Biochemical Genetics

, Volume 55, Issue 3, pp 193–203 | Cite as

Early Prediction of Sepsis Incidence in Critically Ill Patients Using Specific Genetic Polymorphisms

  • Vlad Laurentiu David
  • Muhammed Furkan Ercisli
  • Alexandru Florin RogobeteEmail author
  • Eugen S. Boia
  • Razvan Horhat
  • Razvan Nitu
  • Mircea M. Diaconu
  • Laurentiu Pirtea
  • Ioana Ciuca
  • Delia Horhat
  • Florin George Horhat
  • Monica Licker
  • Sonia Elena Popovici
  • Sonia Tanasescu
  • Calin Tataru


Several diagnostic methods for the evaluation and monitoring were used to find out the pro-inflammatory status, as well as incidence of sepsis in critically ill patients. One such recent method is based on investigating the genetic polymorphisms and determining the molecular and genetic links between them, as well as other sepsis-associated pathophysiologies. Identification of genetic polymorphisms in critical patients with sepsis can become a revolutionary method for evaluating and monitoring these patients. Similarly, the complications, as well as the high costs associated with the management of patients with sepsis, can be significantly reduced by early initiation of intensive care.


miRNAs Biomarkers Genetic polymorphisms Sepsis Critically ill patients 



Intensive care unit


Human leukocyte Antigen


Nuclear transcription factor kappa B


Tumor necrosis factor alpha


Interleukin 6


Interleukin 1 beta


Interleukin 1


Interferon gamma


Multile organ dysfunctions syndrome


Tol-like receptors


Systeic inflammatory response syndrome


Muliple organ dysfunction syndrome


  1. Abdul-Muneer PM, Chandra N, Haorah J (2014) Interactions of oxidative stress and neurovascular inflammation in the pathogenesis of traumatic brain injury. Mol Neurobiol 51(3):966–979. doi: 10.1007/s12035-014-8752-3 CrossRefPubMedGoogle Scholar
  2. Abu-Maziad A, Schaa K, Bell EF et al (2010) Role of polymorphic variants as genetic modulators of infection in neonatal sepsis. Pediatr Res 68:323–329. doi: 10.1203/PDR.0b013e3181e6a068 CrossRefPubMedGoogle Scholar
  3. Adams CA (2011) Sepsis biomarkers in polytrauma patients. Crit Care Clin 27:345–354. doi: 10.1016/j.ccc.2010.12.002 CrossRefPubMedGoogle Scholar
  4. Ahrens P, Kattner E, Köhler B et al (2004) Mutations of genes involved in the innate immune system as predictors of sepsis in very low birth weight infants. Pediatr Res 55:652–656. doi: 10.1203/01.PDR.0000112100.61253.85 CrossRefPubMedGoogle Scholar
  5. An G, Namas RA, Vodovotz Y (2012) Sepsis: from pattern to mechanism and back. Crit Rev Biomed Eng 40:341–351. doi: 10.1002/emmm.201201375 CrossRefPubMedPubMedCentralGoogle Scholar
  6. Annane D (2013) Effects of fluid resuscitation with colloids vs crystalloids on mortality in critically ill patients presenting with hypovolemic shock. JAMA 310(17):1809–1817. doi: 10.1001/jama.2013.280502 CrossRefPubMedGoogle Scholar
  7. Arcaroli JJ, Hokanson JE, Abraham E et al (2009) Extracellular superoxide dismutase haplotypes are associated with acute lung injury and mortality. Am J Respir Crit Care Med 179:105–112. doi: 10.1164/rccm.200710-1566OC CrossRefPubMedGoogle Scholar
