Marcadores moleculares en el diagnóstico y pronóstico de sepsis, sepsis grave y choque séptico

Volumen 65, Número 1, Revista de la Facultad de Medicina

Publicado

2017-01-01

Marcadores moleculares en el diagnóstico y pronóstico de sepsis, sepsis grave y choque séptico

Molecular markers in the diagnosis and prognosis of sepsis, severe sepsis and septic shock

Palabras clave:

Sepsis, Biomarcadores, Polimorfismo genético, Polimorfismo de nucleótido simple, Repeticiones de minisatélite (es)
Sepsis, Biomarkers, Polymorphism, Genetic, Polymorphism, Single Nucleotide, Minisatellite Repeats (en)

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Autores/as

Alfredo Prado-Díaz Universidad Libre - Seccional Cali - Grupo de Investigación en Microbiología Molecular y Enfermedades Infecciosas (GIMMEIN) - Santiago de Cali- Colombia.
Andrés Castillo Universidad del Valle - Sede Cali - Facultad de Ciencias Naturales y Exactas - Departamento de Biología - Cali - Colombia.
Diana Marcela Rojas Universidad Andres Bello - Sede Santiago - Facultad de Medicina - Escuela de Nutrición y Dietética - Santiago de Chile - Chile.
Mónica Chávez-Vivas Universidad Santiago de Cali - Campus Pampalinda - Facultad de Salud - Departamento de Ciencias Biomédicas - Santiago de Cali - Colombia. Universidad Libre de Cali - Seccional Cali - Grupo de Investigación Instituto de Ciencias Biomédicas - Cali - Colombia.

Resumen (es)
Resumen (en)

Introducción. A pesar de los importantes avances en el entendimiento de la patofisiología de la sepsis, la mortalidad que genera sigue siendo alta.

Objetivo. Describir el estado del arte de los biomarcadores moleculares propuestos hasta el momento como potenciales marcadores para el diagnóstico y pronóstico de sepsis, sepsis grave y choque séptico.

Materiales y métodos. Se analizaron los registros de los últimos 14 años que se encontraban en PubMed, en The New England Journal of Medicine (NEJM) y en Illinois Automatic Computer (ILLIAC) con los términos sepsis, genetic polymorphisms, genetic variation y molecular marker. Se clasificaron los artículos por año de publicación y solo se tuvieron en cuenta los publicados durante los últimos 10 años.

Resultados. La búsqueda arrojó 3 370 referencias que cubren más de 30 genes con polimorfismos genéticos que pueden ser empleados como potenciales marcadores de polimorfismos. Estos fueron evaluados para su uso en las diferentes manifestaciones de sepsis, su diagnóstico y progresión. Se describen 20 genes marcadores: cuatro asociados con bacteremia (TLR-1, TLR-2, Proteína C y Selectina-E), nueve con sepsis (IL-1B, IL-1A, IL-6, TNF-α, TLR-1, MBL-1, Hsp70, PAI-1 y MIF-1), siete con sepsis grave (IL-1RN, IL-10, TNF-α, CD14, TREM-1, Caspasa 12 y DEFB-1), cinco con choque séptico (TNF-B, TLR-4, Hsp70, MBL-1 y CD14 ) y tres con disfunción multiorgánica (TLR-1, PAI-1 y Proteína C).

Conclusión. Los polimorfismos genéticos, en su mayoría, han sido probados clínicamente como marcadores de diagnóstico y pronóstico en la sepsis con resultados prometedores por la alta especificidad y sensibilidad en la práctica clínica.

Introduction: Despite important progress in the understanding of the pathophysiology of sepsis, the mortality rates caused by this condition remain high.

Objective: To describe the state of the art on molecular biomarkers proposed as potential markers for the diagnosis and prognosis of sepsis, severe sepsis and septic shock.

Materials and methods: The terms sepsis, genetic polymorphisms, genetic variation and molecular marker were analyzed in the records of the last 14 years of PubMed, the New England Journal of Medicine (NEJM) and Illinois Automatic Computer (ILLIAC). The papers were classified by year of publication; only those published within the last 10 years were taken into account.

