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Multiple Non-coding ANRIL Transcripts Are Associated with Risk of Coronary Artery Disease: a Promising Circulating Biomarker

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Abstract

Multiple ANRIL transcriptional isoforms, such as lncANRIL and circANRIL have been identified. We sought to explore their diagnostic value in patients with coronary artery disease (CAD). First, we selected six target ANRIL isoforms and measured their expression in CAD patients and controls in the peripheral blood. Their diagnostic values were evaluated. circANRIL(exon14-4) was identified as the best potential biomarker. Afterwards, we validated its diagnostic value and evaluated its prognostic value in a larger clinical cohort. Among six tested ANRILs, lncANRIL(exon1) and lncANRIL(exon4-6) in the CAD patients were significantly increased, while circANRIL(exon14-4) was downregulated. circANRIL(exon14-4) had the highest diagnostic value among the three isoforms. The combination of circANRIL(exon14-4) and other factors resulted in a more accurate differentiation of CAD patients. Moreover, lower expression of circANRIL(exon14-4) was associated with higher incidence of MACE. circANRIL(exon14-4) is closely associated with CAD risk and severity, which provides a promising circulating biomarker for CAD diagnosis and prognosis.

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Abbreviations

ANRIL:

Antisense non-coding RNA in the INK4 locus

lncANRIL:

Linear ANRIL

circANRIL:

Circular ANRIL

CAD:

Coronary artery disease

ROC:

Receiver operating characteristic

GS:

Gensini score

DM:

Diabetes mellitus

BMI:

Body mass index

TC:

Total cholesterol

TG:

Total triglycerides

HDL-C:

High-density lipoprotein cholesterol

LDL-C:

Low-density lipoprotein cholesterol

Cr:

Creatinine

hs-CRP:

Hypersensitive C-reactive protein

GAPDH:

Glyceraldehyde 3-phosphate dehydrogenase

AUC:

Area under the receiver operating characteristic curve

OR:

Odds ratio

VSMC:

Vascular smooth muscle cell

MACE:

Major adverse cardiac events

IQR:

Interquartile range

HR:

Hazard ratio

References

  1. Zhao, Z., Li, X., Gao, C., Jian, D., Hao, P., Rao, L., et al. (2017). Peripheral blood circular RNA hsa_circ_0124644 can be used as a diagnostic biomarker of coronary artery disease. Scientific Reports, 7, 39918. https://doi.org/10.1038/srep39918.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Mboi, N., Murty Surbakti, I., Trihandini, I., Elyazar, I., Houston Smith, K., Bahjuri Ali, P., et al. (2018). On the road to universal health care in Indonesia, 1990-2016: A systematic analysis for the global burden of disease study 2016. Lancet, 392(10147), 581–591. https://doi.org/10.1016/S0140-6736(18)30595-6.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Hitchner, E., Zayed, M., Varu, V., Lee, G., Aalami, O., & Zhou, W. (2015). A prospective evaluation of using IVUS during percutaneous superficial femoral artery interventions. Annals of Vascular Surgery, 29(1), 28–33. https://doi.org/10.1016/j.avsg.2014.07.026.

    Article  PubMed  Google Scholar 

  4. Xuan, T. M., Wang, X. X., Pu, X. Y., Han, W. L., & Guo, X. G. (2020). Primary percutaneous coronary intervention in a COVID-19 patient with ST-segment elevation myocardial infarction after lung transplantation: A case report. Journal of Zhejiang University. Science. B, 21(5), 411–415. https://doi.org/10.1631/jzus.B2000182.

    Article  CAS  PubMed  Google Scholar 

  5. Pasmant, E., Sabbagh, A., Vidaud, M., & Bieche, I. (2011). ANRIL, a long, noncoding RNA, is an unexpected major hotspot in GWAS. The FASEB Journal, 25(2), 444–448. https://doi.org/10.1096/fj.10-172452.

