Полиморфизм rs1131769 гена STING1 и предрасположенность к бронхиальной астме среди узбекского населения: исследование типа «случай-контроль»
Kalit so‘zlar:
STING1, rs1131769, бронхиальная астма, путь cGAS-STING, врожденный иммунитетAbstrak
путь циклическая ГМФ-АМФ синтаза — стимулятор генов интерферона (cGAS-STING) представляет собой ключевой сенсор врожденного иммунитета, распознающий цитозольную ДНК и вовлеченный в воспаление дыхательных путей. Полиморфизм rs1131769 гена STING1 (R232H) является подтвержденным вариантом с потерей функции, существенно ослабляющим интерфероновую сигнализацию, однако его связь с бронхиальной астмой ранее не изучалась среди населения Центральной Азии.
Цель: изучить ассоциацию полиморфизма rs1131769 гена STING1 с предрасположенностью к бронхиальной астме среди взрослого узбекского населения
##plugins.themes.default.displayStats.downloads##
Havolalar
1. Shang G, Zhang C, Chen ZJ, Bai XC, Zhang X. Cryo-EM structures of STING reveal its mechanism of activation by cyclic GMP-AMP. Nature. 2019;567(7748):389-393. doi:10.1038/s41586-019-0998-5
2. Ergun SL, Fernandez D, Weiss TM, Li L. STING polymer structure reveals mechanisms for activation, hyperactivation, and inhibition. Cell. 2019;178(2):290-301.e10. doi:10.1016/j.cell.2019.05.036
3. Zhang Z, Zhou H, Ouyang X, Dong Y, Sarapultsev A, Luo S, et al. Multifaceted functions of STING in human health and disease: from molecular mechanism to targeted strategy. Signal Transduct Target Ther. 2022;7:394. doi:10.1038/s41392-022-01252-z
4. Kang J, Wu J, Liu Q, Wu X, Zhao Y, Ren J. Post-translational modifications of STING: a potential therapeutic target. Front Immunol. 2022;13:888147. doi:10.3389/fimmu.2022.888147
5. Li J, Canham SM, Wu H, Henault M, Chen L, et al. Activation of human STING by a molecular glue-like compound. Nat Chem Biol. 2024;20:365-372. doi:10.1038/s41589-023-01434-y
6. Taguchi T, Mukai K, Takaya E, Shindo R. STING operation at the ER/Golgi interface. Front Immunol. 2021;12:646304. doi:10.3389/fimmu.2021.646304
7. Gentili M, Lahaye X, Nadalin F, Nader GPF, Yatim N, et al. STING trafficking as a new dimension of immune signaling. J Exp Med. 2023;220(3):e20220990. doi:10.1084/jem.2022020990
8. Luo W, Zhang L, Luo X, Li Y, Shu HB, Zhong B. An additional site mutation in MITA/STING gain-of-function mutants abolishes the autoimmune SAVI phenotypes and directs a therapeutic strategy. Cell Rep Med. 2025;6(4):101413. doi:10.1016/j.xcrm.2025.101413
9. Jeremiah N, Neven B, Gentili M, Callebaut I, Maschalidi S, et al. Inherited STING-activating mutation underlies a familial inflammatory syndrome with lupus-like manifestations. J Clin Invest. 2014;124(12):5516-5520. doi:10.1172/JCI79100
10. Kennedy RB, Haralambieva IH, Ovsyannikova IG, Voigt EA, Larrabee BR, Schaid DJ, et al. Polymorphisms in STING affect human innate immune responses to poxviruses. Front Immunol. 2020;11:567348. doi:10.3389/fimmu.2020.567348
11. Yi G, Brendel VP, Shu C, Li P, Palanathan S, Cheng Kao C. Single nucleotide polymorphisms of human STING can affect innate immune response to cyclic dinucleotides. PLoS One. 2013;8(10):e77846. doi:10.1371/journal.pone.0077846
