotyped by the real-time polymerase chain reaction (PCR) among 1245 samples (severe COPD with frequent exacerbations (N=331), stable COPD with rare exacerbations (N=290) and control (N=624)). Logistic regression was used to detect the association of studied SNPs in different models.

Significant associations with severe COPD phenotype were identified for SIRT1 (rs3818292) (P=0.0097, OR = 1.49 for AG genotype), SIRT3 (rs3782116) (P = 0.0034, OR =0.63) and SIRT3 (rs536715) (P = 0.00001, OR =0.53) under dominant model, and SIRT6 (rs107251) (P = 0.00001, OR =0.55 for СT genotype). Stable COPD phenotype with rare exacerbations was associated with SIRT1 (rs3818292) (P = 0.0055, OR =1.54 for AG genotype), SIRT3 (rs536715) (P = 0.00001, OR =0.48 under dominant model), and SIRT6 (rs107251) (P = 0.0002, OR =0.54 for СT genotype).

The obtained results indicate the contribution of NAD-dependent deacetylase genes of sirtuin family and cellular senescence mechanisms to COPD development. The SIRT3 (rs3782116) identified as a specific marker for severe COPD phenotype with frequent exacerbations.

хроническая обструктивная болезнь легкихсиртуиныокислительный стрессChronic obstructive pulmonary diseasesirtuinsoxidative stressReferencesAssociation of Sirtuin Gene Polymorphisms with Susceptibility to Coronary Artery Disease in a North Chinese Population / X. Song [et al.] // Biomed. Res. Int. 2022. Vol. 2022. P. 4294008. doi: 10.1155/2022/4294008.Association of Sirtuin Gene Polymorphisms with Susceptibility to Coronary Artery Disease in a North Chinese Population / X. Song [et al.] // Biomed. Res. Int. 2022. Vol. 2022. P. 4294008. doi: 10.1155/2022/4294008.Associations of the NRF2/KEAP1 pathway and antioxidant defense gene polymorphisms with chronic obstructive pulmonary disease / G.F. Korytina [et al.] // Gene. 2019. No.. 692. P. 102-112. doi: 10.1016/j.gene.2018.12.061.Associations of the NRF2/KEAP1 pathway and antioxidant defense gene polymorphisms with chronic obstructive pulmonary disease / G.F. Korytina [et al.] // Gene. 2019. No.. 692. P. 102-112. doi: 10.1016/j.gene.2018.12.061.Autophagy induction by SIRT6 through attenuation of insulin-like growth factor signaling is involved in the regulation of human bronchial epithelial cell senescence / N. Takasaka [et al.] // J. Immunol. 2014. Vol. 192. No.3. P. 958-968. doi: 10.4049/jimmunol.1302341.Autophagy induction by SIRT6 through attenuation of insulin-like growth factor signaling is involved in the regulation of human bronchial epithelial cell senescence / N. Takasaka [et al.] // J. Immunol. 2014. Vol. 192. No.3. P. 958-968. doi: 10.4049/jimmunol.1302341.Barnes P.J., Baker J., Donnelly L.E. Cellular Senescence as a Mechanism and Target in Chronic Lung Diseases // Am. J. Respir. Crit. Care Med. 2019. Vol. 200. No.5. P. 556-564. doi: 10.1164/rccm.201810-1975TR.Barnes P.J., Baker J., Donnelly L.E. Cellular Senescence as a Mechanism and Target in Chronic Lung Diseases // Am. J. Respir. Crit. Care Med. 2019. Vol. 200. No.5. P. 556-564. doi: 10.1164/rccm.201810-1975TR.Finkel T., Deng C.X., Mostoslavsky R. Recent progress in the biology and physiology of sirtuins // Nature. 2009. Vol. 460. No.7255. P. 587-591. doi: 10.1038/nature08197.Finkel T., Deng C.X., Mostoslavsky R. Recent progress in the biology and physiology of sirtuins // Nature. 