Results: The search yielded 3390 references covering more than 30 genes with genetic polymorphisms that can be used as potential polymorphism markers. They were assessed for use in different manifestations, diagnosis and progression of sepsis. Twenty genetic markers are described: four associated with bacteremia (TLR-1, TLR-2, Protein C and Selectin-E), nine with sepsis (IL-1B, IL-1A, IL-6, TNF-α, TLR-1, MBL-1, Hsp70, PAI-1 and MIF-1), seven with severe sepsis (IL-1RN, IL-10, TNF-α, CD14, TREM-1, Caspase 12 and DEFB-1), five with septic shock (TNF-B, TLR-4, Hsp70, MBL-1 and CD14 ), and three with multiorgan dysfunction (TLR-1, PAI-1 and Protein C).

Conclusion: In general, genetic polymorphisms have been clinically tested as diagnostic and prognostic markers of sepsis with promising results due to the high specificity and sensitivity of the clinical practice.

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Quenot JP, Binquet C, Kara F, Martinet O, Ganster F, Navellou JC, et al. The epidemiology of septic shock in French intensive care units: the prospective multicenter cohort EPISS study. Crit Care. 2013;17(2):R65. http://doi.org/bwk2.

Bateman BT, Schmidt U, Berman MF, Bittner EA. Temporal trends in the epidemiology of severe postoperative sepsis after elective surgery: a large, nationwide sample. Anesthesiology. 2010;122(4):917-25. http://doi.org/cts2vv.

Vincent JL, Sakr Y, Sprung CL, Ranieri VM, Reinhart K, Gerlach H, et al. Sepsis in European intensive care units: results of the SOAP study. Crit Care Med. 2006;34(2):344-53. http://doi.org/c4ppj2.

Ortiz G, Dueñas C, Rodríguez F, Barrera L, de La Rosa, Dennis R, et al. Epidemiology of sepsis in Colombian intensive care units. Biomedica. 2014;34(1):40-7. http://doi.org/bwk3.

Iwashyna TJ, Odden A, Rohde J, Bonham C, Kuhn L, Malani P, et al. Identifying patients with severe sepsis using administrative claims: patient-level validation of the angus implementation of the international consensus conference definition of severe sepsis. Med Care. 2014;52(6):e39-43. http://doi.org/bwk4.

Sriskandan S, Altmann DM. The immunology of sepsis. J Pathol. 2008;214(2): 211-23. http://doi.org/fqnh7b.

Faix JD. Biomarkers of sepsis. Crit Rev Clin Lab Sci. 2013;50(1):23-36. http://doi.org/bwk5.

Pierrakos C, Vincent JL. Sepsis biomarkers: a review. Crit Care. 2010;14(1):R15. http://doi.org/b2xxjh.

Tsalik EL, Jaggers LB, Glickman SW, Langley RJ, van Velkinburgh JC, Park LP, et al. Discriminative value of inﬂammatory biomarkers for suspected sepsis. J Emerg Med. 2012;43(1):97-106. http://doi.org/bj4v3n.

Bozza FA, Salluh JI, Japiassu AM, Soares M, Assis EF, Gomes RN, et al. Cytokine profiles as markers of disease severity in sepsis: a multiplex analysis. Crit Care. 2007;11(2):R49. http://doi.org/c5vg76.

Chávez M, Vallejo S. Susceptibilidad genética para el desarrollo de la sepsis bacteriana grave y choque séptico. Rev. Cienc. Salud. 2013 [cited 2016 Dec 31];11(1):93-103. Available from: https://goo.gl/U2yoqK.

Tumangger H, Jamil KF. Contribution of genes polymorphism to susceptibility and outcome of sepsis. Egyp J Med Hum Gen. 2010;11(2):97-103. http://doi.org/d5xqg9.

Gaydou L, Bertuzzi R, Moretti E. Sepsis as a stressor: association with serum levels of cortisol, C reactive protein and interleukin 1β. Acta bioquím. clín. latinoam. 2009 [cited 2016 Dec 31];43(3):299-305. Available from: https://goo.gl/t1GL92.

Kurt AN, Aygun AD, Godekmerdan A, Kurt A, Dogan Y, Yilmaz E. Serum IL-1beta, IL-6, IL-8, and TNF-alpha levels in early diagnosis and management of neonatal sepsis. Mediators Inflamm. 2007 [cited 2016 Dec 31];2007:31397. Available from: https://goo.gl/XQ4mnK.