12. Jin L, Xu LG, Yang IV, Davidson EJ, Schwartz DA, Wurfel MM, et al. Identification and characterization of a loss-of-function human MPYS variant. Genes Immun. 2011;12(4):263-269. doi:10.1038/gene.2010.75
13. Patel S, Blaauboer SM, Tucker HR, Mansouri S, Ruiz-Moreno JS, Hamann L, et al. The common R71H-G230A-R293Q (HAQ) human TMEM173 is a null allele. J Immunol. 2017;198(2):776-787. doi:10.4049/jimmunol.1601585
14. Ruiz-Moreno JS, Hamann L, Shah JA, Verbon A, et al. The common HAQ STING variant impairs cGAS-dependent antibacterial responses and is associated with susceptibility to Legionnaires’ disease in humans. PLoS Pathog. 2018;14(1):e1006829. doi:10.1371/journal.ppat.1006829
15. Nissen SK, Pedersen JG, Helleberg M, Kjaer K, et al. Multiple homozygous variants in the STING-encoding TMEM173 gene in HIV long-term nonprogressors. J Immunol. 2018;200(10):3372-3382. doi:10.4049/jimmunol.1701284
16. Lubbers JM, van der Sluis TC, van der Bilt AR, Kleijn A, et al. Association of homozygous variants of STING1 with outcome in human cervical cancer. Cancer Sci. 2021;112(1):232-243. doi:10.1111/cas.14680
17. Patel S, Jin L. TMEM173 variants and potential importance to human biology and disease. Genes Immun. 2019;20(2):82-89. doi:10.1038/s41435-018-0029-9
18. Froehlich G, Finizio A, Napolano A, et al. The common H232 STING allele shows impaired activities in DNA sensing, susceptibility to viral infection, and in monocyte cell function, while the HAQ variant possesses wild-type properties. Sci Rep. 2023;13:19541. doi:10.1038/s41598-023-46830-5
19. Ablasser A, Goldeck M, Cavlar T, et al. cGAS produces a 2’-5’-linked cyclic dinucleotide second messenger that activates STING. Nature. 2013;498(7454):380-384. doi:10.1038/nature12306
20. Gao P, Ascano M, Wu Y, et al. Cyclic [G(2’,5’)pA(3’,5’)p] is the metazoan second messenger produced by DNA-activated cyclic GMP-AMP synthase. Cell. 2013;153(5):1094-1107. doi:10.1016/j.cell.2013.04.046
21. Zhang C, Shang G, Gui X, et al. Structural basis of STING binding with and phosphorylation by TBK1. Nature. 2019;567(7748):394-398. doi:10.1038/s41586-019-1000-2
22. Puray-Chavez M, Eschbach JE, Xia M, et al. A basally active cGAS-STING pathway limits SARS-CoV-2 replication in a subset of ACE2 positive airway cell models. Nat Commun. 2024;15:8394. doi:10.1038/s41467-024-52803-7
23. Rui Y, Su J, Shen T, et al. Unique and complementary suppression of cGAS-STING and RNA sensing-triggered innate immune responses by SARS-CoV-2 proteins. Signal Transduct Target Ther. 2021;6(1):123. doi:10.1038/s41392-021-00520-x
24. Di Domenico EG, Wang W, Sardu C, et al. The STING/TBK1/IRF3/IFN type I pathway is defective in cystic fibrosis. Front Immunol. 2023;14:1160348. doi:10.3389/fimmu.2023.1160348
25. Kazmierski J, Rub ST, Vyse S, et al. A baseline cellular antiviral state is maintained by cGAS and its most frequent naturally occurring variant rs610913. J Immunol. 2022;209(3):535-547. doi:10.4049/jimmunol.2100991
26. Sripada A, Verma D, Varma R, Sirohi K, Kwiat C, et al. Allergens abrogate antiinflammatory DNA effects and unmask macrophage-driven neutrophilic asthma via ILC2/STING/TNF-alpha signaling. J Clin Invest. 2025;135(16):e187907. doi:10.1172/JCI187907