  8. Baier R, Loggins J, Yanamandra K (2006) IL-10, IL-6 and CD14 polymorphisms and sepsis outcome in ventilated very low birth weight infants. BMC Med 4:10. doi: 10.1186/1741-7015-4-10 CrossRefPubMedPubMedCentralGoogle Scholar
  9. Barber RC, Aragaki CC, Rivera-Chavez FA et al (2004) TLR4 and TNF-alpha polymorphisms are associated with an increased risk for severe sepsis following burn injury. J Med Genet 41:808–813. doi: 10.1136/jmg.2004.021600 CrossRefPubMedPubMedCentralGoogle Scholar
  10. Bedreag OH, Sandesc D, Chiriac SD et al (2016) The use of circulating miRNAs as biomarkers for oxidative stress in critically ill polytrauma patients. Clin Lab 62(3):263–274. doi: 10.7754/Clin.Lab.2015.150740 PubMedGoogle Scholar
  11. Benz F, Roy S, Trautwein C et al (2016) Circulating microRNAs as biomarkers for sepsis. Int J Mol Sci. doi: 10.3390/ijms17010078 PubMedPubMedCentralGoogle Scholar
  12. Blackwell TS, Christman JW (1997) The role of nuclear factor-kappa B in cytokine gene regulation. Am J Respir Cell MolBiol 17:3–9CrossRefGoogle Scholar
  13. Böhrer H, Qiu F, Zimmermann T et al (1997) Role of NFkappaB in the mortality of sepsis. J Clin Invest 100:972–985. doi: 10.1172/JCI119648 CrossRefPubMedPubMedCentralGoogle Scholar
  14. Bosmann M, Ward PA (2013) The inflammatory response in sepsis. Trends Immunol 34:129–136. doi: 10.1016/ CrossRefPubMedGoogle Scholar
  15. Carvalho JK, Moore DB, Luz RA et al (2013) Prediction of sepsis-related outcomes in neonates through systematic genotyping of polymorphisms in genes for innate immunity and inflammation: a narrative review and critical perspective. Sao Paulo Med J 131:338–350. doi: 10.1590/1516-3180.2013.1315519 CrossRefPubMedGoogle Scholar
  16. Chiche L, Forel JM, Thomas G et al (2011) The role of natural killer cells in sepsis. J Biomed Biotechnol 2011:986491. doi: 10.1155/2011/986491 CrossRefPubMedPubMedCentralGoogle Scholar
  17. Choudhury NR, Michlewski G (2012) Terminal loop-mediated control of microRNA biogenesis. Biochem Soc Trans 40:789–793. doi: 10.1042/BST20120053 CrossRefPubMedGoogle Scholar
  18. Chuang T-Y, Chang H-T, Chung K-P et al (2014) High levels of serum macrophage migration inhibitory factor and interleukin 10 are associated with a rapidly fatal outcome in patients with severe sepsis. Int J Infect Dis 20:13–17. doi: 10.1016/j.ijid.2013.12.006 CrossRefPubMedGoogle Scholar
  19. Davenport EE, Burnham KL, Radhakrishnan J et al (2016) Genomic landscape of the individual host response and outcomes in sepsis: a prospective cohort study. Lancet Respir Med 4:259–271. doi: 10.1016/S2213-2600(16)00046-1 CrossRefPubMedPubMedCentralGoogle Scholar
  20. Dong GH, Gong JP, Li JZ et al (2013) Association between gene polymorphisms of IRAK-M and the susceptibility of sepsis. Inflammation 36:1087–1093. doi: 10.1007/s10753-013-9641-z CrossRefPubMedGoogle Scholar
  21. Dumache R, Rogobete AF, Bedreag OH et al (2015) Use of miRNAs as biomarkers in sepsis. Anal Cell Pathol 2015:186716. doi: 10.1155/2015/186716 CrossRefGoogle Scholar
  22. Finnegan EF, Pasquinelli AE (2013) MicroRNA biogenesis: regulating the regulators. Crit Rev Biochem Mol Biol 48:51–68. doi: 10.3109/10409238.2012.738643 CrossRefPubMedGoogle Scholar