Naffaa M, Makhoul BF, Tobia A, Kaplan M, Aronson D, Azzam ZS, et al. Procalcitonin and interleukin 6 for predicting blood culture positivity in sepsis. Am J Emerg Med. 2014;32(5):448-51. http://doi.org/bwk6.

Socha LA, Gowardman J, Silva D, Correcha M, Petrosky N. Elevation in interleukin 13 levels in patients diagnosed with systemic inflammatory response syndrome. Intensive Care Med. 2006;32(2):244-50. http://doi.org/c6wv5x.

Tschoeke SK, Oberholzer A, Moldawer LL. Interleukin-18: a novel prognostic cytokine in bacteria-induced sepsis. Crit Care Med. 2006;34(4):1225-33. http://doi.org/btbkjh.

Lotze MT, Tracey KJ. High-mobility group box 1 protein (HMGB1): nuclear weapon in the immune arsenal. Nat Rev Immunol. 2005;5(4):331-42. http://doi.org/b4tqcz.

Karlsson S, Pettilä V, Tenhunen J, Laru-Sompa R, Hynninen M, Ruokonen E. HMGB1 as a predictor of organ dysfunction and outcome in patients with severe sepsis. Intensive Care Med. 2008;34(6):1046-53. http://doi.org/cqsxkx.

Du J, Li L, Dou Y, Li P, Chen R, Liu H. Diagnostic utility of neutrophil CD64 as a marker for early-onset sepsis in preterm neonates. PLoS One. 2014;9(7):e102647. http://doi.org/bwk7.

Aalto H, Takala A, Kautiainen H, Siitonen S, Repo H. Monocyte CD14 and soluble CD14 in predicting mortality of patients with severe community acquired infection. Scand J Infect Dis. 2007;39(6-7):596-603. http://doi.org/cf3crs.

Ebdrup L, Krog J, Granfeldt A, Tønnesen E, Hokland M. Dynamic expression of the signal regulatory protein alpha and CD18 on porcine PBMC during acute endotoxaemia. Scand J Immunol. 2008;68(4):430-7. http://doi.org/drv5k9.

Saito K, Wagatsuma T, Toyama H, Ejima Y, Hoshi K, Shibusawa M, et al. Sepsis is characterized by the increases in percentages of circulating CD4+CD25+ regulatory T cells and plasma levels of soluble CD25. Tohoku J Exp Med. 2008;216(1):61-8. http://doi.org/dqmp3n.

Nolan A, Weiden M, Kelly A, Hoshino Y, Hoshino S, Mehta N, et al. CD40 and CD80/86 act synergistically to regulate inflammation and mortality in polymicrobial sepsis. Am J Respir Crit Care Med. 2008;177(3):301-8. http://doi.org/bpfqxp.

Takeda K, Akira S. Toll-like receptors in innate immunity. ‎Int Immunol. 2005;17(1):1-14. http://doi.org/c44tzh.

Tsujimoto H, Ono S, Efron PA, Scumpia PO, Moldawer LL, Mochizuki H. Role of Toll-like receptors in the development of sepsis. Shock. 2008;29(3):315-21. http://doi.org/bq3bh3.

Arts RJ, Joosten LA, van der Meer JW, Netea MG. TREM-1: intracellular signaling pathways and interaction with pattern recognition receptors. J Leukoc Biol. 2013;93(2):209-15. http://doi.org/bwmd.

Cehn YX, Li CS. The predictive value of adrenomedullin for development of severe sepsis and septic shock in emergency department. BioMed Res Int. 2013;2013:960101. http://doi.org/bwmf.

Christ-Crain M, Morgenthaler NG, Struck J, Harbarth S, Bergmann A, Müller B. Mid-regional pro-adrenomedullin as a prognostic marker in sepsis: an observational study. Crit Care. 2005;9(6):R816-24. http://doi.org/c7v27t.

Benz F, Roy S, Trautwein C, Roderburg C, Luedde T. Circulating MicroRNAs as Biomarkers for Sepsis. Int J Mol Sci. 2016;17(1):78. http://doi.org/bwmg.

