Abstract
The identification of blood-based markers that help clinicians to diagnose, predict and monitor diseases is a great challenge. In general, the earlier a precise diagnosis and therapy can be applied, the higher the probability of a successful treatment of the patients. Cell-free nucleic acids have promising clinical potential because they can critically be dysregulated during pathogenic processes. They are usually released during cellular stress or tissue injury and related to inflammatory responses caused by a coordinated expression of numerous genes that initiate, sustain and propagate immune responses and tissue remodeling. Although there is a potential for the application of cell-free nucleic acids as clinical assays, their use as potential biomarkers in pathologic conditions is still at the experimental stage, partly due to different qualities of the analyses employed. With the exception of minimally invasive prenatal diagnostic tests, the approaches on circulating, cell-free DNA, mRNA and microRNAs applicable for clinical practice currently remain somewhat elusive.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Lassmann H (2013) Pathology and disease mechanisms in different stages of multiple sclerosis. J Neurol Sci 333(1–2):1–4. doi:10.1016/j.jns.2013.05.010
Beck J, Urnovitz HB, Saresella M, Caputo D, Clerici M, Mitchell WM, Schütz E (2010) Serum DNA motifs predict disease and clinical status in multiple sclerosis. J Mol Diagn 12(3):312–319. doi:10.2353/jmoldx.2010.090170
Saresella M, Marventano I, Guerini FR, Zanzottera M, Delbue S, Marchioni E, Maserati R, Longhi R, Ferrante P, Clerici M (2008) Myelin basic protein-specific T lymphocytes proliferation and programmed cell death in demyelinating diseases. Clin Immunol 129(3):509–517. doi:10.1016/j.clim.2008.08.010
Klose RJ, Bird AP (2006) Genomic DNA methylation: the mark and its mediators. Trends Biochem Sci 31(2):89–97
Liggett T, Melnikov A, Tilwalli S, Yi Q, Chen H, Replogle C, Feng X, Reder A, Stefoski D, Balabanov R, Levenson V (2010) Methylation patterns of cell-free plasma DNA in relapsing-remitting multiple sclerosis. J Neurol Sci 290(1–2):16–21. doi:10.1016/j.jns.2009.12.018
Siegel SR, Mackenzie J, Chaplin G, Jablonski NG, Griffiths L (2012) Circulating microRNAs involved in multiple sclerosis. Mol Biol Rep 39(5):6219–6225. doi:10.1007/s11033-011-1441-7
Gandhi R, Healy B, Gholipour T, Egorova S, Musallam A, Hussain MS, Nejad P, Patel B, Hei H, Khoury S, Quintana F, Kivisakk P, Chitnis T, Weiner HL (2013) Circulating microRNAs as biomarkers for disease staging in multiple sclerosis. Ann Neurol. 73(6):729–740. doi:10.1002/ana.23880
Riezebos RK, Verheugt FW, Laarman GJ, Tijssen JG (2012) The biochemical aspects of a non-ST-segment elevation acute coronary syndrome. Rev Cardiovasc Med 13(2–3):e70–e76
Jing RR, Wang HM, Cui M, Fang MK, Qiu XJ, Wu XH, Qi J, Wang YG, Zhang LR, Zhu JH, Ju SQ (2011) A sensitive method to quantify human cell-free circulating DNA in blood: relevance to myocardial infarction screening. Clin Biochem 44(13):1074–1079. doi:10.1016/j.clinbiochem.2011.06.083
Rainer TH, Lam NY, Man CY, Chiu RW, Woo KS, Lo YM (2006) Plasma beta-globin DNA as a prognostic marker in chest pain patients. Clin Chim Acta 368(1–2):110–113. doi:10.1016/j.cca.2005.12.021
Destouni A, Vrettou C, Antonatos D, Chouliaras G, Traeger-Synodinos J, Patsilinakos S, Kitsiou-Tzeli S, Tsigas D, Kanavakis E (2009) Cell-free DNA levels in acute myocardial infarction patients during hospitalization. Acta Cardiol 64(1):51–57