27. Messaoud-Nacer Y, Culerier E, Rose S, Maillet I, et al. STING-dependent induction of neutrophilic asthma exacerbation in response to house dust mite. Allergy. 2025;80(3):715-737. doi:10.1111/all.16369
28. She L, Barrera GD, Yan L, et al. STING activation in alveolar macrophages and group 2 innate lymphoid cells suppresses IL-33-driven type 2 immunopathology. JCI Insight. 2021;6(3):e143509. doi:10.1172/jci.insight.143509
29. Ozasa K, Temizoz B, Kusakabe T, et al. Cyclic GMP-AMP triggers asthma in an IL-33-dependent manner that is blocked by amlexanox, a TBK1 inhibitor. Front Immunol. 2019;10:2212. doi:10.3389/fimmu.2019.02212
30. Raundhal M, Morse C, Khare A, Oriss TB, et al. Cyclic-di-GMP induces STING-dependent ILC2 to ILC1 shift during innate type 2 lung inflammation. Front Immunol. 2021;12:793553. doi:10.3389/fimmu.2021.793553
31. Coban C, Lee MSJ, Ishii KJ. Tissue-specific immunomodulation by the cGAS-STING pathway: from adjuvants to immunopathology. Int Immunol. 2023;35(11):557-566. doi:10.1093/intimm/dxad058
32. Phipps S, Fowler T, Little N, Yap PLF. STING targeting in lung diseases. Int J Mol Sci. 2022;23(22):11356. doi:10.3390/ijms232211356
33. Radzikowska U, Eljaszewicz A, Tan G, et al. Rhinovirus-induced epithelial RIG-I inflammasome suppresses antiviral immunity and promotes inflammation in asthma and COVID-19. Nat Commun. 2023;14:2329. doi:10.1038/s41467-023-37470-4
34. Doni Jayavelu ND, Benson B, dela Cruz PC, et al. Bronchial epithelial transcriptome reveals dysregulated interferon and inflammatory responses to rhinovirus in exacerbation-prone pediatric asthma. JCI Insight. 2025;10(24):e197711. doi:10.1172/jci.insight.197711
35. Rich HE, Antos D, Melton NR, Alcorn JF, Manni ML. Insights into type I and III interferons in asthma and exacerbations. Front Immunol. 2020;11:574027. doi:10.3389/fimmu.2020.574027
36. Tei R, Iijima K, Matsumoto K, et al. TLR3-driven IFN-beta antagonizes STAT5-activating cytokines and suppresses innate type 2 response in the lung. J Allergy Clin Immunol. 2022;149(3):1044-1059.e5. doi:10.1016/j.jaci.2021.07.041
37. Krug J, Kiefer A, Koelle J, et al. TLR7/8 regulates type I and type III interferon signalling in rhinovirus 1b-induced allergic asthma. Eur Respir J. 2021;57(4):2001562 doi:10.1183/13993003.01562-2020
38. Altman MC, Gill MA, Whalen E, et al. Transcriptome networks identify mechanisms of viral and nonviral asthma exacerbations in children. Nat Immunol. 2019;20(5):637-651. doi:10.1038/s41590-019-0347-8
39. Watson A, Spalluto CM, McCrae C, et al. Dynamics of IFN-beta responses during respiratory viral infection: insights for therapeutic strategies. Am J Respir Crit Care Med. 2020;201(1):83-94. doi:10.1164/rccm.201901-0214OC
40. Hellings PW, Steelant B. Epithelial barriers in allergy and asthma. J Allergy Clin Immunol. 2020;145(6):1499-1509. doi:10.1016/j.jaci.2020.04.010
41. Heijink IH, Kuchibhotla VNS, Roffel MP, et al. Epithelial cell dysfunction, a major driver of asthma development. Allergy. 2020;75(8):1902-1917. doi:10.1111/all.14421