Vasilescu C, Rossi S, Shimizu M, Tudor S, Veronese A, Ferracin M, et al. MicroRNA fingerprints identify miR-150 as a plasma prognostic marker in patients with sepsis. PLoS One. 2009;4(10):e7405. http://doi.org/dh95mf.

1000 Genomes Project Consortium, Abecasis GR, Altshuler D, Auton A, Brooks LD, Durbin RM, et al. A map of human genome variation from population-scale sequencing. Nature. 2010;467(7319):1061-73. http://doi.org/fmk7rw.

Lee PH. Prioritizing SNPs for disease-gene association studies: algorithms and systems. [Doctoral Thesis]. Kingston, Ontario: Queen’s University, Canada; 2009 [cited 2017 Jan 01]. Available from: https://goo.gl/tHRTcD.

Veltman JA, Brunner HG. De novo mutations in human genetic disease. ‎Nat Rev Genet. 2012;13(8):565-75. http://doi.org/bwmw.

Chapman SJ, Hill AV. Human genetic susceptibility to infectious disease. ‎Nat Rev Genet. 2012;13(3):175-88. http://doi.org/bwmx.

Hill AV. Aspects of genetic susceptibility to human infectious diseases. Ann Rev Genet. 2006;40:469-86. http://doi.org/bmsf2b.

Murray MF. Susceptibility to infectious diseases: the importance of host genetics. Clin Infec Dis. 2005;40(2):338-9. http://doi.org/b6bm4f.

Chopra R, Kalaiarasan P, Ali S, Srivastava AK, Aggarwal S, Garg VK, et al. PARK2 and proinflammatory/anti-inflammatory cytokine gene interactions contribute to the susceptibility to leprosy: a case-control study of North Indian population. BMJ Open. 2014;4(2):e004239. http://doi.org/bwmz.

Naderi M, Hashemi M, Hazire-Yazdi L, Taheri M, Moazeni-Roodi A, Eskandari-Nasab E, et al. Association between toll-like receptor2 Arg677Trp and 597T/C gene polymorphisms and pulmonary tuberculosis in Zahedan, Southeast Iran. Braz J Infect Dis. 2013;17(5):516-20. http://doi.org/f2fp4x.

Min-Oo G, Fortin A, Pitari G, Tam M, Stevenson MM, Gros P. Complex genetic control of susceptibility to malaria: positional cloning of the Char9 locus. J Exp Med. 2007;204(3):511-24. http://doi.org/fr38sr.

Cornell TT, Wynn J, Shanley TP, Wheeler DS, Wong HR. Mechanisms and regulation of the gene expression response to sepsis. Pediatrics. 2010;125(6):1248-58. http://doi.org/bc7ztf.

Sutherland AM, Walley KR. Bench-to-bedside review: Association of genetic variation with sepsis. Crit Care. 2009;13(2):210. http://doi.org/cb5524.

Stuber F, Klaschik S, Lehmann LE, Schewe JC, Weber S, Book M. Cytokine promoter polymorphisms in severe sepsis. Clin Infect Dis. 2005;41(Suppl 7):S416-20. http://doi.org/dqr3gs.

Chen H, Wilkins LM, Aziz N, Cannings C, Wyllie DH, Bingle C, et al. Single nucleotide polymorphisms in the human interleukin-1B gene affect transcription according to haplotype context. Hum Mol Genet. 2006;15(4):519-29. http://doi.org/cnw5hm.

Zhang A, Pan W, Gao J, Yue C, Zeng L, Gu W, et al. Associations between interleukin-1 gene polymorphisms and sepsis risk: a meta-analysis. BMC Med Genet. 2014;15:8-22. http://doi.org/bwm2.

Arman A, Soylu O, Yildirim A, Furman A, Ercelen N, Aydogan H, et al. Interleukin-1 receptor antagonist gene VNTR polymorphism is associated with coronary artery disease. Arq Bras Cardiol. 2008;91(5):293-8. http://doi.org/bjh467.

Fang F, Pan J, Li Y, Xu L, Su G, Li G, et al. Association between interleukin-1 receptor antagonist gene 86-bp VNTR polymorphism and sepsis: a meta-analysis. Hum Immunol. 2015;76(1):1-5. doi: http://doi.org/bwm3.