Cui M, Fan M, Jing R, Wang H, Qin J, Sheng H, Wang Y, Wu X, Zhang L, Zhu J, Ju S (2013) Cell-Free circulating DNA: a new biomarker for the acute coronary syndrome. Cardiology 124(2):76–84. doi:10.1159/000345855
Tijsen AJ, Pinto YM, Creemers EE (2012) Circulating microRNAs as diagnostic biomarkers for cardiovascular diseases. Am J Physiol Heart Circ Physiol 303(9):H1085–H1095. doi:10.1152/ajpheart.00191.2012
Olivieri F, Antonicelli R, Lorenzi M, D’Alessandra Y, Lazzarini R, Santini G, Spazzafumo L, Lisa R, La Sala L, Galeazzi R, Recchioni R, Testa R, Pompilio G, Capogrossi MC, Procopio AD (2012) Diagnostic potential of circulating miR-499-5p in elderly patients with acute non ST-elevation myocardial infarction. Int J Cardiol 167:531–536. doi:10.1016/j.ijcard.2012.01.075
Devaux Y, Vausort M, Goretti E, Nazarov PV, Azuaje F, Gilson G, Corsten MF, Schroen B, Lair ML, Heymans S, Wagner DR (2012) Use of circulating microRNAs to diagnose acute myocardial infarction. Clin Chem 58(3):559–567. doi:10.1373/clinchem.2011.173823
Widera C, Gupta SK, Lorenzen JM, Bang C, Bauersachs J, Bethmann K, Kempf T, Wollert KC, Thum T (2011) Diagnostic and prognostic impact of six circulating microRNAs in acute coronary syndrome. J Mol Cell Cardiol 51(5):872–875. doi:10.1016/j.yjmcc.2011.07.011
Yildirim SS, Akman D, Catalucci D, Turan B (2013) Relationship between downregulation of miRNAs and increase of oxidative stress in the development of diabetic cardiac dysfunction: junctin as a target protein of miR-1. Cell Biochem Biophys. doi:10.1007/s12013-013-9672-y
Montgomery RL, Hullinger TG, Semus HM, Dickinson BA, Seto AG, Lynch JM, Stack C, Latimer PA, Olson EN, van Rooij E (2011) Therapeutic inhibition of miR-208a improves cardiac function and survival during heart failure. Circulation 124(14):1537–1547. doi:10.1161/CIRCULATIONAHA.111.030932
Xu WD, Pan HF, Li JH, Ye DQ (2013) MicroRNA-21 with therapeutic potential in autoimmune diseases. Expert Opin Ther Targets 17(6):659–665. doi:10.1517/14728222.2013.773311
Han M, Toli J, Abdellatif M (2011) MicroRNAs in the cardiovascular system. Curr Opin Cardiol 26(3):181–189. doi:10.1097/HCO.0b013e328345983d
Dirnagl U, Iadecola C, Moskowitz MA (1999) Pathobiology of ischaemic stroke: an integrated view. Trends Neurosci 22(9):391–397. doi:10.1016/S0166-2236(99)01401-0
Tsai NW, Lin TK, Chen SD, Chang WN, Wang HC, Yang TM, Lin YJ, Jan CR, Huang CR, Liou CW, Lu CH (2011) The value of serial plasma nuclear and mitochondrial DNA levels in patients with acute ischemic stroke. Clin Chim Acta 412(5–6):476–479. doi:10.1016/j.cca.2010.11.036
Rainer TH, Wong LK, Lam W, Yuen E, Lam NY, Metreweli C, Lo YM (2003) Prognostic use of circulating plasma nucleic acid concentrations in patients with acute stroke. Clin Chem 49(4):562–569
Lam NY, Rainer TH, Wong LK, Lam W, Lo YM (2006) Plasma DNA as a prognostic marker for stroke patients with negative neuroimaging within the first 24 h of symptom onset. Resuscitation 68(1):71–78. doi:10.1016/j.resuscitation.2005.05.021
Rainer TH, Wong KS, Lam W, Lam NY, Graham CA, Lo YM (2007) Comparison of plasma beta-globin DNA and S-100 protein concentrations in acute stroke. Clin Chim Acta 376(1–2):190–196. doi:10.1016/j.cca.2006.08.025
Koutsis G, Siasos G, Spengos K (2013) The emerging role of microRNA in stroke. Curr Topics Med Chem 13(13):1573–1588
Angus DC, Linde-Zwirble WT, Lidicker J, Clermont G, Carcillo J, Pinsky MR (2001) Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit Care Med 29(7):1303–1310
