Home About us Editorial board Ahead of print Current issue Archives Submit article Instructions Advertise Search Subscribe Contacts Login 
  • Users Online: 40
  • Home
  • Print this page
  • Email this page


 
 Table of Contents  
REVIEW ARTICLE
Year : 2014  |  Volume : 1  |  Issue : 1  |  Page : 8-15

Sepsis genomics: Stepping forward toward sepsis prevention?


1 Department of Pediatrics, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Puducherry, India
2 Department of Microbiology, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Puducherry, India

Date of Web Publication13-Jun-2014

Correspondence Address:
Dr. Ballambattu Vishnu Bhat
Department of Pediatrics, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Puducherry - 605 006
India
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2349-4220.134444

Get Permissions

  Abstract 

The era of personalized medicine has already begun and now it is time to initiate personalized prevention strategies against diseases. Infectious diseases have a higher mortality than any other illness, especially in developing countries. Among newborns and young children the situation is even worse. The microorganisms are becoming resistant to almost all known antibiotics. Hence, it is imperative to improve the preventive strategies against infections. 'Pathogens are everywhere, but not every individual is getting diseased,' - this basic logical thinking needs to look into the genetic predisposition/host susceptibility to sepsis. Interestingly, genetic studies have shown that the type of infecting organism, outcome of infections, and mortality can be predetermined by analyzing an individual's genome. Exploration of inter-individual genetic variations and their association with sepsis will help in the development of new prognostic markers to provide novel personalized therapeutics and predict the outcome. In this review article, we discuss the genetic variations and their association with sepsis, studied by various researchers in different regions.

Keywords: Diagnostic, genetic association, genomics, prognostic marker, sepsis


How to cite this article:
Dhas BB, Ashmi H, Bhat BV. Sepsis genomics: Stepping forward toward sepsis prevention?. Int J Adv Med Health Res 2014;1:8-15

How to cite this URL:
Dhas BB, Ashmi H, Bhat BV. Sepsis genomics: Stepping forward toward sepsis prevention?. Int J Adv Med Health Res [serial online] 2014 [cited 2019 Aug 22];1:8-15. Available from: http://www.ijamhrjournal.org/text.asp?2014/1/1/8/134444


  Introduction Top


Genetic risk factors are the recent prognostic/diagnostic markers that save numerous lives from various diseases like cancer. Sepsis susceptibility and outcome are predictable by decoding the genomics of an individual. Although several confounding factors are involved in sepsis progression and mortality, the host immune response to infections is based on the genetic nature of each individual. Genetic association studies have shown that sepsis susceptibility, mortality, and even the type of infecting pathogen are associated with genetic variations. This article provides insights into the genomics associated with sepsis and its applicability in clinical practice.

Candidate gene polymorphisms

For more than a decade, the candidate genes involved in the pathophysiology of sepsis have been analyzed for the association of their single-nucleotide polymorphisms (SNPs) with sepsis and its outcome, like multiple organ dysfunction (MOD), shock, and mortality.

Tumor necrosis factor

Among the most studied cytokine polymorphisms, the tumor necrosis factor alpha (TNF-α) polymorphism has drawn more attention from genomic researchers, especially the 308 G/A polymorphism. Although the polymorphism has been studied very descriptively, yet its association with sepsis remains uncertain. Several studies have claimed that TNF-α-308A is associated with sepsis susceptibility and mortality. However, some studies have shown no association with either susceptibility or outcome or both. [1],[2],[3] Other than 308G/A, SNPs like 238G/A, 376G/A, +489G/A, and -863C/A were also studied. [Table 1] highlights some TNF-α polymorphisms associated with sepsis.
Table 1: TNF-α polymorphisms associated with sepsis and its outcome

Click here to view


Phumeetham et al., have found no association of the TNF-α (-308) polymorphism with sepsis/septic shock in Thai pediatric patients. [17] Contrastingly, a significant association was found between these in Brazilian pediatric patients by Azevedo et al.[7]

The NcO1 TNFB1/B2 polymorphism in the tumor necrosis factor beta (TNF-β) gene was analyzed in post-traumatic patients, and it was found that the homozygous TNFB2 is associated with severe sepsis. [18] Further studies are required to identify the significance of TNF polymorphisms in clinical situations.