Chauhan M, McGuire W. Interleukin-6 (-174C) polymorphism and the risk of sepsis in very low birth weight infants: meta-analysis. Arch Dis Child Fetal Neonatal Ed. 2008;93(6):F427-9. http://doi.org/bgw7k8.

Schlüter B, Raufhake C, Erren M, Schotte H, Kipp F, Rust S, et al. Effect of the interleukin-6 promoter polymorphism (-174 G/C) on the incidence and outcome of sepsis. Crit Care Med. 2002;30(1):32-7. http://doi.org/dgphf7.

Martín-Loeches I, Violan JS, Blanquer J, Aspa J, Rodríguez-Gallego C, Rodríguez-de Castro F, et al. Effect of the IL-6 promoter polymorphism -174 G/C on risk and outcome of pneumonia. Crit Care. 2008;12(Suppl 2):P465. http://doi.org/fk94tw.

Ahrens P, Kattner E, Köhler B, Härtel C, Seidenberg J, Segerer H, et al. Mutations of genes involved in the innate immune system as predictors of sepsis in very low birth weight infants. Pediatr Res. 2004;55(4):652-6. http://doi.org/bjmhk2.

Cardoso CP, de Oliveira AJ, Botoni FA, Porto IC, Alves-Filho JC, de Queiroz-Cunha F, et al. Interleukin-10 rs2227307 and CXCR2 rs1126579 polymorphisms modulate the predisposition to septic shock. Mem Inst Oswaldo Cruz. 2015;110(4):453-60. http://doi.org/bwm4.

Schulte W, Bernhagen J, Bucala R. Cytokines in sepsis: potent immunoregulators and potential therapeutic targets—an updated view. Mediators Inflamm. 2013;2013:165974. http://doi.org/bwm5.

Kang X, Kim HJ, Ramirez M, Salameh S, Ma X. The septic shock-associated IL-10 -1082 A>G polymorphism mediates allele-specific transcription via poly (ADP-ribose) polymerase 1 in macrophages engulfing apoptotic cells. ‎J Immunol. 2010;184(7):3718-24. http://doi.org/dwfx6f.

Stanilova SA, Miteva LD, Karakolev ZT, Stefanov CS. Interleukin-10 -1082 promoter polymorphism in association with cytokine production and sepsis susceptibility. Intensive Care Med. 2006;32(2):260-6. http://doi.org/fw2xm7.

Baier RJ, Loggins J, Yanamandra K. IL-10, IL-6 and CD14 polymorphisms and sepsis outcome in ventilated very low birth weight infants. BMC Med. 2006;4:10. http://doi.org/bs9x6d.

Shu Q, Fang X, Chen Q, Stuber F. IL-10 polymorphism is associated with increased incidence of severe sepsis. Chin Med J. 2003 [cited 2017 Jan 01];116(11):1756-9. Available from: https://goo.gl/egAcHM.

O’Keefe GE, Hybki DL, Munford RS. The G/A single nucleotide polymorphism at the -308 position in the tumor necrosis factor-α promoter increases the risk for severe sepsis after trauma. J Trauma. 2002;52(5):817-26. http://doi.org/frwppz.

Teuffel O, Ethier MC, Beyene J, Sung L. 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. 2010;38(1):276-82. http://doi.org/c5zb57.

Schueller AC, Heep A, Kattner E, Kroll M, Wisbauer M, Sander J, et al. Prevalence of two tumor necrosis factor gene polymorphisms in premature infants with early onset sepsis. Biol Neonate. 2006;90(4):229-32. http://doi.org/dq3q6z.

Ávila-Paskulin DD, Fallavena PR, Paludo FJ, Borges TJ, Picanço JB, Dias FS, et al. TNF -308G>A promoter polymorphism (rs1800629) and outcome from critical illness. Braz J Infect Dis. 2011;15(3):231-8. http://doi.org/f2j8nw.

Odwyer M, White M, McManus R, Ryan T. TNFα promoter single nucleotide polymorphisms may influence gene expression in patients with severe sepsis. Crit Care. 2007;11(Suppl 2):P448. http://doi.org/bjk69d.