Zeerleder S, Zwart B, Wuillemin WA, Aarden LA, Groeneveld AB, Caliezi C, van Nieuwenhuijze AE, van Mierlo GJ, Eerenberg AJ, Lämmle B, Hack CE (2003) Elevated nucleosome levels in systemic inflammation and sepsis. Crit Care Med 31(7):1947–1951. doi:10.1097/01.CCM.0000074719.40109.95
Dwivedi DJ, Toltl LJ, Swystun LL, Pogue J, Liaw KL, Weitz JI, Cook DJ, Fox-Robichaud AE, Liaw PC; the Canadian Critical Care Translational Biology Group (2012) Prognostic utility and characterization of cell-free DNA in patients with severe sepsis. Crit Care 16(4):R151. doi:10.1186/cc11466
Saukkonen K, Lakkisto P, Pettila V, Varpula M, Karlsson S, Ruokonen E, Pulkki K; Finnsepsis Study Group (2008) Cell-free plasma DNA as a predictor of outcome in severe sepsis and septic shock. Clin Chem 54(6):1000–1007. doi:10.1373/clinchem.2007.101030
Wang HJ, Zhang PJ, Chen WJ, Feng D, Jia YH, Xie LX (2012) Four serum microRNAs identified as diagnostic biomarkers of sepsis. J Trauma Acute Care Surg 73(4):850–854. doi:10.1097/TA.0b013e31825a7560
Haneklaus M, Gerlic M, O’Neill LA, Masters SL (2013) miR-223: infection, inflammation and cancer. J Intern Med. doi:10.1111/joim.12099
Zhuang G, Meng C, Guo X, Cheruku PS, Shi L, Xu H, Li H, Wang G, Evans AR, Safe S, Wu C, Zhou B (2012) A novel regulator of macrophage activation: miR-223 in obesity-associated adipose tissue inflammation. Circulation 125(23):2892–2903. doi:10.1161/CIRCULATIONAHA.111.087817
Cheng HS, Sivachandran N, Lau A, Boudreau E, Zhao JL, Baltimore D, Delgado-Olguin P, Cybulsky MI, Fish JE (2013) MicroRNA-146 represses endothelial activation by inhibiting pro-inflammatory pathways. EMBO Mol Med 5(7):949–966. doi:10.1002/emmm.201202318
Bologa RM, Levine DM, Parker TS, Cheigh JS, Serur D, Stenzel KH, Rubin AL (1998) Interleukin-6 predicts hypoalbuminemia, hypocholesterolemia, and mortality in hemodialysis patients. Am J Kidney Dis 32(1):107–114. doi:10.1053/ajkd.1998.v32.pm9669431
Atamaniuk J, Kopecky C, Skoupy S, Säemann MD, Weichhart T (2012) Apoptotic cell-free DNA promotes inflammation in haemodialysis patients. Nephrol Dial Transplant 27(3):902–905. doi:10.1093/ndt/gfr695
Korabecna M, Pazourkova E, Horinek A, Mokrejsova M, Tesar V (2012) Alterations in methylation status of immune response genes promoters in cell-free DNA during a hemodialysis procedure. Expert Opin Biol Ther 12(Suppl 1):S27–33. doi:10.1517/14712598.2012.676034
Martino F, Lorenzen J, Schmidt J, Schmidt M, Broll M, Görzig Y, Kielstein JT, Thum T (2012) Circulating microRNAs are not eliminated by hemodialysis. PLoS One 7(6):e38269. doi:10.1371/journal.pone.0038269
Emilian C, Goretti E, Prospert F, Pouthier D, Duhoux P, Gilson G, Devaux Y, Wagner DR (2012) MicroRNAs in patients on chronic hemodialysis (MINOS study). Clin J Am Soc Nephrol 7(4):619–623. doi:10.2215/CJN.10471011
Dippold RP, Vadigepalli R, Gonye GE, Patra B, Hoek JB (2013) Chronic ethanol feeding alters miRNA expression dynamics during liver regeneration. Alcohol Clin Exp Res 37(Suppl 1):E59–E69. doi:10.1111/j.1530-0277.2012.01852.x
Cermelli S, Ruggieri A, Marrero JA, Ioannou GN, Beretta L (2011) Circulating microRNAs in patients with chronic hepatitis C and non-alcoholic fatty liver disease. PLoS One 6(8):e23937. doi:10.1371/journal.pone.0023937
Zhang Y, Jia Y, Zheng R, Guo Y, Wang Y, Guo H, Fei M, Sun S (2010) Plasma microRNA-122 as a biomarker for viral-, alcohol-, and chemical-related hepatic diseases. Clin Chem 56(12):1830–1838. doi:10.1373/clinchem.2010.147850
