References

vavilov

Вавиловский журнал генетики и селекции

Vavilov Journal of Genetics and Breeding

2500-3259

Institute of Cytology and Genetics of Siberian Branch of the RAS

10.18699/VJGB-23-62

vavilov-3861

Research Article

БИОТЕХНОЛОГИЯ В ПОСТГЕНОМНУЮ ЭРУ

MEDICAL GENETICS

Роль генов PI3K/AKT/mTOR-сигнального каскада и сиртуинов в развитии хронической обструктивной болезни легких

Role of PI3K/AKT/mTOR signaling pathway and sirtuin genes in chronic obstructive pulmonary disease development

https://orcid.org/0000-0002-1695-5173

Корытина

Г. Ф.

Korytina

G. F.

Уфа

Ufa

guly_kory@mail.ru

https://orcid.org/0000-0003-0043-5090

Ахмадишина

Л. З.

Akhmadishina

L. Z.

Уфа

Ufa

https://orcid.org/0000-0002-0663-7219

Маркелов

В. А.

Markelov

V. A.

Уфа

Ufa

https://orcid.org/0000-0002-1518-774X

Азнабаева

Ю. Г.

Aznabaeva

Y. G.

Уфа

Ufa

https://orcid.org/0000-0002-2944-4428

Кочетова

О. В.

Kochetova

O. V.

Уфа

Ufa

https://orcid.org/0000-0001-8823-8678

Насибуллин

Т. Р.

Nasibullin

T. R.

Уфа

Ufa

https://orcid.org/0009-0003-0710-6705

Ларкина

А. П.

Larkina

A. P.

Уфа

Ufa

https://orcid.org/0000-0003-4127-078X

Хуснутдинова

Н. Н.

Khusnutdinova

N. N.

Уфа

Ufa

https://orcid.org/0000-0003-2386-6707

Загидуллин

Н. Ш.

Zagidullin

N. Sh.

Уфа

Ufa

https://orcid.org/0000-0001-8900-2480

Викторова

Т. В.

Victorova

T. V.

Уфа

Ufa

Институт 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; Bashkir State Medical UniversityRussian Federation

Институт 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 Federation

Башкирский государственный медицинский университетРоссияBashkir State Medical UniversityRussian Federation

2023

08092023

275512521

2023

Корытина Г.Ф., Ахмадишина Л.З., Маркелов В.А., Азнабаева Ю.Г., Кочетова О.В., Насибуллин Т.Р., Ларкина А.П., Хуснутдинова Н.Н., Загидуллин Н.Ш., Викторова Т.В.

Korytina G.F., Akhmadishina L.Z., Markelov V.A., Aznabaeva Y.G., Kochetova O.V., Nasibullin T.R., Larkina A.P., Khusnutdinova N.N., Zagidullin N.S., Victorova T.V.

This work is licensed under a Creative Commons Attribution 4.0 License.

https://vavilov.elpub.ru/jour/article/view/3861

Хроническая обструктивная болезнь легких (ХОБЛ) – многофакторное заболевание дыхательной системы, развивающееся в результате комплексного взаимодействия молекулярно-генетических и средовых факторов, тесно связанных с образом жизни. Цель исследования – анализ комбинированного вклада генов PI3K/AKT/mTOR-сигнального каскада (PIK3R1, AKT1, MTOR, PTEN) и сиртуинов (SIRT1, SIRT3, SIRT6) в риск развития хронической обструктивной болезни легких. В работе использованы образцы ДНК 1245 индивидов. Полиморфные варианты генов SIRT1 (rs3758391, rs3818292), SIRT3 (rs3782116, rs536715), SIRT6 (rs107251), AKT1 (rs2494732), PIK3R1 (rs10515070, rs831125, rs3730089), MTOR (rs2295080, rs2536), PTEN (rs701848, rs2735343) анализировали методом полимеразной цепной реакции в реальном времени. Логистическую регрессию использовали для выявления ассоциации полиморфных локусов в различных моделях. Проводили линейный регрессионный анализ для оценки вклада генотипов изучаемых локусов в вариабельность показателей функции внешнего дыхания и индекса курения. Установлена ассоциация генов: SIRT1 (rs3818292) (P = 0.001, OR = 1.51 для генотипа AG), SIRT3 (rs3782116) (P = 0.0055, OR = 0.69) и SIRT3 (rs536715) (P = 0.00001, OR = 0.50) в доминантной модели; SIRT6 (rs107251) (P = 0.00001, OR = 0.55 для генотипа СT), PIK3R1: (rs10515070 (P = 0.0023, OR = 1.47 для генотипа AT), rs831125 (P = 0.00001, OR = 2.28 для генотипа AG), rs3730089 (P = 0.0007, OR = 1.73 для генотипа GG)) и PTEN: (rs701848 (P = 0.0015, OR = 1.35 в лог-аддитивной модели) и rs2735343 (P = 0.0001, OR = 1.64 для генотипа GC)). Обнаружена вариабельность показателей функции легочного дыхания в зависимости от полиморфных вариантов генов SIRT1 (rs3818292), SIRT3 (rs3782116), PIK3R1 (rs3730089) и MTOR (rs2536). Идентифицированы ген-генные сочетания, ассоциированные с ХОБЛ; наибольший риск развития ХОБЛ определялся сочетанием аллеля G гена PIK3R1 (rs831125) с генотипом GG гена SIRT3 (rs536715) (OR = 3.45). Полученные результаты полигенного анализа указывают на взаимодействие генов, кодирующих сиртуины SIRT3, SIRT2, SIRT6 и PI3KR1, PTEN, MTOR, и находят подтверждение в функциональной взаимосвязи сиртуинов и PI3K/AKT/mTOR-сигнального каскада.