  23. Gao J, Zhang A, Wang X et al (2015) Association between the TLR2 Arg753Gln polymorphism and the risk of sepsis: a meta-analysis. Crit Care 19:416. doi: 10.1186/s13054-015-1130-3 CrossRefPubMedPubMedCentralGoogle Scholar
  24. Gu W, Du D, Huang J et al (2008) Identification of interleukin-6 promoter polymorphisms in the Chinese Han population and their functional significance. Crit Care Med 36(5):1437–1443. doi: 10.1097/CCM.0b013e31816a0adb CrossRefPubMedGoogle Scholar
  25. Gu W, Zeng L, Zhou J et al (2010) Clinical relevance of 13 cytokine gene polymorphisms in Chinese major trauma patients. Intensive Care Med 36:1261–1265. doi: 10.1007/s00134-010-1797-5 CrossRefPubMedGoogle Scholar
  26. Gupta DL, Nagar PK, Kamal VK et al (2015) Clinical relevance of single nucleotide polymorphisms within the 13 cytokine genes in North Indian trauma hemorrhagic shock patients. Scand J Trauma Resusc Emerg Med 23:96. doi: 10.1186/s13049-015-0174-3 CrossRefPubMedPubMedCentralGoogle Scholar
  27. Harding D, Dhamrait S, Millar A et al (2003) Is interleukin-6 −174 genotype associated with the development of septicemia in preterm infants? Pediatrics 112:800–803CrossRefPubMedGoogle Scholar
  28. Huang H, Xu R, Lin F et al (2014) High circulating CD39(+) regulatory T cells predict poor survival for sepsis patients. Int J Infect Dis 30C:57–63. doi: 10.1016/j.ijid.2014.11.006 Google Scholar
  29. Huang H, Xu R, Lin F et al (2015) High circulating CD39+ regulatory T cells predict poor survival for sepsis patients. Int J Infect Dis 30:e57–e63. doi: 10.1016/j.ijid.2014.11.006 CrossRefGoogle Scholar
  30. Jessen KM, Lindboe SB, Petersen AL et al (2007) Common TNF-alpha, IL-1 beta, PAI-1, uPA, CD14 and TLR4 polymorphisms are not associated with disease severity or outcome from Gram negative sepsis. BMC Infect Dis 7:108. doi: 10.1186/1471-2334-7-108 CrossRefPubMedPubMedCentralGoogle Scholar
  31. Kalayci D, Dikmen B, Kaçmaz M et al (2014) Plasma levels of interleukin-10 and nitric oxide in response to two different desflurane anesthesia flow rates. Brazilian J Anesthesiol 64:292–298. doi: 10.1016/j.bjane.2013.06.008 CrossRefGoogle Scholar
  32. Keel M, Trentz O (2005) Pathophysiology of polytrauma. Injury 36:691–709. doi: 10.1016/j.injury.2004.12.037 CrossRefPubMedGoogle Scholar
  33. Lin T, Maita D, Thundivalappil SR et al (2015) Hemopexin in severe inflammation and infection: mouse models and human diseases. Crit Care 19:1–8. doi: 10.1186/s13054-015-0885-x CrossRefGoogle Scholar
  34. Liu T, Fei Z, Gangavarapu KJ et al (2013) Interleukin-6 and JAK2/STAT3 signaling mediate the reversion of dexamethasone resistance after dexamethasone withdrawal in 7TD1 multiple myeloma cells. Leuk Res 37:1322–1328. doi: 10.1016/j.leukres.2013.06.026 CrossRefPubMedPubMedCentralGoogle Scholar
  35. Luan Y, Yao Y, Xiao X, Sheng Z (2015) Insights into the apoptotic death of immune cells in sepsis. J Interferon Cytokine Res 35:17–22. doi: 10.1089/jir.2014.0069 CrossRefPubMedPubMedCentralGoogle Scholar