Interleukins

Interleukins include both pro- and anti- inflammatory cytokines. IL-1β may lead to septic shock and organ failure and serves as a primary mediator of systemic inflammatory response syndrome (SIRS). [19] IL-6 acts as a potential diagnostic marker for infections. IL-10, an anti-inflammatory cytokine, also plays a significant role in the inflammatory pathway of sepsis. Variations in the structure of these genes may lead to altered gene expression, which may result in the modification of the host immune system. Some of the interleukin polymorphisms are tabulated below [Table 2].
Table 2: Interleukin polymorphisms associated with sepsis

Click here to view


An in vitro study by Kang et al., has shown that -1082G > A of IL-10 interacts with the nuclear protein, PARP-1 (Poly ADP-ribose polymerase I), which is a transcription repressor and regulates the production of IL-10. [36]

Toll-like receptors

Toll-like receptors act as sensors against pathogen invasion, triggering the host's immune response. They also play the role of receptors for endogenous ligands that may lead to tissue damage. [37] Changes in toll-like receptor (TLR) expression may cause favorable/adverse effects in the host immune response. Polymorphism in TLRs has been studied in various populations, yet its functional significance in sepsis remains unexplored. TLR4 polymorphisms and their association with sepsis have given more conflicting results, in particular the SNPs, Asp299Gly (+896 A/G) and Thr399Ile (+1196 C/T). In [Table 3], we have listed some of the polymorphisms analyzed in TLRs associated with sepsis.
Table 3: TLR polymorphisms associated with sepsis

Click here to view


In contrast to the above discussed studies [Table 3], Shan et al., did not find any association of TLR4 (Asp299Gly and Thr399Ile) polymorphisms with sepsis, but suggested a large study on the TLR2 Arg753Gln polymorphism among Chinese Han children. [47] A meta-analysis that included 17 studies in the Caucasian population, with a total of 2,212 cases and 3,880 controls showed that TLR4 polymorphisms, Asp299Gly and Thr399Ile, were not associated with sepsis susceptibility. [48] In vitro studies by Fiqueroa et al., showed that D299G TLR4 polymorphism interfered with TLR4 dimerization and assembly of intracellular docking platforms for recruitment of adapters like MyD88 and TRIF. [49]

Apart from TLRs, other receptors like CD14 also play a major role in innate immunity during sepsis. CD14 along with TLR4 and MD2 forms the lipopolysaccharide (LPS) receptor complex. [50] Polymorphic variants in CD14 and other cell surface receptors are given in [Table 4].
Table 4: Association of SNPs in cell surface receptors with sepsis

Click here to view


FcgammaRIIA polymorphisms are widely studied in association with the antibody response in pneumonia, [54] malaria, [55] autoimmune diseases like systemic lupus erythematosus (SLE), [52] and inflammatory diseases like rheumatoid arthritis. [56] As the cell surface receptors play a vital role in the triggering of infection and molecular mechanism of the inflammatory pathway, polymorphism in its genetic structure may lead to significant alterations in disease conditions.

Recently studied single-nucleotide polymorphisms and their association with sepsis

Genetic studies related to sepsis have been found in abundance during recent years. The research is now extended to the genes, other than the innate immunity genes. Apart from the generally studied genes like TNF-α, and interleukins, tremendous knowledge has been created about other associated genes by recent studies. This shows the rapid and vigorous growth of genomics and its applicability in clinical settings. In [Table 5], we have listed the polymorphisms analyzed in the last three years, in the different protein molecules involved in sepsis pathophysiology.
Table 5: Association of various SNPs with sepsis and its outcome

Click here to view


Haplotype tagging single-nucleotide polymorphisms

Tag SNPs are single nucleotide polymorphisms that are non-randomly associated with alleles at other loci in the chromosome. Analysis of Tag SNP reduces the burden of studying each individual SNP separately, and is highly beneficial in genetic association studies that use whole-genome sequencing. Tag SNPs are usually identified using the HapMap database by Linkage Disequilibrium analysis or PHASE (software used to reconstruct haplotype and estimation of the recombination rate).

