The сontribution of FOXO family transcription factor genes (FOXO1, FOXO3) to chronic obstructive pulmonary disease

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) (P_adj = 0.0018, OR = 1.44 for the AG genotype) and FOXO3A (rs2253310) (P_adj = 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.

1. Agustí A., Celli B.R., Criner G.J., Halpin D., Anzueto A., Barnes P., Bourbeau J. Global initiative for chronic obstructive lung disease 2023 report: GOLD executive summary. Eur Respir J. 2023;61(4): 230-239. doi 10.1183/13993003.00239-2023

2. Bagam P., Kaur G., Singh D.P., Batra S. In vitro study of the role of FOXO transcription factors in regulating cigarette smoke extractinduced autophagy. Cell Biol Toxicol. 2021;37(4):531-553. doi 10.1007/s10565-020-09556-y

3. Brandsma C.A., Van den Berge M., Hackett T.L., Brusselle G., Timens W. Recent advances in chronic obstructive pulmonary disease pathogenesis: from disease mechanisms to precision medicine. J Pathol. 2020;250(5):624-635. doi 10.1002/path.5364

4. Cao G., Lin M., Gu W., Su Z., Duan Y., Song W., Liu H., Zhang F. The rules and regulatory mechanisms of FOXO3 on inflammation, metabolism, cell death and aging in hosts. Life Sci. 2023;328:121877. doi 10.1016/j.lfs.2023.121877

5. Chen J.X., Yang L., Sun L., Chen W., Wu J., Zhang C.F., Liu K.Y., Bai L., Lu H.G., Gao T., Tian H., Jiang S.L. Sirtuin 3 ameliorates lung senescence and improves type II alveolar epithelial cell function by enhancing the FoxO3a-dependent antioxidant defense me­ chanism. Stem Cells Dev. 2021;30(17):843-855. doi 10.1089/scd. 2021.0099

6. Chung S., Kim J.Y., Song M.A., Park G.Y., Lee Y.G., Karpurapu M., Englert J.A., Ballinger M.N., Pabla N., Chung H.Y., Christman J.W. FoxO1 is a critical regulator of M2-like macrophage activation in allergic asthma. Allergy. 2019;74(3):535-548. doi 10.1111/all.13626

7. Di Vincenzo S., Heijink I.H., Noordhoek J.A., Cipollina C., Siena L., Bruno A., Ferraro M., Postma D.S., Gjomarkaj M., Pace E. SIRT1/ FoxO3 axis alteration leads to aberrant immune responses in bronchial epithelial cells. J Cell Mol Med. 2018;22(4):2272-2282. doi 10.1111/jcmm.13509

8. Domej W., Oettl K., Renner W. Oxidative stress and free radicals in COPD – implications and relevance for treatment. Int J Chron Obstruct Pulmon Dis. 2014;9:1207-1224. doi 10.2147/COPD.S51226

9. Farhan M., Silva M., Xingan X., Huang Y., Zheng W. Role of FOXO transcription factors in cancer metabolism and angiogenesis. Cells. 2020;9(7):1586. doi 10.3390/cells9071586

10. Geerdink J.X., Simons S.O., Pike R., Stauss H.J., Heijdra Y.F., Hurst J.R. Differences in systemic adaptive immunity contribute to the ‘frequent exacerbator’ COPD phenotype. Respir Res. 2016;17(1):140. doi 10.1186/s12931-016-0456-y

11. González J.R., Armengol L., Solé X., Guinó E., Mercader J.M., Esti­ vill X., Moreno V. SNPassoc: an R package to perform whole genome association studies. Bioinformatics. 2007;23(5):644-645. doi 10.1093/bioinformatics/btm025

12. Gui T., Burgering B.M.T. FOXOs: masters of the equilibrium. FEBS J. 2022;289(24):7918-7939. doi 10.1111/febs.16221

13. Guo J., Nie J., Chen Z., Wang X., Hu H., Xu J., Lu J., Ma L., Ji H., Yuan J., Xu B. Cold exposure-induced endoplasmic reticulum stress regulates autophagy through the SIRT2/FoxO1 signaling pathway. J Cell Physiol. 2022;237(10):3960-3970. doi 10.1002/jcp.30856

14. Hagenbuchner J., Ausserlechner M.J. Mitochondria and FOXO3: breath or die. Front Physiol. 2013;4:147. doi 10.3389/fphys.2013.00147

15. Hussain S., Yadav S.S., Dwived.i P., Banerjee M., Usman K., Nath R., Khattri S. SNPs of FOXO1 and their interactions contributes to the enhanced risk of diabetes among elderly individuals. DNA Cell Biol. 2022;41(4):381-389. doi 10.1089/dna.2021.1139

16. Hwang J.W., Rajendrasozhan S., Yao H., Chung S., Sundar I.K., Huyck H.L., Pryhuber G.S., Kinnula V.L., Rahman I. FOXO3 deficiency leads to increased susceptibility to cigarette smoke-induced inflammation, airspace enlargement, and chronic obstructive pulmonary disease. J Immunol. 2011;187(2): 987-998. doi 10.4049/jimmunol.1001861

17. Jiang H., Xu Y., Jiang Y., Li Y. FOXO3 activation prevents cellular senescence in emphysema induced by cigarette smoke. COPD. 2023; 20(1):80-91. doi 10.1080/15412555.2022.2164262