Delongui F, Carvalho CM, Ehara MA, Kaminami M, Bonametti AM, Maeda JM, et al. Association of tumor necrosis factor β genetic polymorphism and sepsis susceptibility. Exp Ther Med. 2011;2(2):349-56. http://doi.org/ccxj6r.

Wurfel MM, Gordon AC, Holden TD, Radella F, Strout J, Kajikawa O, et al. Toll-like receptor 1 polymorphisms affect innate immune responses and outcomes in sepsis. Am J Respir Crit Care Med. 2008;178(7):710-20. http://doi.org/b5bnwz.

Sutherland AM, Walley KR, Russell JA. 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. 2005;33(3):638-44. http://doi.org/dcnksm.

Wang H, Wei Y, Zeng Y, Qin Y, Xiong B, Qin G, et al. The association of polymorphisms of TLR4 and CD14 genes with susceptibility to sepsis in a Chinese population. BMC Med Genet. 2014;15:123. http://doi.org/bwm6.

Van der Graaf CA, Netea MG, Morré SA, Den Heijer M, Verweij PE, Van der Meer JW, et al. Toll-like receptor 4 Asp299Gly/ Thr399Ile polymorphisms are a risk factor for Candida bloodstream infection. Eur Cytokine Netw. 2006 [cited 2017 Jan 02];17(1):29-34. Available from: https://goo.gl/2iV3Tn.

Schröder NW, Schumann RR. Single nucleotide polymorphisms of Toll-like receptors and susceptibility to infectious disease. Lancet Infect Dis. 2005;5(3):156-64. http://doi.org/ffwwmv.

Zhang A, Yue C, Gu W, Du J, Wang H, Jiang J. Association between CD14 Promoter -159C/T Polymorphism and the Risk of Sepsis and Mortality: A Systematic Review and Meta-Analysis. PLoS One. 2013;8(8):e71237. http://doi.org/bwm7.

Jung ES, Kim SW, Moon CM, Shin DJ, Son NH, Kim ES, et al. Relationships between genetic polymorphisms of triggering receptor expressed on myeloid cells-1 and inflammatory bowel diseases in the Korean population. Life Sci. 2011;89(9-10):289-94. http://doi.org/d4r72t.

Gordon AC, Waheed U, Hansen TK, Hitman GA, Garrard CS, Turner MW, et al. Mannose-binding lectin polymorphisms in severe sepsis: relationship to levels, incidence, and outcome. Shock. 2006;25(1):88-93. http://doi.org/bn52zj.

Smithson A, Muñoz A, Suárez B, Soto SM, Perello R, Soriano A, et al. Association between mannose-binding lectin deficiency and septic shock following acute pyelonephritis due to Escherichia coli. Clin Vaccine Immunol. 2007;14(3):256-61. http://doi.org/c8dd9q.

Ramakrishna K, Pugazhendhi S, Kabeerdoss J, Peter JV. Association between heat shock protein 70 gene polymorphisms and clinical outcomes in intensive care unit patients with sepsis. Indian J Crit Care Med. 2014;18(4):205-11. http://doi.org/bwnr.

Sapru A, Quasney MW. Host Genetics and Pediatric Sepsis. Open Infl J. 2011 [cited 2017 Jan 02];4(Suppl 1-M10):82-100. Available from: https://goo.gl/aOC6VY.

Chen QX, Lv C, Huang LX, Cheng BL, Xie GH, Wu SJ, et al. Genomic variations within DEFB1 are associated with the susceptibility to and the fatal outcome of severe sepsis in Chinese Han population. Genes Immun. 2007;8(5):439-43. http://doi.org/dvj4pb.

Fang X, Lv C, Chen Q, Huang L. Contribution of genomic variations within human β-defensin 1 to incidence and outcome of severe sepsis. Crit Care. 2007;11(Suppl 2):P447. http://doi.org/dckc5j.

García-Segarra G, Espinosa G, Tassies D, Oriola J, Aibar J, Bové A, et al. Increased mortality in septic shock with the 4G/4G genotype of plasminogen activator inhibitor 1 in patients of white descent. Intensive Care Med. 2007;33(8):1354-62. http://doi.org/bncrns.