    Article  CAS  PubMed  Google Scholar 

  6. Schaefer, A. S., Richter, G. M., Groessner-Schreiber, B., Noack, B., Nothnagel, M., El Mokhtari, N. E., et al. (2009). Identification of a shared genetic susceptibility locus for coronary heart disease and periodontitis. PLoS Genetics, 5(2), e1000378. https://doi.org/10.1371/journal.pgen.1000378.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Bochenek, G., Hasler, R., El Mokhtari, N. E., Konig, I. R., Loos, B. G., Jepsen, S., et al. (2013). The large non-coding RNA ANRIL, which is associated with atherosclerosis, periodontitis and several forms of cancer, regulates ADIPOR1, VAMP3 and C11ORF10. Human Molecular Genetics, 22(22), 4516–4527. https://doi.org/10.1093/hmg/ddt299.

    Article  CAS  PubMed  Google Scholar 

  8. Cho, H., Shen, G. Q., Wang, X., Wang, F., Archacki, S., Li, Y., et al. (2019). Long noncoding RNA ANRIL regulates endothelial cell activities associated with coronary artery disease by up-regulating CLIP1, EZR, and LYVE1 genes. The Journal of Biological Chemistry, 294(11), 3881–3898. https://doi.org/10.1074/jbc.RA118.005050.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Kotake, Y., Nakagawa, T., Kitagawa, K., Suzuki, S., Liu, N., Kitagawa, M., et al. (2011). Long non-coding RNA ANRIL is required for the PRC2 recruitment to and silencing of p15(INK4B) tumor suppressor gene. Oncogene, 30(16), 1956–1962. https://doi.org/10.1038/onc.2010.568.

    Article  CAS  Google Scholar 

  10. Li, Z., Huang, C., Bao, C., Chen, L., Lin, M., Wang, X., et al. (2015). Exon-intron circular RNAs regulate transcription in the nucleus. Nature Structural & Molecular Biology, 22(3), 256–264. https://doi.org/10.1038/nsmb.2959.

    Article  CAS  Google Scholar 

  11. Li, P., Chen, S., Chen, H., Mo, X., Li, T., Shao, Y., et al. (2015). Using circular RNA as a novel type of biomarker in the screening of gastric cancer. Clinica Chimica Acta, 444, 132–136. https://doi.org/10.1016/j.cca.2015.02.018.

    Article  CAS  Google Scholar 

  12. Palazzo, A. F., & Lee, E. S. (2015). Non-coding RNA: What is functional and what is junk? Frontiers in Genetics, 6, 2. https://doi.org/10.3389/fgene.2015.00002.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Yari, M., Bitarafan, S., Broumand, M. A., Fazeli, Z., Rahimi, M., Ghaderian, S. M. H., et al. (2018). Association between long noncoding RNA ANRIL expression variants and susceptibility to coronary artery disease. International Journal of Molecular and Celullar Medicine, 7(1), 1–7. https://doi.org/10.22088/IJMCM.BUMS.7.1.1.

    Article  CAS  Google Scholar 

  14. Holdt, L. M., Beutner, F., Scholz, M., Gielen, S., Gabel, G., Bergert, H., et al. (2010). ANRIL expression is associated with atherosclerosis risk at chromosome 9p21. Arteriosclerosis, Thrombosis, and Vascular Biology, 30(3), 620–627. https://doi.org/10.1161/ATVBAHA.109.196832.

    Article  CAS  PubMed  Google Scholar 

  15. Gensini, G. G. (1983). A more meaningful scoring system for determining the severity of coronary heart disease. The American Journal of Cardiology, 51(3), 606. https://doi.org/10.1016/s0002-9149(83)80105-2.

    Article  CAS  PubMed  Google Scholar 

  16. Sinning, C., Lillpopp, L., Appelbaum, S., Ojeda, F., Zeller, T., Schnabel, R., et al. (2013). Angiographic score assessment improves cardiovascular risk prediction: The clinical value of SYNTAX and Gensini application. Clinical Research in Cardiology, 102(7), 495–503. https://doi.org/10.1007/s00392-013-0555-4.