18. Klinpudtan N., Allsopp R.C., Kabayama M., Godai K., Gondo Y., Masui Y., Akagi Y. The association between longevity-associated FOXO3 allele and heart disease in septuagenarians and octogena­ rians: the SONIC study. J Gerontol A Biol Sci Med Sci. 2022;77(8): 1542-1548. doi 10.1093/gerona/glab204

19. Korytina G.F., Akhmadishina L.Z., Aznabaeva Y.G., Kochetova O.V., Zagidullin N.S., Kzhyshkowska J.G., Zagidullin S.Z., Viktoro­ va T.V. Associations of the NRF2/KEAP1 pathway and antioxidant defense gene polymorphisms with chronic obstructive pulmonary disease. Gene. 2019;692:102-112. doi 10.1016/j.gene.2018.12.061

20. Korytina G.F., Akhmadishina L.Z., Kochetova O.V., Aznabaeva Y.G., Izmailova S.M., Zagidullin S.Z., Victorova T.V. Association of CRP, CD14, pro-inflammatory cytokines and their receptors (TNFA, LTA, TNFRSF1A, TNFRSF1B, IL1B, and IL6) genes with chronic obstructive pulmonary disease development. Russ J Genet. 2020;56,972-981. doi 10.1134/S1022795420080086 (in Russian)

21. 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. Role of PI3K/AKT/mTOR signaling pathway and sirtuin genes in chronic obstructive pulmonary disease development. Vavilovskii Zhurnal Genetiki i Selektsii = Vavilov J Genet Breed. 2023;27(5):512-521. doi 10.18699/VJGB- 23-62

22. Li Y., Tian X., Luo J., Bao T., Wang S., Wu X. Molecular mechanisms of aging and anti-aging strategies. Cell Commun Signal. 2024;22(1): 285. doi 10.1186/s12964-024-01663-1

23. Liu J.Q., Zhang .L., Yao J., Yao S., Yuan T. AMPK alleviates endoplasmic reticulum stress by inducing the ER-chaperone ORP150 via FOXO1 to protect human bronchial cells from apoptosis. Biochem Biophys Res Commun. 2018;497(2):564-570. doi 10.1016/j.bbrc.2018.02.095

24. Luo X., Zeng W., Tang J., Liu W., Yang J., Chen H., Jiang L., Zhou X., Huang J., Zhang S., Du L., Shen X., Chi H., Wang H. Multi-modal transcriptomic analysis reveals metabolic dysregulation and immune responses in chronic obstructive pulmonary disease. Sci Rep. 2024; 14(1):22699. doi 10.1038/s41598-024-71773-w

25. Mahlooji M.A., Heshmati A., Kheiripour N., Ghasemi H., Asl S.S., Solgi G., Ranjbar A., Hosseini A. Evaluation of protective effects of curcumin and nanocurcumin on aluminium phosphide-induced subacute lung injury in rats: modulation of oxidative stress through SIRT1/FOXO3 signalling pathway. Drug Res (Stuttg). 2022;72(2): 100-108. doi 10.1055/a-1647-2418

26. Santana C.V.N., Magno L.A.V., Ramos A.V., Rios M.A., Sandrim V.C., De Marco L.A., de Miranda D.M., Romano-Silva M.A. Genetic variations in AMPK, FOXO3A, and POMC increase the risk of extreme obesity. J Obes. 2024;2024:3813621. doi 10.1155/2024/3813621

27. Soerensen M., Nygaard M., Dato S., Stevnsner T., Bohr V.A., Christensen K., Christiansen L. Association study of FOXO3A SNPs and aging phenotypes in Danish oldest-old individuals. Aging Cell. 2015;14(1):60-66. doi 10.1111/acel.12295

28. Ward L.D., Kellis M. HaploReg v4: systematic mining of putative causal variants, cell types, regulators and target genes for human complex traits and disease. Nucleic Acids Res. 2016;44(D1):D877- D881. doi 10.1093/nar/gkv1340

29. Xue T., Dong F., Gao J., Zhong X. Identification of related-genes of T cells in lung tissue of chronic obstructive pulmonary disease based on bioinformatics and experimental validation. Sci Rep. 2024;14(1): 12042. doi 10.1038/s41598-024-62758-w

30. Yao H., Chung S., Hwang J.W., Rajendrasozhan S., Sundar I.K., Dean D.A., McBurney M.W., Guarente L., Gu W., Rönty M., Kinnula V.L., Rahman I. SIRT1 protects against emphysema via FOXO3- mediated reduction of premature senescence in mice. J Clin Invest. 2012;122(6):2032-2045. doi 10.1172/JCI60132

31. Zang L., Chi J., Bi S., Tao Y., Wang R., Li L. SIRT3 improves alveolar epithelial cell damage caused by bronchopulmonary dysplasia through deacetylation of FOXO1. Allergol Immunopathol (Madr). 2023;51(2):191-204. doi 10.15586/aei.v51i2.710

32. Zhu M., Ye M., Wang J., Ye L., Jin M. Construction of potential miRNA-mRNA regulatory network in COPD plasma by bioinformatics analysis. Int J Chron Obstruct Pulmon Dis. 2020;15:2135- 2145. doi 10.2147/COPD.S255262