Document Type : Original Article

Authors

1 Department of Biology, Islamic Azad University, Zarghan Branch, Zarghan, Iran

2 Clinical Neurology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran

3 Laboratory of Basic Sciences, Mohammad Rasul Allah Research Tower, Shiraz University of Medical Sciences, Shiraz, Iran

4 Noncmmunicable Diseases Research Center, Fasa University of Medical Sciences, Fasa, Iran

5 Department of Biology, Zarghan Branch, Islamic Azad University, Zarghan, Iran

Abstract

Background: Long non-coding ribonucleic acids (lncRNAs) have been implicated as possible circulating stroke indicators. This study focused on the expression status of antisense non-coding ribonucleic acid in the INK4 locus (ANRIL) and myocardial infarction associated transcript (MIAT) in patients with cerebral venous thrombosis (CVT).
Methods: In this study, fifty patients with CVT and one hundred age/gender-matched individuals as controls were included. The circulating levels of ANRIL and MIAT in the first 24 hours after admission were evaluated using the quantitative real-time polymerase chain reaction (RT-PCR) method. We compared the expression levels of ANRIL and MIAT between patients and controls using the independent two-sample t-test. Subgroup analysis was used to investigate the association of lncRNAs with clinical characteristics in patients with CVT. Receiver operating characteristic (ROC) curve analyses were conducted to evaluate the diagnostic value of two lncRNAs in patient assessment.
Results: The relative expression of lncRNAs ANRIL and MIAT significantly decreased in patients compared to the control. ANRIL and MIAT were shown as potential markers for discriminating patients with CVT from the healthy controls with an area under the curve (AUC) of 0.98 and 0.99, respectively.
Conclusion: For the first time, we found down-regulation and diagnostic potential of lncRNAs-ANRIL and MIAT in the blood of patients with CVT.