    Article  CAS  PubMed  Google Scholar 

  17. Huang, M., Zhong, Z., Lv, M., Shu, J., Tian, Q., & Chen, J. (2016). Comprehensive analysis of differentially expressed profiles of lncRNAs and circRNAs with associated co-expression and ceRNA networks in bladder carcinoma. Oncotarget, 7(30), 47186–47200. https://doi.org/10.18632/oncotarget.9706.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Aarabi, G., Zeller, T., Heydecke, G., Munz, M., Schafer, A., & Seedorf, U. (2018). Roles of the Chr.9p21.3 ANRIL locus in regulating inflammation and implications for anti-inflammatory drug target identification. Frontiers in Cardiovascular Medicine, 5, 47. https://doi.org/10.3389/fcvm.2018.00047.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Qin, M., Liu, G., Huo, X., Tao, X., Sun, X., Ge, Z., et al. (2016). Hsa_circ_0001649: A circular RNA and potential novel biomarker for hepatocellular carcinoma. Cancer Biomarkers, 16(1), 161–169. https://doi.org/10.3233/CBM-150552.

    Article  CAS  PubMed  Google Scholar 

  20. Gutowska, K., Formanowicz, D., & Formanowicz, P. (2017). The effect of cigarette smoking on endothelial damage and atherosclerosis development - Modeled and analyzed using Petri nets. Archives of Control Sciences, 27. https://doi.org/10.1515/acsc-2017-0013.

  21. Yang, Y., Cai, Y., Wu, G., Chen, X., Liu, Y., Wang, X., et al. (2015). Plasma long non-coding RNA, CoroMarker, a novel biomarker for diagnosis of coronary artery disease. Clinical Science (London, England), 129(8), 675–685. https://doi.org/10.1042/CS20150121.

    Article  CAS  Google Scholar 

  22. Shan, K., Jiang, Q., Wang, X. Q., Wang, Y. N., Yang, H., Yao, M. D., et al. (2016). Role of long non-coding RNA-RNCR3 in atherosclerosis-related vascular dysfunction. Cell Death & Disease, 7(6), e2248. https://doi.org/10.1038/cddis.2016.145.

    Article  CAS  Google Scholar 

  23. Rahimi, E., Ahmadi, A., Boroumand, M. A., Mohammad Soltani, B., & Behmanesh, M. (2018). Association of ANRIL expression with coronary artery disease in type 2 diabetic patients. Cell Journal, 20(1), 41–45. https://doi.org/10.22074/cellj.2018.4821.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Hu, Y., & Hu, J. (2019). Diagnostic value of circulating lncRNA ANRIL and its correlation with coronary artery disease parameters. Brazilian Journal of Medical and Biological Research, 52(8), e8309. https://doi.org/10.1590/1414-431X20198309.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Liu, Z. F., Hu, W. W., Li, R., Gao, Y., Yan, L. L., & Su, N. (2020). Expression of lncRNA-ANRIL in patients with coronary heart disease before and after treatment and its short-term prognosis predictive value. European Review for Medical and Pharmacological Sciences, 24(1), 376–384. https://doi.org/10.26355/eurrev_202001_19936.

    Article  PubMed  Google Scholar 

  26. Nawaz, S. K., Noreen, A., Rani, A., Yousaf, M., & Arshad, M. (2015). Association of the rs10757274 SNP with coronary artery disease in a small group of a Pakistani population. Anatolian Journal of Cardiology, 15(9), 709–715. https://doi.org/10.5152/akd.2014.5470.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Chi, J. S., Li, J. Z., Jia, J. J., Zhang, T., Liu, X. M., & Yi, L. (2017). Long non-coding RNA ANRIL in gene regulation and its duality in atherosclerosis. Journal of Huazhong University of Science and Technology. Medical Sciences, 37(6), 816–822. https://doi.org/10.1007/s11596-017-1812-y.

