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BMC Medical Genetics
Published in: BMC Medical Genetics 1/2019

Open Access 01-12-2019 | Septicemia | Research article

The association between interleukin-6 gene -174G/C single nucleotide polymorphism and sepsis: an updated meta-analysis with trial sequential analysis

Authors: Yao Chen, Yanyan Hu, Zhenju Song

Published in: BMC Medical Genetics | Issue 1/2019

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Abstract

Background

This article intends to explore the association between interleukin-6 gene (IL-6) -174 G/C single nucleotide polymorphism (SNP) and the risk and mortality of sepsis by conducting this updated meta-analysis with trial sequential analysis.

Methods

References were made to PubMed, Web of Science, China National Knowledge Infrastructure for studies available by September 2018. Each publication was screened for its eligibility and data accessible. Statistical analysis was conducted on Stata 14.1 and TSA software 0.9.5.10 Beta

Results

Twenty studies (including 3282 cases and 4926 controls) and eight studies (including 610 cases and 1856 controls) were respectively enrolled in the analysis on the association between IL-6-174 G/C polymorphism and the risk and mortality of sepsis. The results did not present any association between IL-6-174 G/C polymorphism and the risk and mortality of sepsis. An exception was that IL-6-174 G/C polymorphism was correlated with worse outcome in non-adults in recessive model, co-dominant model (CC vs. GG) and allelic model, while trial sequential analysis revealed it could be a false positive result nevertheless.