Xu J, Wu C, Che X, Wang L, Yu D, Zhang T, Huang L, Li H, Tan W, Wang C, Lin D (2011) Circulating microRNAs, miR-21, miR-122, and miR-223, in patients with hepatocellular carcinoma or chronic hepatitis. Mol Carcinog 50(2):136–142. doi:10.1002/mc.20712
Lu TX, Rothenberg ME (2013) Diagnostic, functional, and therapeutic roles of microRNA in allergic diseases. J Allergy Clin Immunol 132:3–13. doi:S0091-6749(13)00686-6
Starkey LP, Dear J, Platt V, Simpson KJ, Craig DG, Antoine DJ, French NS, Dhaun N, Webb DJ, Costello EM, Neoptolemos JP, Moggs J, Goldring CE, Park BK (2011) Circulating microRNAs as potential markers of human drug-induced liver injury. Hepatology 54(5):1767–1776. doi:10.1002/hep.24538
Jenkins RH, Martin J, Phillips AO, Bowen T, Fraser DJ (2012) Transforming growth factor beta1 represses proximal tubular cell microRNA-192 expression through decreased hepatocyte nuclear factor DNA binding. Biochem J 443(2):407–416. doi:10.1042/BJ20111861
Lorenzen JM, Kielstein JT, Hafer C, Gupta SK, Kümpers P, Faulhaber-Walter R, Haller H, Fliser D, Thum T (2011) Circulating miR-210 predicts survival in critically ill patients with acute kidney injury. Clin J Am Soc Nephrol 6(7):1540–1546. doi:10.2215/CJN.00430111
Liu F, Lou YL, Wu J, Ruan QF, Xie A, Guo F, Cui SP, Deng ZF, Wang Y (2012) Upregulation of microRNA-210 regulates renal angiogenesis mediated by activation of VEGF signaling pathway under ischemia/perfusion injury in vivo and in vitro. Kidney Blood Pressure Res 35(3):182–191. doi:10.1159/000331054
Besselink MG, van Santvoort HC, Witteman BJ, Gooszen HG; Dutch Acute Pancreatitis Study Group (2007) Management of severe acute pancreatitis: it’s all about timing. Curr Opin Crit Care 13(2):200–206. doi:10.1097/MCC.0b013e328015b8af
Bagul A, Pushpakom S, Boylan J, Newman W, Siriwardena AK (2006) Quantitative analysis of plasma DNA in severe acute pancreatitis. JOP 7(6):602–607
Gornik I, Wagner J, Gasparovic V, Lauc G, Gornik O (2009) Free serum DNA is an early predictor of severity in acute pancreatitis. Clin Biochem 42(1–2):38–43. doi:10.1016/j.clinbiochem.2008.09.121
Gornik O, Gornik I, Wagner J, Radić D, Lauc G (2011) Evaluation of cell-free DNA in plasma and serum as early predictors of severity in acute pancreatitis. Pancreas 40(5):787–788. doi:10.1097/MPA.0b013e3182143e93
Gadi VK, Nelson JL, Boespflug ND, Guthrie KA, Kuhr CS (2006) Soluble donor DNA concentrations in recipient serum correlate with pancreas-kidney rejection. Clin Chem 52(3):379–382. doi:10.1373/clinchem.2005.058974
Lui YY, Chik KW, Chiu RW, Ho CY, Lam CW, Lo YM (2002) Predominant hematopoietic origin of cell-free DNA in plasma and serum after sex-mismatched bone marrow transplantation. Clin Chem 48(3):421–427
Troppmann C, Gillingham KJ, Benedetti E, Almond PS, Gruessner RW, Najarian JS, Matas AJ (1995) Delayed graft function, acute rejection, and outcome after cadaver renal transplantation. The multivariate analysis. Transplantation 59(7):962–968
GarcÃa Moreira V, Prieto GarcÃa B, Baltar MartÚn JM, Ortega SuÃrez F, Alvarez FV (2009) Cell-free DNA as a noninvasive acute rejection marker in renal transplantation. Clin Chem 55(11):1958–1966. doi:10.1373/clinchem.2009.129072
El-Matbouly M, El-Menyar A, Al-Thani H, Tuma M, El-Hennawy H, AbdulRahman H, Parchani A, Peralta R, Asim M, El-Faramawy A, Zarour A, Latifi R (2013) Traumatic brain injury in Qatar: age matters-insights from a 4-year observational study. ScientificWorldJournal 2013:354920. doi:10.1155/2013/354920
