vavilovВавиловский журнал генетики и селекцииVavilov Journal of Genetics and Breeding2500-3259Institute of Cytology and Genetics of Siberian Branch of the RAS10.18699/vjgb-25-90vavilov-4810Research ArticleМЕДИЦИНСКАЯ ГЕНЕТИКАMEDICAL GENETICSВклад генов транскрипционных факторов семейства FOXO (FOXO1, FOXO3) в развитие хронической обструктивной болезни легкихThe сontribution of FOXO family transcription factor genes (FOXO1, FOXO3) to chronic obstructive pulmonary diseaseМаркеловВ. А.MarkelovV. A.

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АхмадишинаЛ. З.AkhmadishinaL. Z.

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НасибуллинТ. Р.NasibullinT. R.

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АзнабаеваЮ. Г.AznabaevaY. G.

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КочетоваО. В.KochetovaO. V.

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ХуснутдиноваН. Н.KhusnutdinovaN. N.

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ИзмайловаС. М.IzmailovaS. M.

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ЗагидуллинН. ШюZagidullinN. Sh.

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КорытинаГ. Ф.KorytinaG. F.

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guly_kory@mail.ruИнститут биохимии и генетики – обособленное структурное подразделение Уфимского федерального исследовательского центра Российской академии наук; Башкирский государственный медицинский университетРоссияInstitute of Biochemistry and Genetics – Subdivision of the Ufa Federal Research Centre of the Russian Academy of Sciences; Bashkortostan State Medical UniversityRussian FederationИнститут биохимии и генетики – обособленное структурное подразделение Уфимского федерального исследовательского центра Российской академии наук; Уфимский государственный нефтяной технический университетРоссияInstitute of Biochemistry and Genetics – Subdivision of the Ufa Federal Research Centre of the Russian Academy of Sciences; Ufa State Petroleum Technological UniversityRussian FederationИнститут биохимии и генетики – обособленное структурное подразделение Уфимского федерального исследовательского центра Российской академии наукРоссияInstitute of Biochemistry and Genetics – Subdivision of the Ufa Federal Research Centre of the Russian Academy of SciencesRussian FederationБашкирский государственный медицинский университетРоссияBashkortostan State Medical UniversityRussian Federation202509102025296828837Copyright © Маркелов В.А., Ахмадишина Л.З., Насибуллин Т.Р., Азнабаева Ю.Г., Кочетова О.В., Хуснутдинова Н.Н., Измайлова С.М., Загидуллин Н.Ш., Корытина Г.Ф., 20252025Маркелов В.А., Ахмадишина Л.З., Насибуллин Т.Р., Азнабаева Ю.Г., Кочетова О.В., Хуснутдинова Н.Н., Измайлова С.М., Загидуллин Н.Ш., Корытина Г.Ф.Markelov V.A., Akhmadishina L.Z., Nasibullin T.R., Aznabaeva Y.G., Kochetova O.V., Khusnutdinova N.N., Izmailova S.M., Zagidullin N.S., Korytina G.F.This work is licensed under a Creative Commons Attribution 4.0 License.https://vavilov.elpub.ru/jour/article/view/4810

Хроническая обструктивная болезнь легких (ХОБЛ) – многофакторное заболевание дыхательной системы, является третьей ведущей (после ишемической болезни сердца и инсульта) причиной смерти в мире. В рамках наиболее актуальных концепций патогенеза ХОБЛ ключевое значение уделяется ускоренному клеточному старению. Транскрипционные факторы семейства FOXO – важные ключевые компоненты сигнальных путей клеточного старения. Цель исследования – выявление ассоциации полиморфных вариантов генов FOXO1 (rs12585277, rs9549240) и FOXO3A (rs 2253310, rs3800231) с развитием ХОБЛ и фенотипами заболевания. В работе использованы образцы ДНК больных ХОБЛ (N = 710) и здоровых индивидов (N = 655). Полиморфные локусы анализировали методом ПЦР в реальном времени. Впервые показаны значимые ассоциации полиморфных локусов генов FOXO1 (rs12585277) и FOXO3A (rs2253310) с ХОБЛ и фенотипами заболевания. Ассоциация с ХОБЛ установлена с локусами генов FOXO1 (rs12585277) (Padj = 0.0018, OR = 1.44 генотип AG) и FOXO3A (rs2253310) (Padj = 5.926 × 10–7, OR = 1.99 генотип GG). Обнаружена вариабельность показателей индекса курения (в пачках/ лет), жизненной емкости легких и форсированной жизненной емкости легких в зависимости от полиморфных вариантов локусов FOXO1 (rs9549240 и rs12585277) и FOXO3A (rs2253310). Идентифицирована значимая многофакторная регрессионная модель формирования ХОБЛ, в которую вошли полиморфные варианты генов FOXO1 (rs12585277) и FOXO3A (rs2253310), индекс курения и возраст обследуемых (P = 5.25 × 10–93, AUC = 0.864). Многофакторная регрессионная модель развития фенотипа ХОБЛ с частыми обострениями включала генотип AG локуса FOXO1 (rs12585277), индекс курения и возраст (AUC = 0.897, P = 4.1 × 10–86). Cвязанные с аутофагией, окислительным стрессом и клеточным гомеостазом транскрипционные факторы семейства FOXO как потенциальные биомаркеры и мишени для терапии могут стать основой для разработки новой стратегии диагностики и лечения хронической обструктивной болезни легких.

Chronic obstructive pulmonary disease (COPD) is a multifactorial disease of the respiratory system and is the third leading cause of death worldwide. In the framework of the most relevant concepts of COPD pathogenesis, the key focus is on accelerated cellular senescence. FOXO family transcription factors are important hub components of cellular senescence signaling pathways. The objective of the study is to identify the association of FOXO1 (rs12585277, rs9549240), and FOXO3A (rs2253310, rs3800231) genes polymorphic variants with COPD and disease phenotypes. DNA samples from COPD patients (N = 710) and healthy individuals (N = 655) were used, polymorphic loci were analyzed by real-time PCR. For the first time, significant associations of FOXO1 (rs12585277) and FOXO3A (rs2253310) gene polymorphic loci with COPD and disease phenotypes were shown. Association with COPD was established with FOXO1 (rs12585277) (Padj = 0.0018, OR = 1.44 for the AG genotype) and FOXO3A (rs2253310) (Padj = 5.926 × 10–7, OR = 1.99 for the GG genotype). A significant genotype-dependent variation of smoking index (in pack/years), vital capacity and forced vital capacity was revealed for FOXO1 (rs9549240, rs12585277) and FOXO3A (rs2253310) loci. Multiple regression and ROC analysis identified highly informative COPD risk model, which included polymorphic variants of the FOXO1 (rs12585277) and FOXO3A (rs2253310) genes, smoking index and age (P = 5.25 × 10–93, AUC = 0.864). The multivariate regression model of the COPD “frequent exacerbator” phenotype included the AG genotype of FOXO1 (rs12585277), smoking index and age (AUC = 0.897, P = 4.1 × 10–86). FOXO family transcription factors involved in autophagy, oxidative stress and cellular homeostasis may provide a platform for a new diagnostic and treatment strategy for COPD as potential biomarkers and targets for therapy.

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