Conclusions

IL-6-174 G/C polymorphism is not associated with the risk and mortality of sepsis. Trial sequential analysis showed that a large sample size was needed to get a more reliable result of the association between IL-6-174 G/C polymorphism and sepsis in non-adults.
Appendix
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Literature
1.
Goulden R, Hoyle MC, Monis J, et al. qSOFA, SIRS and NEWS for predicting inhospital mortality and ICU admission in emergency admissions treated as sepsis. Emerg Med J. 2018;35(6):345–9.PubMedCrossRef
2.
Singer M, Deutschman CS, Seymour CW, et al. The third international consensus definitions for Sepsis and septic shock (Sepsis-3). JAMA. 2016;315(8):801–10.PubMedPubMedCentralCrossRef
3.
Monneret G, Venet F. Sepsis-induced immune alterations monitoring by flow cytometry as a promising tool for individualized therapy. Cytometry B Clin Cytom. 2016;90(4):376–86.PubMedCrossRef
4.
5.
Chauhan N, Tiwari S, Jain U. Potential biomarkers for effective screening of neonatal sepsis infections: an overview. Microb Pathog. 2017;107:234–42.PubMedCrossRef
6.
Tanaka T, Narazaki M, Kishimoto T. Immunotherapeutic implications of IL-6 blockade for cytokine storm. Immunotherapy. 2016;8(8):959–70.PubMedCrossRef
7.
Cole SW, Arevalo JM, Takahashi R, et al. Computational identification of gene-social environment interaction at the human IL6 locus. Proc Natl Acad Sci U S A. 2010;107(12):5681–6.PubMedPubMedCentralCrossRef
8.
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.PubMedCrossRef
9.
Gao JW, Zhang AQ, Pan 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.PubMedPubMedCentralCrossRef
10.
Allam G, Alsulaimani AA, Alzaharani AK, Nasr A. Neonatal infections in Saudi Arabia: association with cytokine gene polymorphisms. Cent Eur J Immunol. 2015;40(1):68–77.PubMedPubMedCentralCrossRef
11.
Mao ZR, Zhang SL, Feng B. Association of IL-10 (−819T/C, −592A/C and -1082A/G) and IL-6-174G/C gene polymorphism and the risk of pneumonia-induced sepsis. Biomarkers. 2017;22(2):106–12.PubMedCrossRef
12.
Feng B, Mao ZR, Pang K, Zhang SL, Li L. Association of tumor necrosis factor alpha -308G/a and interleukin-6 -174G/C gene polymorphism with pneumonia-induced sepsis. J Crit Care. 2015;30(5):920–3.PubMedCrossRef
13.
Lorente L, Martin MM, Perez-Cejas A, et al. Association between Interleukin-6 Promoter Polymorphism (−174 G/C), Serum Interleukin-6 Levels and Mortality in Severe Septic Patients. Int J Mol Sci. 2016;17(11).pii: E1861.
14.
Jimenez-Sousa MA, Medrano LM, Liu P, et al. IL-6 rs1800795 polymorphism is associated with septic shock-related death in patients who underwent major surgery: a preliminary retrospective study. Ann Intensive Care. 2017;7(1):22.PubMedPubMedCentralCrossRef
15.
Zeng X, Zhang Y, Kwong JS, et al. The methodological quality assessment tools for preclinical and clinical studies, systematic review and meta-analysis, and clinical practice guideline: a systematic review. J Evid Based Med. 2015;8(1):2–10.PubMedCrossRef
16.
Harding D, Dhamrait S, Millar A, et al. Montgomery H. Is interleukin-6 -174 genotype associated with the development of septicemia in preterm infants? Pediatrics. 2003;112(4):800–3.PubMedCrossRef
17.
Barber RC, Aragaki CC, Rivera-Chavez FA, Purdue GF, Hunt JL, Horton JW. TLR4 and TNF-alpha polymorphisms are associated with an increased risk for severe sepsis following burn injury. J Med Genet. 2004;41(11):808–13.PubMedPubMedCentralCrossRef
18.
McDaniel DO, Hamilton J, Brock M, et al. Molecular analysis of inflammatory markers in trauma patients at risk of postinjury complications. J Trauma. 2007;63(1):147–58.PubMedCrossRef
19.
Accardo Palumbo A, Forte GI, Pileri D, et al. Analysis of IL-6, IL-10 and IL-17 genetic polymorphisms as risk factors for sepsis development in burned patients. Burns. 2012;38(2):208–13.PubMedCrossRef
20.
Carregaro F, Carta A, Cordeiro JA, Lobo SM, Silva EH, Leopoldino AM. Polymorphisms IL10-819 and TLR-2 are potentially associated with sepsis in brazilian patients. Mem Inst Oswaldo Cruz. 2010;105(6):649–56.PubMedCrossRef
21.
Gopel W, Hartel C, Ahrens P, et al. Interleukin-6-174-genotype, sepsis and cerebral injury in very low birth weight infants. Genes Immun. 2006;7(1):65–8.PubMedCrossRef
22.
23.
Yang MX, Feng K, Zhang HX, et al. Correlation between IL-6 gene polymorphisms and sepsis of Chinese Han population in Henan province. Med J Chin PLA. 2011;36(1):71–2.
24.
Shimada T, Oda S, Sadahiro T, et al. Outcome prediction in sepsis combined use of genetic polymorphisms - a study in Japanese population. Cytokine. 2011;54(1):79–84.PubMedCrossRef
25.
Shalhub S, Junker CE, Imahara SD, Mindrinos MN, Dissanaike S, O'Keefe GE. Variation in the TLR4 gene influences the risk of organ failure and shock posttrauma: a cohort study. J Trauma. 2009;66(1):115–23.PubMedPubMedCentralCrossRef