Tag SNPs or htSNPs (haplotype tagging SNPs) in the MD-2 gene was studied by Zeng et al., in two different populations in China (Chongqing in southwestern China and Zhejiang in eastern China), using the pyrosequencing method. They found three SNPs, rs7843858, rs11465996, and rs2114169, to be htSNPs, but only rs11465996 was associated with sepsis susceptibility and multiple organ dysfunction syndrome (MODS) in both populations. [81] Out of the three htSNPs (rs1898830, rs3804099, and rs7656411) for the TLR2 gene, only rs3804099 was significantly associated with sepsis morbidity and MODS. [82]

Chen et al., analyzed two functional polymorphisms −1641A/G and −1654C/T in the Protein C gene and found that the haplotype −1641A/−1654C was associated with organ dysfunction and outcome of sepsis in the Chinese Han population. [83] Haplotype −20A/−44C/−52G in DEFB1 served as a protection factor for severe sepsis in the Chinese population, in contrast, the −20G/−44G/−52G haplotype was a risk factor for adverse outcomes. [84] In Caucasian patients with sepsis, haplotype GAA of the Fibrinogen-beta-gene (htSNPS: −854 G/A,455 G/A, and +9006 G/A) was found to be associated with reduced mortality and reduced severity of organ dysfunction. [85] In contrast, the haplotype - 592C/734G/3367G of the IL-10 gene is associated with increased mortality and organ dysfunction in patients with sepsis and pneumonia. [86]

Haplogroups

Haplogroups are used to define genetic populations, with similar haplotypes having the same SNPs. Y-chromosome (Y-DNA) haplogroups and mitochondrial DNA (mtDNA) haplogroups are the widely known haplogroups. Haplogroups have a common ancestor and are restricted to geographical locations. Identification of a single SNP and its association with a disease in a haplogroup serves as a prognostic marker for the entire population.

Yang et al. found that the mtDNA haplogroup R can be used to predict the outcome of septic encephalopathy in the Chinese Han population. The R haplogroup delivers high probability of neurological recovery, when compared to the non-R haplogroup. [87] Previously in the same population, they had found that the R haplogroup was a predictor of sepsis outcome and was associated with long-term survival in sepsis patients. [88] The MHC haplotype, AH8.1, was found to confer a protective effect toward septic shock in chronic obstructive pulmonary disease (COPD) patients, in the Caucasian population. [89] Baudouin et al., showed that the mtDNA haplogroup H is a predictor of the outcome and is associated with 180 days of survival in European patients with severe sepsis. [90]

Tandem repeats or microsatellites

Tandem repeats are the repetition of two or more nucleotides and are adjacent to each other. When two to six nucleotides are repeated, it is called microsatellites or short tandem repeats. Microsatellite instability, which is caused by a defect in the DNA mismatch repair may act as a significant risk factor for diseases like cancer [91] and schizophrenia. [92] In sepsis, microsatellites in genes like HMOX1, [65] TNFα and β, [93] eNOS, [94] and IL-10,[95] were studied. Flores et al., showed association of the CXCL2 -665(AC)n microsatellite with sepsis susceptibility in the Spanish population. [96]

Copy number variations

Copy Number Variations (CNVs) are found throughout the human genome. CNVs may alter gene expression by causing a variation in the number of gene copies. CNVs are significant in assessing risk for diseases like cancer and human deficiency virus (HIV). [97] Chen et al., studied CNVs in DEFA1/DEFA3 among post-traumatic sepsis patients and found that the high copy number of DEFA1/DEFA3 (>8) is associated with severe sepsis. [98] In contrast, no association was found in DEFB4/DEFB103 copy numbers (2 to 9) with the Staphylococcus aureus sepsis. [99] Apart from these two studies, no other study is available with regard to CNVs in relation to sepsis. More research is necessary to confirm CNVs as prognostic markers of sepsis.

Epigenomics: The next?

Before experiencing the entire sweetness of genomics, researchers cracked out a new concept, 'Epigenomics,' which may explain the host's non-genetic risk factors that alter disease conditions, via modifying the underlying gene expression. DNA methylation and Histone modification are the two major processes involved in epigenomics. MicroRNAs (miRNAs) also play a vital role in epigenetic processes.