    Article  CAS  Google Scholar 

  28. Lai, F., Orom, U. A., Cesaroni, M., Beringer, M., Taatjes, D. J., Blobel, G. A., et al. (2013). Activating RNAs associate with mediator to enhance chromatin architecture and transcription. Nature, 494(7438), 497–501. https://doi.org/10.1038/nature11884.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Cheng, J., Cai, M. Y., Chen, Y. N., Li, Z. C., Tang, S. S., Yang, X. L., et al. (2017). Variants in ANRIL gene correlated with its expression contribute to myocardial infarction risk. Oncotarget, 8(8), 12607–12619. https://doi.org/10.18632/oncotarget.14721.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Holdt, L. M., Hoffmann, S., Sass, K., Langenberger, D., Scholz, M., Krohn, K., et al. (2013). Alu elements in ANRIL non-coding RNA at chromosome 9p21 modulate atherogenic cell functions through trans-regulation of gene networks. PLoS Genetics, 9(7), e1003588. https://doi.org/10.1371/journal.pgen.1003588.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Ashwal-Fluss, R., Meyer, M., Pamudurti, N. R., Ivanov, A., Bartok, O., Hanan, M., et al. (2014). circRNA biogenesis competes with pre-mRNA splicing. Molecular Cell, 56(1), 55–66. https://doi.org/10.1016/j.molcel.2014.08.019.

    Article  CAS  PubMed  Google Scholar 

  32. Holdt, L. M., Stahringer, A., Sass, K., Pichler, G., Kulak, N. A., Wilfert, W., et al. (2016). Circular non-coding RNA ANRIL modulates ribosomal RNA maturation and atherosclerosis in humans. Nature Communications, 7, 12429. https://doi.org/10.1038/ncomms12429.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Wang, L., Shen, C., Wang, Y., Zou, T., Zhu, H., Lu, X., et al. (2019). Identification of circular RNA Hsa_circ_0001879 and Hsa_circ_0004104 as novel biomarkers for coronary artery disease. Atherosclerosis, 286, 88–96. https://doi.org/10.1016/j.atherosclerosis.2019.05.006.

    Article  CAS  PubMed  Google Scholar 

  34. Teeuw, W. J., Laine, M. L., Bizzarro, S., & Loos, B. G. (2015). A Lead ANRIL polymorphism is associated with elevated CRP levels in periodontitis: A pilot case-control study. PLoS One, 10(9), e0137335. https://doi.org/10.1371/journal.pone.0137335.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Zhang, X. O., Wang, H. B., Zhang, Y., Lu, X., Chen, L. L., & Yang, L. (2014). Complementary sequence-mediated exon circularization. Cell, 159(1), 134–147. https://doi.org/10.1016/j.cell.2014.09.001.

    Article  CAS  PubMed  Google Scholar 

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Funding

This research was supported by the Program of National Natural Science Foundation of China (No. 81470370); the Key Projects of Zhejiang Medical and Health Science and Technology Plan (Provincial and Ministerial Co-construction) (No. WKJ-ZJ-1819); and the Fundamental Research Funds for the Zhejiang Province Universities (No. 2019XZZX003-15).

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Author notes

  1. Juan Fang and Zhicheng Pan are equally contributed to this article as co-first authors.

Authors and Affiliations

  1. Department of Cardiology, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou, 310003, Zhejiang, China

    Juan Fang, Zhicheng Pan, Dongfei Wang, Jialan Lv, Yang Dong, Rui Xu, Xiang Yin, Xudong Xie, Xingxiang Wang & Xiaogang Guo

  2. Division of Cardiology, The Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu, China

    Yunpeng Jin

  3. Zhejiang province key laboratory of pancreatic diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China

    Jianpeng Sheng

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Correspondence to Xiaogang Guo.

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The authors declare that they have no conflict of interest.

Ethics Statement

This study was approved by the Ethics Committee of the First Affiliated Hospital, School of Medicine, Zhejiang University (ethics approval No. IIT20200141A) and complied with the ethical principles of the Declaration of Helsinki of 1975, as revised in 2000.

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Informed consent was obtained from all patients for being included in the study.

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Associate Editor Junjie Xiao oversaw the review of this article

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Fang, J., Pan, Z., Wang, D. et al. Multiple Non-coding ANRIL Transcripts Are Associated with Risk of Coronary Artery Disease: a Promising Circulating Biomarker. J. of Cardiovasc. Trans. Res. 14, 229–237 (2021). https://doi.org/10.1007/s12265-020-10053-0

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