2009. Vol. 460. No.7255. P. 587-591. doi: 10.1038/nature08197.Genetic Advances in Chronic Obstructive Pulmonary Disease. Insights from COPDGene / M.F. Ragland [et al.] // Am J. Respir. Crit. Care. Med. 2019. Vol. 200. No. 6. P. 677-690. doi: 10.1164/rccm.201808-1455SO.Genetic Advances in Chronic Obstructive Pulmonary Disease. Insights from COPDGene / M.F. Ragland [et al.] // Am J. Respir. Crit. Care. Med. 2019. Vol. 200. No. 6. P. 677-690. doi: 10.1164/rccm.201808-1455SO.Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: 2023 report [электронный ресурс]. Доступ по ссылке https://goldcopd.org/2023-gold-report-2/Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: 2023 report [электронный ресурс]. Доступ по ссылке https://goldcopd.org/2023-gold-report-2/Kirkham P.A., Barnes P.J. Oxidative stress in COPD // Chest. 2013. Т.144. No.1. P. 266-273. doi: 10.1378/chest.12-2664Kirkham P.A., Barnes P.J. Oxidative stress in COPD // Chest. 2013. Т.144. No.1. P. 266-273. doi: 10.1378/chest.12-2664Kugel S., Mostoslavsky R. Chromatin and beyond: the multitasking roles for SIRT6 // Trends Biochem. Sci. 2014. Vol. 39. No.2. P. 72-81. doi:10.1016/j.tibs.2013.12.002.Kugel S., Mostoslavsky R. Chromatin and beyond: the multitasking roles for SIRT6 // Trends Biochem. Sci. 2014. Vol. 39. No.2. P. 72-81. doi:10.1016/j.tibs.2013.12.002.Roles of sirtuin family members in chronic obstructive pulmonary disease / J.R. Zhang [et al.] // Respir. Res. 2022. Vol. 23. No.1. P.66. doi: 10.1186/s12931-022-01986-y.Roles of sirtuin family members in chronic obstructive pulmonary disease / J.R. Zhang [et al.] // Respir. Res. 2022. Vol. 23. No.1. P.66. doi: 10.1186/s12931-022-01986-y.SIRT3: A New Regulator of Cardiovascular Diseases / W. Sun [et al.] // Oxid. Med. Cell Longev. 2018. Vol. 2018. P. 7293861. doi: 10.1155/2018/7293861.SIRT3: A New Regulator of Cardiovascular Diseases / W. Sun [et al.] // Oxid. Med. Cell Longev. 2018. Vol. 2018. P. 7293861. doi: 10.1155/2018/7293861.SIRT1, an antiinflammatory and antiaging protein, is decreased in lungs of patients with chronic obstructive pulmonary disease / S. Rajendrasozhan [et al.] // Am. J. Respir. Crit. Care Med. 2008. Vol. 177. No.8. P. 861-870. doi: 10.1164/rccm.200708-1269OC.SIRT1, an antiinflammatory and antiaging protein, is decreased in lungs of patients with chronic obstructive pulmonary disease / S. Rajendrasozhan [et al.] // Am. J. Respir. Crit. Care Med. 2008. Vol. 177. No.8. P. 861-870. doi: 10.1164/rccm.200708-1269OC.Sirt3 Impairment and SOD2 Hyperacetylation in Vascular Oxidative Stress and Hypertension / A.E. Dikalova [et al.] // Circ. Res. 2017. Vol. 121. No.5. P. 564-574. doi: 10.1161/CIRCRESAHA.117.310933.Sirt3 Impairment and SOD2 Hyperacetylation in Vascular Oxidative Stress and Hypertension / A.E. Dikalova [et al.] // Circ. Res. 2017. Vol. 121. No.5. P. 564-574. doi: 10.1161/CIRCRESAHA.117.310933.SIRT1 negatively regulates amyloid-beta-induced inflammation via the NF-κB pathway / L. Cao [et al.] // Braz. J. Med. Biol. Res. 2013. Vol. 46. No.8. P. 659-669. doi: 10.1590/1414-431X20132903.SIRT1 negatively regulates amyloid-beta-induced inflammation via the NF-κB pathway / L. Cao [et al.] // Braz. J. Med. Biol. Res. 2013. Vol. 46. No.8. P. 659-669. doi: 10.1590/1414-431X20132903.The sirtuin family in health and disease / Q.J. Wu [et al.] // Signal Transduct. Target Ther. 2022. Vol. 7. No.1. P. 402. doi: 10.1038/s41392-022-01257-8.The sirtuin family in health and disease / Q.J. Wu [et al.] // Signal Transduct. Target Ther. 2022. Vol. 7. No.1. P. 402. doi: 10.1038/s41392-022-01257-8.

The authors declare that there are no conflicts of interest present.