Immunosuppression that follows severe sepsis is regulated by immune-related genes. The expression of these genes can be modified by histone acetylation/methylation. Repressive histone methylation has been found in the promoter region of IFN-γ and GATA-3 transcription factors the in naïve CD4+ T-cells, in sepsis mice models. [100] Histone acetylation is controlled by histone acetylases and histone deacetylases (HDACs). Studies performed by Li et al., revealed that septic shock caused hypoacetylation of nuclear proteins, can be reversed by administering HDAC inhibitors (HDACI). The HDACIs prevented cell death, reduced inflammation, and eventually improved survival of the animal models in septic shock. [101] An in vitro study by Gazzar et al., showed that silencing of TNF-α expression during endotoxin tolerance occurs by the combined action of H3K9 methylation and CpG (TNF-α promoter) methylation. H3 histone is methylated on lysine 9 by histone methyltransferase, G9a. TNF-α promoter CpG methylation is catalyzed by Dnmt3a/b (DNA methyltransferases) and HP1 (Heterochromatin protein 1). [102]

The role of miRNAs in the diagnosis of sepsis was very clearly stated in the recent studies. In particular, miR-146a and miR-223 are significant prognostic/diagnostic markers of sepsis. [103],[104] Some other significant miRNAs are miR-150, [103],[105] miR-499-5p, [106] miR-15a, and miR-16. [107] These potential biomarkers are also capable of distinguishing sepsis from the systemic inflammatory response syndrome.

Future direction for sepsis genomics studies

Lack of potential diagnostic or prognostic markers for sepsis makes it a dreadful disease, which holds the highest mortality. Genetic association studies build up hope for newer diagnostic/prognostic methods in the treatment of sepsis. In this modern era, a large number of small scale researches have been done on the genetic association of sepsis. The sensitivity and specificity to use genetic variations as prognostic markers is yet to be determined. Large-scale studies like Genome Wide Association Studies have already begun and started cracking this hurdle. Multicentric studies are required to understand the significance of genetic variations in different populations. The bridge between bench to bedside has to be built to put genetic associations into clinical practice. For overcoming such obstacles, hopefully, sepsis genomics will help us in directing treatment against infectious pathogens and possibly the eradication of sepsis.

 
  References Top

1.Gordon AC, Lagan AL, Aganna E, Cheung L, Peters CJ, McDermott MF, et al. TNF and TNFR polymorphisms in severe sepsis and septic shock: A prospective multicentre study. Genes Immun 2004;5:631-40.  Back to cited text no. 1
    
2.Garnacho-Montero J, Aldabo-Pallas T, Garnacho-Montero C, Cayuela A, Jiménez R, Barroso S, et al. Timing of adequate antibiotic therapy is a greater determinant of outcome than are TNF and IL-10 polymorphisms in patients with sepsis. Crit Care 2006;10:R111.  Back to cited text no. 2
    
3.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;90:229-32.  Back to cited text no. 3
    
4.Kothari N, Bogra J, Abbas H, Kohli M, Malik A, Kothari D, et al. Tumor necrosis factor gene polymorphism results in high TNF level in sepsis and septic shock. Cytokine 2013;61:676-81.  Back to cited text no. 4
    
5.Song Z, Song Y, Yin J, Shen Y, Yao C, Sun Z, et al. Genetic variation in the TNF gene is associated with susceptibility to severe sepsis, but not with mortality. PLoS One 2012;7:e46113.  Back to cited text no. 5
    
6.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;60:249-56.  Back to cited text no. 6
    
7.Azevedo ZM, Moore DB, Lima FC, Cardoso CC, Bougleux R, Matos GI, et al. Tumor necrosis factor (TNF) and lymphotoxin-alpha (LTA) single nucleotide polymorphisms: Importance in ARDS in septic pediatric critically ill patients. Hum Immunol 2012;73:661-7.  Back to cited text no. 7
    
8.Shimada T, Oda S, Sadahiro T, Nakamura M, Hirayama Y, Watanabe E, et al. Outcome prediction in sepsis combined use of genetic polymorphisms - a study in Japanese population. Cytokine 2011;54:79-84.  Back to cited text no. 8
    
9.Surbatovic M, Grujic K, Cikota B, Jevtic M, Filipovic N, Romic P, et al. Polymorphisms of genes encoding tumor necrosis factor-alpha, interleukin-10, cluster of differentiation-14 and interleukin-1ra in critically ill patients. J Crit Care 2010;25:542.e1-8.  Back to cited text no. 9
    
10.Teuffel O, Ethier MC, Beyene J, Sung L. Association between tumor necrosis factor-alpha promoter −308 A/G polymorphism and susceptibility to sepsis and sepsis mortality: A systematic review and meta-analysis. Crit Care Med 2010;38:276-82.  Back to cited text no. 10
    
11.Duan ZX, Gu W, Zhang LY, Jiang DP, Zhou J, Du DY, et al. Tumor necrosis factor alpha gene polymorphism is associated with the outcome of trauma patients in Chinese Han population. J Trauma 2011;70:954-8.  Back to cited text no. 11
    