Keywords

  1. Wasay M, Kaul S, Menon B, Dai AI, Saadatnia M, Malik A, et al. Asian study of cerebral venous thrombosis. J Stroke Cerebrovasc Dis 2019; 28(10): 104247.
  2. Vasaghi GM, Habibagahi M, Hooshmandi E, Tabrizi R, Arsang-Jang S, Barzegar Z, et al. The hospitalization rate of cerebral venous sinus thrombosis before and during COVID-19 pandemic era: A single-center retrospective cohort study. J Stroke Cerebrovasc Dis 2022; 31(7): 106468.
  3. Shakibajahromi B, Ashjazadeh N, Safari A, Borhani-Haghighi A. Changes in trend of cerebral venous sinus thrombosis. Iran
    J Neurol 2019; 18(1): 33-4.
  4. de Freitas GR, Bogousslavsky J. Risk factors of cerebral vein and sinus thrombosis. Front Neurol Neurosci 2008; 23: 23-54.
  5. Ding J, Song B, Xie X, Li X, Chen Z, Wang Z, et al. Inflammation in cerebral venous thrombosis. Front Immunol 2022; 13: 833490.
  6. Izadi S, Borhani-Haghighi A, Bastani K, Kardeh B, Yadollahi-Khales G, Neydavoodi M. Circulating levels of interleukin-10 and -17 in patients with cerebral sinovenous thrombosis (CSVT) in acute and subacute stages: A prospective case-control study. Iran J Immunol 2018; 15(3): 221-7.
  7. Furlan G, Rougeulle C. Function and evolution of the long noncoding RNA circuitry orchestrating X-chromosome inactivation in mammals. Wiley Interdiscip Rev RNA 2016; 7(5): 702-22.
  8. Su H, Liu B, Chen H, Zhang T, Huang T, Liu Y, et al. LncRNA ANRIL mediates endothelial dysfunction through BDNF downregulation in chronic kidney disease. Cell Death Dis 2022; 13(7): 661.
  9. Zeng R, Song XJ, Liu CW, Ye W. LncRNA ANRIL promotes angiogenesis and thrombosis by modulating microRNA-99a and microRNA-449a in the autophagy pathway. Am J Transl Res 2019; 11(12): 7441-8.
  10. Hu Y, Hu J. Diagnostic value of circulating lncRNA ANRIL and its correlation with coronary artery disease parameters. Braz J Med Biol Res 2019; 52(8): e8309.
  11. Pasmant E, Sabbagh A, Vidaud M, Bieche I. ANRIL, a long, noncoding RNA, is an unexpected major hotspot in GWAS. FASEB J 2011; 25(2): 444-8.
  12. Ulivi L, Squitieri M, Cohen H, Cowley P, Werring DJ. Cerebral venous thrombosis: A practical guide. Pract Neurol 2020; 20(5): 356-67.
  13. Sun C, Huang L, Li Z, Leng K, Xu Y, Jiang X, et al. Long non-coding RNA MIAT in development and disease: a new player in an old game. J Biomed Sci 2018; 25(1): 23.
  14. Yan ZS, Zhang NC, Li K, Sun HX, Dai XM, Liu GL. Upregulation of long non-coding RNA myocardial infarction-associated transcription is correlated with coronary artery stenosis and elevated inflammation in patients with coronary atherosclerotic heart disease. Kaohsiung J Med Sci 2021; 37(12): 1038-47.
  15. Rinde LB, Lind C, Smabrekke B, Njolstad I, Mathiesen EB, Wilsgaard T, et al. Impact of incident myocardial infarction on the risk of venous thromboembolism: the Tromso Study. J Thromb Haemost 2016; 14(6): 1183-91.
  16. Janghorbani M, Zare M, Saadatnia M, Mousavi SA, Mojarrad M, Asgari E. Cerebral vein and dural sinus thrombosis in adults in Isfahan, Iran: Frequency and seasonal variation. Acta Neurol Scand 2008; 117(2): 117-21.
  17. Zhou X, Han X, Wittfeldt A, Sun J, Liu C, Wang X, et al. Long non-coding RNA ANRIL regulates inflammatory responses as a novel component of NF-kappaB pathway. RNA Biol 2016; 13(1): 98-108.
  18. Schmittgen TD, Livak KJ. Analyzing real-time PCR data by the comparative C(T) method. Nat Protoc 2008; 3(6): 1101-8.
  19. Yang J, Gu L, Guo X, Huang J, Chen Z, Huang G, et al. LncRNA ANRIL Expression and ANRIL gene polymorphisms contribute to the risk of ischemic stroke in the Chinese han population. Cell Mol Neurobiol 2018; 38(6): 1253-69.
  20. Fathy N, Kortam MA, Shaker OG, Sayed NH. Long noncoding RNAs MALAT1 and ANRIL gene variants and the risk of cerebral ischemic stroke: An association study. ACS Chem Neurosci 2021; 12(8): 1351-62.
  21. Tan C, Liu J, Wei J, Yang S. Effects of ANRIL variants on the risk of ischemic stroke: a meta-analysis. Biosci Rep 2019; 39(5): BSR20182127.
