Recently, a letter from Dingsdag et al. discussed the importance of microRNAs (miRs) in severely ill COVID‐19 patients as recently published by us. 1 The authors highlighted the importance of pro‐fibrotic microRNA miR‐21 in this context. 2 In general, patients suffering from the same pathological condition can manifest differences in the severity of symptoms depending upon the variability in their genetic and transcriptomic composition. In this regard, single nucleotide polymorphism variants (SNPs) are substantially important because it has already been shown that certain SNPs contribute to symptom expression in the context of COVID‐19 infection. 3 The letter emphasized that 3′ UTRs of certain mRNAs of the transcriptome contain binding sites for miR‐21, which could serve a therapeutic target in this regard. A gene locus associated with the severity of COVID‐19, including an intronic segment of the LZTFL1 gene, is associated with the above SNPs. 3 , 4 One particular SNP (rs35624553) in transcribed RNA is in proximity to the miR‐21 target site. Due to the proximity of this binding site, the authors assume that alterations in the levels of miR‐21 could regulate LZTFL1 gene products, eventually leading to organ fibrosis and inflammatory processes.
Therefore, the authors of the letter hypothesize that a targeted study with manipulation of miR‐21 could lead to substantial insight into the development of severe COVID‐19 symptoms. By precisely modulating the post‐transcriptional changes at the cellular level in COVID‐19 patients, Dingsdag et al. were able to corelate cellular processes with extracellular findings.
The importance of SNPs and their association with the patient outcome has already been discussed in cancer. 5 In the context of colorectal carcinoma, SNPs located near the targets of miRs have been shown to influence disease risk. 6 Moreover, an association between the miR‐related polymorphism and clinical outcome of patients was also demonstrated in non‐small‐cell lung carcinoma. 7 In future studies, the importance of SNPs and their interactions with miRs on gene regulation must also be considered.
Various in vitro models are suitable for further mechanistic studies. Of particular interest are cardiovascular or pulmonary cells infected with SARS‐CoV‐2 to evaluate cell‐type specific interactions. Cells differentiated from human induced pluripotent stem cells are particularly suitable for meaningful validation of transcriptional and post‐transcriptional regulations. In connection with COVID‐19, our group has already demonstrated that the angiotensin‐converting enzyme 2 receptor is regulated by miRs and is increased in differentiated cardiomyocytes where it serves as an entry receptor for SARS‐CoV‐2. 8
In summary, the genetic and transcriptomic component plays an essential role concerning symptom expression in SARS‐CoV‐2 infection. Thus, by modulating miRs and their targets, it may be possible to influence COVID‐19 symptom expression in the future.
Acknowledgement
Open Access funding enabled and organized by Projekt DEAL.
References
- 1. Garg A, Seeliger B, Derda AA, Xiao K, Gietz A, Scherf K, Sonnenschein K, Pink I, Hoeper MM, Welte T, Bauersachs J, David S, Bär C, Thum T. Circulating cardiovascular microRNAs in critically ill COVID‐19 patients. Eur J Heart Fail 2021;23:468–475. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2. Thum T, Gross C, Fiedler J, Fischer T, Kissler S, Bussen M, Galuppo P, Just S, Rottbauer W, Frantz S, Castoldi M, Soutschek J, Koteliansky V, Rosenwald A, Basson MA, Licht JD, Pena JT, Rouhanifard SH, Muckenthaler MU, Tuschl T, Martin GR, Bauersachs J, Engelhardt S. MicroRNA‐21 contributes to myocardial disease by stimulating MAP kinase signalling in fibroblasts. Nature 2008;456:980–984. [DOI] [PubMed] [Google Scholar]
- 3. Wang A, Chiou J, Poirion OB, Buchanan J, Valdez MJ, Verheyden JM, Hou X, Kudtarkar P, Narendra S, Newsome JM, Guo M, Faddah DA, Zhang K, Young RE, Barr J, Sajti E, Misra R, Huyck H, Rogers L, Poole C, Whitsett JA, Pryhuber G, Xu Y, Gaulton KJ, Preissl S, Sun X; NHLBI LungMap Consortium . Single‐cell multiomic profiling of human lungs reveals cell‐type‐specific and age‐dynamic control of SARS‐CoV2 host genes. Elife 2020;9:e62522. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4. Zeberg H, Paabo S. The major genetic risk factor for severe COVID‐19 is inherited from Neanderthals. Nature 2020;587:610–612. [DOI] [PubMed] [Google Scholar]
- 5. Manikandan M, Munirajan AK. Single nucleotide polymorphisms in microRNA binding sites of oncogenes: implications in cancer and pharmacogenomics. OMICS 2014;18:142–154. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6. Karimzadeh MR, Zarin M, Ehtesham N, Khosravi S, Soosanabadi M, Mosallaei M, Pourdavoud P. MicroRNA binding site polymorphism in inflammatory genes associated with colorectal cancer: literature review and bioinformatics analysis. Cancer Gene Ther 2020;27:739–753. [DOI] [PubMed] [Google Scholar]
- 7. Pu X, Roth JA, Hildebrandt MA, Ye Y, Wei H, Minna JD, Lippman SM, Wu X. MicroRNA‐related genetic variants associated with clinical outcomes in early‐stage non‐small cell lung cancer patients. Cancer Res 2013;73:1867–1875. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8. Lu D, Chatterjee S, Xiao K, Riedel I, Wang Y, Foo R, Bär C, Thum T. MicroRNAs targeting the SARS‐CoV‐2 entry receptor ACE2 in cardiomyocytes. J Mol Cell Cardiol 2020;148:46–49. [DOI] [PMC free article] [PubMed] [Google Scholar]