Chronic obstructive pulmonary disease (COPD) is a multifactorial disease of the respiratory system which develops as a result of a complex interaction of genetic and environmental factors closely related to lifestyle. We aimed to assess the combined effect of the PI3K/AKT/mTOR signaling pathway (PIK3R1, AKT1, MTOR, PTEN) and sirtuin (SIRT1, SIRT3, SIRT6) genes to COPD risk. SNPs of SIRT1 (rs3758391, rs3818292), SIRT3 (rs3782116, rs536715), SIRT6 (rs107251), AKT1 (rs2494732), PIK3R1 (rs10515070, rs831125, rs3730089), MTOR (rs2295080, rs2536), PTEN (rs701848, rs2735343) genes were genotyped by real-time polymerase chain reaction (PCR) among 1245 case and control samples. Logistic regression was used to detect the association of SNPs in different models. Linear regression analyses were performed to estimate the relationship between SNPs and lung function parameters and smoking pack-years. Significant associations with COPD were identified for SIRT1 (rs3818292) (P = 0.001, OR = 1.51 for AG), SIRT3 (rs3782116) (P = 0.0055, OR = 0.69) and SIRT3 (rs536715) (P = 0.00001, OR = 0.50) under the dominant model, SIRT6 (rs107251) (P = 0.00001, OR = 0.55 for СT), PIK3R1: (rs10515070 (P = 0.0023, OR = 1.47 for AT), rs831125 (P = 0.00001, OR = 2.28 for AG), rs3730089 (P = 0.0007, OR = 1.73 for GG)), PTEN: (rs701848 (P = 0.0015, OR = 1.35 under the log-additive model), and rs2735343 (P = 0.0001, OR = 1.64 for GC)). A significant genotype-dependent variation of lung function parameters was observed for SIRT1 (rs3818292), SIRT3 (rs3782116), PIK3R1 (rs3730089), and MTOR (rs2536). Gene-gene combinations that remained significantly associated with COPD were obtained; the highest risk of COPD was conferred by a combination of G allele of the PIK3R1 (rs831125) gene and GG of SIRT3 (rs536715) (OR = 3.45). The obtained results of polygenic analysis indicate the interaction of genes encoding sirtuins SIRT3, SIRT2, SIRT6 and PI3KR1, PTEN, MTOR and confirm the functional relationship between sirtuins and the PI3K/AKT/mTOR signaling pathway.

хроническая обструктивная болезнь легкихPI3K/AKT/mTOR-сигнальный каскадсиртуиныклеточное старениеокислительный стресс

chronic obstructive pulmonary diseasePI3K/AKT/mTOR signaling pathwaysirtuinscellular senescenceoxidative stress

The study was performed with the support of the grant of Russian Science Foundation 23-25-00019 (http://rscf.ru/project/ 23-25-00019/). The work was performed using the equipment of the Centre for Collective Use“Biomika” and the unique KODINK research facility (Institute of Biochemistry and Genetics, Ufa Federal Research Centre, Russian Academy of Sciences).

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