  22. Liu ZF, Hu WW, Li R, Gao Y, Yan LL, Su N. Expression of lncRNA-ANRIL in patients with coronary heart disease before and after treatment and its short-term prognosis predictive value. Eur Rev Med Pharmacol Sci 2020; 24(1): 376-84.
  23. Murray R, Bryant J, Titcombe P, Barton SJ, Inskip H, Harvey NC, et al. DNA methylation at birth within the promoter of ANRIL predicts markers of cardiovascular risk at 9 years. Clin Epigenetics 2016; 8(1): 90.
  24. Folkersen L, Kyriakou T, Goel A, Peden J, Malarstig A, Paulsson-Berne G, et al. Relationship between CAD risk genotype in the chromosome 9p21 locus and gene expression. Identification of eight new ANRIL splice variants. PLoS One 2009; 4(11): e7677.
  25. Razeghian-Jahromi I, Karimi AA, Zibaeenezhad MJ. The role of ANRIL in atherosclerosis. Dis Markers 2022; 2022: 8859677.
  26. Kong Y, Hsieh CH, Alonso LC. ANRIL: A lncRNA at the CDKN2A/B locus with roles in cancer and metabolic disease. Front Endocrinol (Lausanne) 2018; 9: 405.
  27. Lou N, Liu G, Pan Y. Long noncoding RNA ANRIL as a novel biomarker in human cancer. Future Oncol 2020; 16(35): 2981-95.
  28. Deng L, Guo Y, Liu J, Chen S, Wang X, Zhao H, et al. Long noncoding RNA ANRIL knockdown attenuates neuroinflammation following ischemic stroke via suppressing the expression of NF-kappaB in vitro and in vivo. Neurol Res 2021; 43(9): 767-77.
  29. Wufuer A, Luohemanjiang X, Du L, Lei J, Shabier M, Han DF, et al. ANRIL overexpression globally induces expression and alternative splicing of genes involved in inflammation in HUVECs. Mol Med Rep 2023; 27(2): 27.
  30. Xia H, Li S, He Y, Ren Q, Qin S. Long non-coding RNA ANRIL serves as a potential marker of disease risk, inflammation, and disease activity of pediatric inflammatory bowel disease. Clin Res Hepatol Gastroenterol 2022; 46(4): 101895.
  31. Feng L, Guo J, Ai F. Circulating long noncoding RNA ANRIL downregulation correlates with increased risk, higher disease severity and elevated pro-inflammatory cytokines in patients with acute ischemic stroke. J Clin Lab Anal 2019; 33(1): e22629.
  32. Bajko Z, Motataianu A, Stoian A, Barcutean L, Andone S, Maier S, et al. Gender differences in risk factor profile and clinical characteristics in 89 consecutive cases of cerebral venous thrombosis. J Clin Med 2021; 10(7): 1382.
  33. Coutinho JM, Ferro JM, Canhao P, Barinagarrementeria F, Cantu C, Bousser MG, et al. Cerebral venous and sinus thrombosis in women. Stroke 2009; 40(7): 2356-61.
  34. Zhang S, Zhang Y, Wang N, Wang Y, Nie H, Zhang Y, et al. Long non-coding RNA MIAT impairs neurological function in ischemic stroke via up-regulating microRNA-874-3p-targeted IL1B. Brain Res Bull 2021; 175: 81-9.
  35. Zhu M, Li N, Luo P, Jing W, Wen X, Liang C, et al. Peripheral blood leukocyte expression of lncrna miat and its diagnostic and prognostic value in ischemic stroke. J Stroke Cerebrovasc Dis 2018; 27(2): 326-37.
  36. Tan J, Liu S, Jiang Q, Yu T, Huang K. LncRNA-MIAT increased in patients with coronary atherosclerotic heart disease. Cardiol Res Pract 2019; 2019: 6280194.
  37. Amiri M, Mokhtari MJ, Bayat M, Safari A, Dianatpuor M, Tabrizi R, et al. Expression and diagnostic values of MIAT, H19, and NRON long non-coding RNAs in multiple sclerosis patients. Egyptian Journal of Medical Human Genetics 2022; 23(1): 46.
  38. Wang Y, Fu L, Lu T, Zhang G, Zhang J, Zhao Y, et al. Clinicopathological and prognostic significance of long non-coding RNA MIAT in human cancers: A review and meta-analysis. Front Genet 2021; 12: 729768.
  39. Yan B, Yao J, Liu JY, Li XM, Wang XQ, Li YJ, et al. lncRNA-MIAT regulates microvascular dysfunction by functioning as a competing endogenous RNA. Circ Res 2015; 116(7): 1143-56.
  40. Yu C, Yang K, Meng X, Cao B, Wang F. Downregulation of long noncoding RNA MIAT in the retina of diabetic rats with tail-vein injection of human umbilical-cord mesenchymal stem cells. Int J Med Sci 2020; 17(5): 591-8.
  41. Wang Z, Kun Y, Lei Z, Dawei W, Lin P, Jibo W. LncRNA MIAT downregulates IL-1beta, TNF-a to suppress macrophage inflammation but is suppressed by ATP-induced NLRP3 inflammasome activation. Cell Cycle 2021; 20(2): 194-203.