42. Hewitt RJ, Lloyd CM. Regulation of immune responses by the airway epithelial cell landscape. Nat Rev Immunol. 2021;21(6):347-362. doi:10.1038/s41577-020-00477-9
43. Frey A, Lunding LP, Ehlers JC, et al. More than just a barrier: the immune functions of the airway epithelium in asthma pathogenesis. Front Immunol. 2020;11:761. doi:10.3389/fimmu.2020.00761
44. Steelant B, Wawrzyniak P, Martens K, et al. Blocking histone deacetylase activity as a novel target for epithelial barrier defects in patients with allergic rhinitis. J Allergy Clin Immunol. 2019;144(5):1242-1253.e7. doi:10.1016/j.jaci.2019.04.027
45. Liu T, Zhou YT, Wang LQ, et al. NOD-like receptor family, pyrin domain containing 3 (NLRP3) contributes to inflammation, pyroptosis, and mucin production in human airway epithelium on rhinovirus infection. J Allergy Clin Immunol. 2019;144(3):777-787.e9. doi:10.1016/j.jaci.2019.05.006
46. DeStefano S, Grychtol R, Funken D, et al. NLRP3 regulates epithelial barrier integrity and protects from airway hyperresponsiveness in experimental allergic asthma. Front Immunol. 2025;16:1655205. doi:10.3389/fimmu.2025.1655205
47. Mdkhana B, Saheb Sharif-Askari N, Ramakrishnan RK, et al. Nucleic acid sensor STING drives remodeling and its inhibition enhances steroid responsiveness in chronic obstructive pulmonary disease. PLoS One. 2023;18(7):e0284061. doi:10.1371/journal.pone.0284061
48. Sharif-Askari NS, Mdkhana B, Ramakrishnan RK, et al. H-151 STING inhibitor reverts the resistance of human primary COPD fibroblasts to steroid treatment. Int J Mol Sci. 2024;25(4):2318. doi:10.3390/ijms25042318
49. Decout A, Katz JD, Venkatraman S, Ablasser A. The cGAS-STING pathway as a therapeutic target in inflammatory diseases. Nat Rev Immunol. 2021;21(9):548-569. doi:10.1038/s41577-021-00524-z
50. Jabeen MF, Sanderson ND, Tinè M, et al. Species-level, metagenomic and proteomic analysis of microbe-immune interactions in severe asthma. Allergy. 2024;79(11):2966-2980. doi:10.1111/all.16269
51. Versi A, Azim A, Ivan FX, et al. A severe asthma phenotype of excessive airway Haemophilus influenzae relative abundance associated with sputum neutrophilia. Clin Transl Med. 2024;14(8):e70007. doi:10.1002/ctm2.70007
52. Zhou CM, Wang B, Wu Q, et al. Identification of cGAS as an innate immune sensor of extracellular bacterium Pseudomonas aeruginosa. iScience. 2021;24(1):101928. doi:10.1016/j.isci.2020.101928
53. Gao H, Luo Z, Ji Y, et al. Accumulation of microbial DNAs promotes islet inflammation and beta cell abnormalities in obesity in mice. Nat Commun. 2022;13:565. doi:10.1038/s41467-022-28239-2
54. Zhan X, Cui R, Geng X, et al. LPS-induced mitochondrial DNA synthesis and release facilitate RAD50-dependent acute lung injury. Signal Transduct Target Ther. 2021;6(1):103. doi:10.1038/s41392-021-00494-7
55. Agaronyan K, Sharma L, Vaidyanathan B, et al. Tissue remodeling by an opportunistic pathogen triggers allergic inflammation. Immunity. 2022;55(5):895-911.e10. doi:10.1016/j.immuni.2022.04.001
56. Barcik W, Boutin RCT, Sokolowska M, Finlay BB. The role of lung and gut microbiota in the pathology of asthma. Immunity. 2020;52(2):241-255. doi:10.1016/j.immuni.2020.01.007