Rainer TH (2001) Plasma DNA, prediction and post-traumatic complications. Clin Chim Acta 313(1–2):81–85. doi:10.1016/S0009-8981(01)00653-2
Lo YM, Rainer TH, Chan LY, Hjelm NM, Cocks RA (2000) Plasma DNA as a prognostic marker in trauma patients. Clin Chem 46(3):319–323
Macher H, Egea-Guerrero JJ, Revuelto-Rey J, Gordillo-Escobar E, Enamorado-Enamorado J, Boza A, Rodriguez A, Molinero P, Guerrero JM, Dominguez-Roldán JM, Murillo-Cabezas F, Rubio A (2012) Role of early cell-free DNA levels decrease as a predictive marker of fatal outcome after severe traumatic brain injury. Clin Chim Acta 414:12–17. doi:10.1016/j.cca.2012.08.001
Rainer TH, Lo YM, Chan LY, Lam NY, Lit LC, Cocks RA (2001) Derivation of a prediction rule for posttraumatic organ failure using plasma DNA and other variables. Ann N Y Acad Sci 945:211–220
Chen D, Pan S, Zhang S, Huang P, Xia W, Xie E, Gu B, Wang F, Xu J, Xu T, Lu Y, Yang D, Lu S (2011) The clinical significance of plasma DNA quantification for quake trauma patients. In: Gahan PB (ed) Circulating nucleic acids in plasma and serum. Springer, Dordrecht, pp 171–182
Fox A, Gal S, Fisher N, Smythe J, Wainscoat J, Tyler MP, Watt SM, Harris AL (2008) Quantification of circulating cell-free plasma DNA and endothelial gene RNA in patients with burns and relation to acute thermal injury. Burns 34(6):809–816. doi:10.1016/j.burns.2007.10.003
Altrichter J, Zedler S, Kraft R, Faist E, Mitzner SR, Sauer M, Windolf J, Scholz M, Lögters T (2010) Neutrophil-derived circulating free DNA (cfDNA/NETs), a potential prognostic marker for mortality in patients with severe burn injury. Eur J Trauma Emerg Surg 36:551–557
Brinkmann V, Zychlinsky A (2007) Beneficial suicide: why neutrophils die to make NETs. Nat Rev Microbiol 5(8):577–582. doi:10.1038/nrmicro1710
Redell JB, Moore AN, Ward NH 3rd, Hergenroeder GW, Dash PK (2010) Human traumatic brain injury alters plasma microRNA levels. J Neurotrauma 27(12):2147–2156. doi:10.1089/neu.2010.1481
Franceschi C (2007) Inflammaging as a major characteristic of old people: can it be prevented or cured? Nutr Rev 65(12 Pt 2):S173–S176
Bandeen-Roche K, Walston JD, Huang Y, Semba RD, Ferrucci L (2009) Measuring systemic inflammatory regulation in older adults: evidence and utility. Rejuvenation Res 12(6):403–410. doi:10.1089/rej.2009.0883
Jylhava J, Kotipelto T, Raitala A, Jylhä M, Hervonen A, Hurme M (2011) Aging is associated with quantitative and qualitative changes in circulating cell-free DNA: the Vitality 90+ study. Mech Ageing Dev 132(1–2):20–26. doi:10.1016/j.mad.2010.11.001
Jylhava J, Nevalainen T, Marttila S, Jylhä M, Hervonen A, Hurme M (2013) Characterization of the role of distinct plasma cell-free DNA species in age-associated inflammation and frailty. Aging Cell 12(3):388–397. doi:10.1111/acel.12058
Mittra I, Nair NK, Mishra PK (2012) Nucleic acids in circulation: are they harmful to the host? J Biosci 37(2):301–312
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2015 Springer Science+Business Media Dordrecht
About this chapter
Cite this chapter
Schwarzenbach, H. (2015). CNAPS and General Medicine. In: Gahan, P. (eds) Circulating Nucleic Acids in Early Diagnosis, Prognosis and Treatment Monitoring. Advances in Predictive, Preventive and Personalised Medicine, vol 5. Springer, Dordrecht. https://doi.org/10.1007/978-94-017-9168-7_7
Download citation
DOI: https://doi.org/10.1007/978-94-017-9168-7_7
Published:
Publisher Name: Springer, Dordrecht
Print ISBN: 978-94-017-9167-0
Online ISBN: 978-94-017-9168-7
eBook Packages: MedicineMedicine (R0)