12.Shalhub S, Pham TN, Gibran NS, O'keefe GE. Tumor necrosis factor gene variation and the risk of mortality after burn injury: A cohort study. J Burn Care Res 2009;30:105-11.  Back to cited text no. 12
    
13.Hedberg CL, Adcock K, Martin J, Loggins J, Kruger TE, Baier RJ. Tumor necrosis factor alpha −308 polymorphism associated with increased sepsis mortality in ventilated very low birth weight infants. Pediatr Infect Dis J 2004;23:424-8.  Back to cited text no. 13
    
14.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;41:808-13.  Back to cited text no. 14
    
15.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 interleukine-10 gene polymorphisms on clinical outcome in Japanese critically ill patients. J Surg Res 2005;129:322-8.  Back to cited text no. 15
    
16.Pappachan JV, Coulson TG, Child NJ, Markham DJ, Nour SM, Pulletz MC, et al. Mortality in adult intensive care patients with severe systemic inflammatory response syndromes is strongly associated with the hypo-immune TNF −238A polymorphism. Immunogenetics 2009;61:657-62.  Back to cited text no. 16
    
17.Phumeetham S, Chat-Uthai N, Manavathongchai M, Viprakasit V. Genetic association study of tumor necrosis factor-alpha with sepsis and septic shock in Thai pediatric patients. J Pediatr (Rio J) 2012;88:417-22.  Back to cited text no. 17
    
18.Majetschak M, Flohé S, Obertacke U, Schröder J, Staubach K, Nast-Kolb D, et al. Relation of a TNF gene polymorphism to severe sepsis in trauma patients. Ann Surg 1999;230:207-14.  Back to cited text no. 18
    
19.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.  Back to cited text no. 19
    
20.Wan QQ, Ye QF, Ma Y, Zhou JD. Genetic association of interleukin-1β (−511C/T) and its receptor antagonist (86-bpVNTR) gene polymorphism with susceptibility to bacteremia in kidney transplant recipients. Transplant Proc 2012;44:3026-8.  Back to cited text no. 20
    
21.Gu W, Zeng L, Zhang LY, Jiang DP, Du DY, Hu P, et al. Association of interleukin 4 −589T/C polymorphism with T(H)1 and T(H)2 bias and sepsis in Chinese major trauma patients. J Trauma 2011;71:1583-7.  Back to cited text no. 21
    
22.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;36:1437-43.  Back to cited text no. 22
    
23.Michalek J, Svetlikova P, Fedora M, Klimovic M, Klapacova L, Bartosova D, et al. Interleukin-6 gene variants and the risk of sepsis development in children. Hum Immunol 2007;68:756-60.  Back to cited text no. 23
    
24.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;34:413-8.  Back to cited text no. 24
    
25.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;30:32-7.  Back to cited text no. 25
    
26.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.  Back to cited text no. 26
    
27.Wacharasint P, Nakada TA, Boyd JH, Russell JA, Walley KR. AA genotype of IL-8 −251A/T is associated with low PaO(2)/FiO(2) in critically ill patients and with increased IL-8 expression. Respirology 2012;17:1253-60.  Back to cited text no. 27
    
28.Abu-Maziad A, Schaa K, Bell EF, Dagle JM, Cooper M, Marazita ML, et al. Role of polymorphic variants as genetic modulators of infection in neonatal sepsis. Pediatr Res 2010;68:323-9.  Back to cited text no. 28
    
29.Accardo Palumbo A, Forte GI, Pileri D, Vaccarino L, Conte F, D'Amelio L, et al. Analysis of IL-6, IL-10 and IL-17 genetic polymorphisms as risk factors for sepsis development in burned patients. Burns 2012;38:208-13.  Back to cited text no. 29
    
30.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;32:260-6.  Back to cited text no. 30
    
31.Shu Q, Fang X, Chen Q, Stuber F. IL-10 polymorphism is associated with increased incidence of severe sepsis. Chin Med J (Engl) 2003;116:1756-9.  Back to cited text no. 31
    
32.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;105:649-56.  Back to cited text no. 32
    
33.Lowe PR, Galley HF, Abdel-Fattah A, Webster NR. Influence of interleukin-10 polymorphisms on interleukin-10 expression and survival in critically ill patients. Crit Care Med 2003;31:34-8.  Back to cited text no. 33
    