  36. Ma Y, Vilanova D, Atalar K et al (2013) Genome-wide sequencing of cellular microRNAs identifies a combinatorial expression signature diagnostic of sepsis. PLoS ONE 8(10):e75918. doi: 10.1371/journal.pone.0075918 CrossRefPubMedPubMedCentralGoogle Scholar
  37. Potts MB, Koh SE, Whetstone WD et al (2006) Traumatic injury to the immature brain: inflammation, oxidative injury, and iron-mediated damage as potential therapeutic targets. NeuroRx 3:143–153. doi: 10.1016/j.nurx.2006.01.006 CrossRefPubMedPubMedCentralGoogle Scholar
  38. Roderburg C, Luedde M, Vargas Cardenas D et al (2013) Circulating microRNA-150 serum levels predict survival in patients with critical illness and sepsis. PLoS ONE 8(1):e54612. doi: 10.1371/journal.pone.0054612 CrossRefPubMedPubMedCentralGoogle Scholar
  39. Schnetzke U, Spies-Weisshart B, Yomade O et al (2015) Polymorphisms of Toll-like receptors (TLR2 and TLR4) are associated with the risk of infectious complications in acute myeloid leukemia. Genes Immun 16:83–88. doi: 10.1038/gene.2014.67 CrossRefPubMedGoogle Scholar
  40. Schoenberg MH, Weiss M, Radermacher P (1998) Outcome of patients with sepsis and septic shock after ICU treatment. Langenbeck’s Arch Surg 383:44–48CrossRefGoogle Scholar
  41. Sfera A, Price AI, Gradini R et al (2015) Proteomic and epigenomic markers of sepsis-induced delirium (SID). Front Mol Biosci 2:59. doi: 10.3389/fmolb.2015.00059 CrossRefPubMedPubMedCentralGoogle Scholar
  42. Shao Y, Li J, Cai Y et al (2014) The functional polymorphisms of miR-146a are associated with susceptibility to severe sepsis in the Chinese population. Mediators Inflamm 2014:916202. doi: 10.1155/2014/916202 CrossRefPubMedPubMedCentralGoogle Scholar
  43. Shi D, Song Z, Yin J et al (2014) Genetic variation in the tissue factor gene is associated with clinical outcome in severe sepsis patients. Crit Care 18:631. doi: 10.1186/s13054-014-0631-9 CrossRefPubMedPubMedCentralGoogle Scholar
  44. Simsek T, Uzelli Simsek H, Canturk NZ (2014) Response to trauma and metabolic changes: posttraumatic metabolism. Turkish J Surg 30:153–159. doi: 10.5152/UCD.2014.2653 CrossRefGoogle Scholar
  45. Su L, Liu C, Li C et al (2012) Dynamic changes in serum soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) and its gene polymorphisms are associated with sepsis prognosis. Inflammation 35:1833–1843. doi: 10.1007/s10753-012-9504-z CrossRefPubMedGoogle Scholar
  46. Sun X, Icli B, Wara AK et al (2012) MicroRNA-181b regulates NF-κB—mediated vascular inflammation. J Clin Invest 122:1–18. doi: 10.1172/JCI61495DS1 CrossRefGoogle Scholar
  47. Sutherland AM, Walley KR, Russell JA (2005) Polymorphisms in CD14, mannose-binding lectin, and Toll-like receptor-2 are associated with increased prevalence of infection in critically ill adults. Crit Care Med 33(3):638–644CrossRefPubMedGoogle Scholar
  48. Tacke F, Roderburg C, Benz F et al (2014) Levels of circulating miR-133a are elevated in sepsis and predict mortality in critically ill patients. Crit Care Med 42(5):1096–1104. doi: 10.1097/CCM.0000000000000131 CrossRefPubMedGoogle Scholar
  49. Teuffel O, Ethier M-C, Beyene J, Sung L (2010) Association between tumor necrosis factor-α promoter −308 A/G polymorphism and susceptibility to sepsis and sepsis mortality: a systematic review and meta-analysis. Crit Care Med 38(1):276–282CrossRefPubMedGoogle Scholar