Binder A, Endler G, Müller M, Mannhalter C, Zenz W, European Meningococcal Study Group. 4G4G genotype of the plasminogen activator inhibitor-1 promoter polymorphism associates with disseminated intravascular coagulation in children with systemic meningococcemia. J Thromb Haemost. 2007;5(10):2049-54. http://doi.org/b457jf.

Yende S, Angus DC, Kong L, Kellum JA, Weissfeld L, Ferrell R, et al. The influence of macrophage migration inhibitory factor gene polymorphisms on outcome from community-acquired pneumonia. FASEB J. 2009;23(8):2403-11. http://doi.org/cj8dt2.

Saleh M, Vaillancourt JP, Graham RK, Huyck M, Srinivasula SM, Alnemri ES, et al. Differential modulation of endotoxin responsiveness by human caspase-12 polymorphisms. Nature. 2004;429(6987):75-9. http://doi.org/frbn5z.

Mejía SP, Grajales PJ, Jaimes FA, Bedoya G, López J, Arango JC, et al. Presencia de un polimorfismo de la CSP-12 relacionado con susceptibilidad a sepsis grave en una muestra de tres poblaciones colombianas. Iatreia. 2010 [cited 2017 Jan 02];23(2):127-34. Available from: https://goo.gl/Sl1MJn.

Chen QX, Wu SJ, Wang HH, Lv C, Cheng BL, Xie GH, et al. Protein C -1641A/-1654C haplotype is associated with organ dysfunction and the fatal outcome of severe sepsis in Chinese Han population. Hum Genet. 2008;123(3):281-7. http://doi.org/bjm9h4.

Marsik C, Sunder-Plassmann R, Jilma B, Kovar FM, Mannhalter C, Wagner O, et al. The C-reactive protein (+)1444C/T alteration modulates the inflammation and coagulation response in human endotoxemia. Clin Chem. 2006;52(10):1952-7. http://doi.org/c64cgg.

Jilma B, Marsik C, Kovar F, Wagner OF, Jilma-Stohlawetz P, Endler G. The single nucleotide polymorphism Ser128Argn in the E-selectin gene is associated with enhanced coagulation during human endotoxemia. Blood. 2005;105(6):2380-3. http://doi.org/b764z8.

Gao J, Zhang A, Pan W, Yue C, Zeng L, Gu W, et al. Association between IL-6 -174G/C Polymorphism and the Risk of Sepsis and Mortality: A Systematic Review and Meta-Analysis. PLoS One. 2015;10(3):e0118843. http://doi.org/bwns.

Tischendorf JJ, Yagmur E, Scholten D, Vidacek D, Koch A, Winograd R, et al. The interleukin-6 (IL6)- 174 G/C promoter genotype is associated with the presence of septic shock and the ex vivo secretion of IL6. Int J Immunogenet. 2007;34(6):413-8. http://doi.org/fpkk6s.

Gu W, Du DY, Huang J, Zhang LY, Liu Q, Zhu PF, et al. Identification of interleukin-6 promoter polymorphisms in the Chinese Han population and their functional significance. Crit Care Med. 2008;36(5):1437-43. http://doi.org/bfs46j.

Chen Q, Zhou H, Wu S, Wang H, Lv C, Cheng B, et al. Lack of association between TREM-1 gene polymorphisms and severe sepsis in a Chinese Han population. Hum Immunol. 2008;69(3):220-6. http://doi.org/bmnxg3.

Nakada TA, Hirasawa H, Oda S, Shiga H, Matsuda K, Nakamura M, et al. Influence of toll-like receptor 4, CD14, tumor necrosis factor, and interleukin-10 gene polymorphisms on clinical outcome in Japanese critically ill patients. J Surg Res. 2005;129(2):322-8. http://doi.org/cqp73t.

Russell JA, Wellman H, Walley KR. Protein C rs2069912 C allele is associated with increased mortality from severe sepsis in North Americans of East Asian ancestry. Hum Genet. 2008;123(6):661-3. http://doi.org/ftc95d.

Garnacho-Montero J, Garnacho-Montero MC, Ortiz-Leyba C, Aldabó T. Polimorfismos genéticos en la sepsis. Med Intensiva. 2005;29(3):185-91. http://doi.org/dn24w2.

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