57. Haag SM, Gulen MF, Reymond L, Gibelin A, Abrami L, et al. Targeting STING with covalent small-molecule inhibitors. Nature. 2018;559(7713):269-273. doi:10.1038/s41586-018-0287-8
58. Di Domizio J, Peschke B, Preissler T, et al. The cGAS-STING pathway drives type I interferon immunopathology in COVID-19. Nature. 2022;609(7925):145-151. doi:10.1038/s41586-022-04421-w
59. Shmuel-Galia L, Yahalom A, Bhatt R, et al. Dysbiosis exacerbates colitis by promoting ubiquitination and accumulation of the innate immune adaptor STING in myeloid cells. Immunity. 2021;54(7):1432-1446.e7. doi:10.1016/j.immuni.2021.05.008
60. Liao K, Xiong Y, Wang X. The cGAS-STING pathway in COPD: targeting its role and therapeutic potential. Respir Res. 2024;25:440. doi:10.1186/s12931-024-02915-x
61. Thim-Uam A, Prabakaran T, Tansakul M, et al. STING mediates lupus via activation of conventional dendritic cell maturation and plasmacytoid dendritic cell differentiation. iScience. 2020;23(9):101530. doi:10.1016/j.isci.2020.101530
62. Hamann L, Ruiz-Moreno JS, Szwed M, et al. STING SNP R293Q is associated with a decreased risk of aging-related diseases. Gerontology. 2019;65(2):145-154. doi:10.1159/000492972
63. Bai J, Cervantes C, He S, He J, et al. Mitochondrial stress-activated cGAS-STING pathway inhibits thermogenic program and contributes to overnutrition-induced obesity in mice. Commun Biol. 2020;3:257. doi:10.1038/s42003-020-0986-1
64. Tabyshova A, Emilov B, Postma MJ, et al. Prevalence and economic burden of respiratory diseases in Central Asia and Russia: a systematic review. Int J Environ Res Public Health. 2020;17(20):7483. doi:10.3390/ijerph17207483
65. Vinnikov D, Raushanova A, Mukatova I, et al. Asthma control in Kazakhstan: need for urgent action. BMC Pulm Med. 2023;23(1):7. doi:10.1186/s12890-022-02287-2
66. Kumar V, Bennett EA, Zhao D, et al. Genetic continuity of Bronze Age ancestry with increased Steppe-related ancestry in Late Iron Age Uzbekistan. Mol Biol Evol. 2021;38(11):4908-4917. doi:10.1093/molbev/msab216
67. Anchita, Zhupankhan A, Khaibullina Z, et al. Health impact of drying Aral Sea: One Health and socio-economical approach. Water. 2021;13(22):3196. doi:10.3390/w13223196
68. Rzymski P, Marszelewski W, Rybak M, et al. Health impacts of the Aral Sea disaster: current state, research gaps, and mitigation perspectives. Ambio. 2026;55:1-15. doi:10.1007/s13280-026-02385-z
69. Normurod L, Nilufar K, Roza K, et al. Population health in Uzbekistan: emerging public health trends and widening regional disparities. Open Public Health J. 2026;19:e18749445444843. doi:10.2174/0118749445444843260427094045
70. Koide S, Kuchitsu Y, Taguchi T. Cell biological insights into human STING variants. Cell Struct Funct. 2025;50(1):135-144. doi:10.1247/csf.25020
71. Feshchenko Y, Iashyna L, Nugmanova D, et al. Chronic obstructive pulmonary disease, bronchial asthma and allergic rhinitis in the adult population within the Commonwealth of Independent States: rationale and design of the CORE study. BMC Pulm Med. 2017;17:131. doi:10.1186/s12890-017-0471-x



