  50. Trancă SD, Laura C, Hagă N (2014) Biomarkers in polytrauma induced systemic inflammatory response syndrome and sepsis—a narrative review. Rom J Anaesth Int Care 21:118–122Google Scholar
  51. Treszl A, Kocsis I, Szathmári M et al (2003) Genetic variants of TNF-α, IL-1β, IL-4 receptor α-chain, IL-6 and IL-10 genes are not risk factors for sepsis in low-birth-weight infants. Neonatology 83:241–245CrossRefGoogle Scholar
  52. Wang J, Yu M, Yu G et al (2010) Serum miR-146a and miR-223 as potential new biomarkers for sepsis. Biochem Biophys Res Commun 394:184–188. doi: 10.1016/j.bbrc.2010.02.145 CrossRefPubMedGoogle Scholar
  53. Wang H, Meng K, Chen WJ et al (2012a) Serum miR-574-5p. Shock 37:263–267. doi: 10.1097/SHK.0b013e318241baf8 CrossRefPubMedGoogle Scholar
  54. Wang H, Zhang P, Chen W et al (2012b) Serum microRNA signatures identified by Solexa sequencing predict sepsis patients’ mortality: a prospective observational study. PLoS ONE 7:1–9. doi: 10.1371/journal.pone.0038885 Google Scholar
  55. Wang L, Wang HC, Chen C et al (2013) Differential expression of plasma miR-146a in sepsis patients compared with non-sepsis-SIRS patients. Exp Ther Med 5:1101–1104. doi: 10.3892/etm.2013.937 PubMedPubMedCentralGoogle Scholar
  56. Wang H, Wei Y, Zeng Y et al (2014a) The association of polymorphisms of TLR4 and CD14 genes with susceptibility to sepsis in a Chinese population. BMC Med Genet 15:123. doi: 10.1186/s12881-014-0123-4 CrossRefPubMedPubMedCentralGoogle Scholar
  57. Wang H, Yu B, Deng J et al (2014b) Serum miR-122 correlates with short-term mortality in sepsis patients. Crit Care 18:1–4. doi: 10.1186/s13054-014-0704-9 Google Scholar
  58. Wattanathum A, Manocha S, Groshaus H et al (2005) Interleukin-10 haplotype associated with increased mortality in critically ill patients with sepsis from pneumonia but not in patients with extrapulmonary sepsis. Chest 128:1690–1698. doi: 10.1378/chest.128.3.1690 CrossRefPubMedGoogle Scholar
  59. Zhang L, Dong L-Y, Li Y-J et al (2012) The microRNA miR-181c controls microglia-mediated neuronal apoptosis by suppressing tumor necrosis factor. J Neuroinflammation 9:211. doi: 10.1186/1742-2094-9-211 PubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Vlad Laurentiu David
    • 1
  • Muhammed Furkan Ercisli
    • 2
  • Alexandru Florin Rogobete
    • 1
    • 3
    Email author
  • Eugen S. Boia
    • 1
  • Razvan Horhat
    • 1
  • Razvan Nitu
    • 1
  • Mircea M. Diaconu
    • 1
  • Laurentiu Pirtea
    • 1
  • Ioana Ciuca
    • 1
  • Delia Horhat
    • 1
  • Florin George Horhat
    • 1
  • Monica Licker
    • 1
  • Sonia Elena Popovici
    • 2
  • Sonia Tanasescu
    • 1
  • Calin Tataru
    • 4
  1. 1.Faculty of Medicine“Victor Babes” University of Medicine and PharmacyTimisoaraRomania
  2. 2.Faculty of MedicineAtaturk UniversityErzurumTurkey
  3. 3.Clinic of Anesthesia and Intensive CareEmergency County Hospital “Pius Brinzeu”TimisoaraRomania
  4. 4.Faculty of Medicine“Carol Davila” University of Medicine and PharmacyBucharestRomania

Personalised recommendations