26.
Reiman M, Kujari H, Ekholm E, et al. Interleukin-6 polymorphism is associated with chorioamnionitis and neonatal infections in preterm infants. J Pediatr. 2008;153(1):19–24.PubMedCrossRef
27.
Tischendorf JJ, Yagmur E, Scholten D, 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.PubMedCrossRef
28.
Schlüter B, Raufhake C, Erren M, et al. Effect of the interleukin-6 promoter polymorphism (−174G/C) on the incidence and outcome of sepsis. Crit Care Med. 2002;30(1):32–7.PubMedCrossRef
29.
Balding J, Healy CM, Livingstone WJ, et al. Genomic polymorphic profiles in an Irish population with meningococcaemia: is it possible to predict severity and outcome of disease? Genes Immun. 2003;4(8):533–40.PubMedCrossRef
30.
Treszl A, Kocsis I, Szathmari M, et al. Genetic variants of TNF-[FC12] a, IL-1beta, IL-4 receptor [FC12]a-chain, IL-6 and IL-10 genes are not risk factors for sepsis in low-birth-weight infants. Biol Neonate. 2003;83(4):241–5.PubMedCrossRef
31.
Ahrens P, Kattner E, Kohler B, 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.PubMedCrossRef
32.
Michalek J, Svetlikova P, Fedora M, et al. Interleukin-6 gene variants and the risk of sepsis development in children. Hum Immunol. 2007;68(9):756–60.PubMedCrossRef
33.
Sipahi T, Pocan H, Akar N. Effect of various genetic polymorphisms on the incidence and outcome of severe sepsis. Clin Appl Thromb Hemost. 2006;12(1):47–54.PubMedCrossRef
34.
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.PubMedPubMedCentralCrossRef
35.
Sabeļnikovs O, Ñikitina-Zaķe L, Vanags I. Association of Interleukin 6 promoter polymorphism (−174G/C) with IL-6 level and outcome in severe Sepsis. Proceedings of the Latvian Academy of Sciences Section B Natural, Exact, and Applied Sciences. 2008;62(4–5):162–4.CrossRef
36.
Sole-Violan J, de Castro F, Garcia-Laorden MI, et al. Genetic variability in the severity and outcome of community-acquired pneumonia. Respir Med. 2010;104(3):440–7.PubMedCrossRef
37.
Davis SM, Clark EA, Nelson LT, Silver RM. The association of innate immune response gene polymorphisms and puerperal group A streptococcal sepsis. Am J Obstet Gynecol. 2010;202(3):308.e1–8.CrossRef
38.
Watanabe E, Zehnbauer BA, Oda S, Sato Y, Hirasawa H, Buchman TG. Tumor necrosis factor −308 polymorphism (rs1800629) is associated with mortality and ventilator duration in 1057 Caucasian patients. Cytokine. 2012;60(1):249–56.PubMedPubMedCentralCrossRef
39.
Martin-Loeches I, Sole-Violan J. Rodriguez de Castro F, et al. variants at the promoter of the interleukin-6 gene are associated with severity and outcome of pneumococcal community-acquired pneumonia. Intensive Care Med. 2012;38(2):256–62.PubMedCrossRef
40.
Abdel-Hady H, El-Naggar M, El-Nady G, Badr R, El-Daker M. Genetic polymorphisms of IL-6–174 and IL-10–1082 in full term neonates with late onset blood stream infections. J Pediatr Infect Dis. 2009;4:357–65.
41.
Fishman D, Faulds G, Jeffery R, et al. The effect of novel polymorphisms in the interleukin-6 (IL-6) gene on IL-6 transcription and plasma IL-6 levels, and an association with systemic-onset juvenile chronic arthritis. J Clin Invest. 1998;102(7):1369–76.PubMedPubMedCentralCrossRef
42.
Terry CF, Loukaci V, Green FR. Cooperative influence of genetic polymorphisms on interleukin 6 transcriptional regulation. J Biol Chem. 2000;275(24):18138–44.PubMedCrossRef
43.
Kilpinen S, Hulkkonen J, Wang XY, Hurme M. The promoter polymorphism of the interleukin-6 gene regulates interleukin-6 production in neonates but not in adults. Eur Cytokine Netw. 2001;12(1):62–8.PubMed
44.
Starr ME, Saito M, Evers BM, Saito H. Age-associated increase in cytokine production during systemic inflammation—II: the role of IL-1β in age-dependent IL-6 upregulation in adipose tissue. J Gerontol Ser A Biol Med Sci. 2015;70(12):1508–15.CrossRef
45.
46.
Lim CS, Zheng S, Kim YS, et al. The −174 G to C polymorphism of interleukin-6 gene is very rare in Koreans. Cytokine. 2002;19(1):52–4.PubMedCrossRef
47.
Zhai R, Liu G, Yang C, Huang C, Wu C, Christiani DC. The G to C polymorphism. at −174 of the interleukin-6 gene is rare in a Southern Chinese population. Pharmacogenetics. 2001;11(8):699–701.PubMedCrossRef
Metadata
Title
The association between interleukin-6 gene -174G/C single nucleotide polymorphism and sepsis: an updated meta-analysis with trial sequential analysis
Authors
Yao Chen
Yanyan Hu
Zhenju Song
Publication date
01-12-2019
Publisher
BioMed Central
Published in
BMC Medical Genetics / Issue 1/2019
Electronic ISSN: 1471-2350
DOI
https://doi.org/10.1186/s12881-019-0766-2

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