34.Nakada TA, Russell JA, Boyd JH, Walley KR. IL17A genetic variation is associated with altered susceptibility to Gram-positive infection and mortality of severe sepsis. Crit Care 2011;15:R254.  Back to cited text no. 34
    
35.Cai LL, Xiang W, Xie YQ, Liao F, Feng XW, Zhang DF, et al. Correlations between serum interleukin-18 (IL-18) level, IL-18 gene promoter polymorphisms and the development of sepsis in children. Zhonghua Er Ke Za Zhi 2010;48:9-14.  Back to cited text no. 35
    
36.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;184:3718-24.  Back to cited text no. 36
    
37.Tsujimoto H, Ono S, Efron PA, Scumpia PO, Moldawer LL, Mochizuki H. Role of Toll-like receptors in the development of sepsis. Shock 2008;29:315-21.  Back to cited text no. 37
    
38.Plantinga TS, Johnson MD, Scott WK, van de Vosse E, Velez Edwards DR, Smith PB, et al. Toll-like receptor 1 polymorphisms increase susceptibility to candidemia. J Infect Dis 2012;205:934-43.  Back to cited text no. 38
    
39.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;33:638-44.  Back to cited text no. 39
    
40.Woehrle T, Du W, Goetz A, Hsu HY, Joos TO, Weiss M, et al. Pathogen specific cytokine release reveals an effect of TLR2 Arg753Gln during Candida sepsis in humans. Cytokine 2008;41:322-9.  Back to cited text no. 40
    
41.Duan ZX, Gu W, Zhang LY, Du DY, Hu P, Huang J, et al. Clinical relevance of the TLR4 11367 polymorphism in patients with major trauma. Arch Surg 2009;144:1144-8.  Back to cited text no. 41
    
42.Yuan FF, Marks K, Wong M, Watson S, de Leon E, McIntyre PB, et al. Clinical relevance of TLR2, TLR4, CD14 and FcgammaRIIA gene polymorphisms in Streptococcus pneumoniae infection. Immunol Cell Biol 2008;86:268-70.  Back to cited text no. 42
    
43.Lorenz E, Mira JP, Frees KL, Schwartz DA. Relevance of mutations in the TLR4 receptor in patients with gram-negative septic shock. Arch Intern Med 2002;162:1028-32.  Back to cited text no. 43
    
44.Agnese DM, Calvano JE, Hahm SJ, Coyle SM, Corbett SA, Calvano SE, et al. Human toll-like receptor 4 mutations but not CD14 polymorphisms are associated with an increased risk of gram-negative infections. J Infect Dis 2002;186:1522-5.  Back to cited text no. 44
    
45.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;17:29-34.  Back to cited text no. 45
    
46.Chen KH, Zeng L, Gu W, Zhou J, Du DY, Jiang JX. Polymorphisms in the toll-like receptor 9 gene associated with sepsis and multiple organ dysfunction after major blunt trauma. Br J Surg 2011;98:1252-9.  Back to cited text no. 46
    
47.Shan XO, Wu Y, Ye J, Ding ZY, Qian C, Zhou AH. Gene polymorphisms of Toll-like receptors in Chinese Han children with sepsis in Wenzhou. Zhonghua Er Ke Za Zhi 2010;48:15-8.  Back to cited text no. 47
    
48.Zhu L, Li X, Miao C. Lack of association between TLR4 Asp299Gly and Thr399Ile polymorphisms and sepsis susceptibility: A meta-analysis. Gene 2012;501:213-8.  Back to cited text no. 48
    
49.Figueroa L, Xiong Y, Song C, Piao W, Vogel SN, Medvedev AE. The Asp299Gly polymorphism alters TLR4 signaling by interfering with recruitment of MyD88 and TRIF. J Immunol 2012;188:4506-15.  Back to cited text no. 49
    
50.Wright SD, Ramos RA, Tobias PS, Ulevitch RJ, Mathison JC. CD14, a receptor for complexes of lipopolysaccharide (LPS) and LPS binding protein. Science 1990;249:1431-3.  Back to cited text no. 50
    
51.Yuan FF, Wong M, Pererva N, Keating J, Davis AR, Bryant JA, et al. FcgammaRIIA polymorphisms in Streptococcus pneumoniae infection. Immunol Cell Biol 2003;81:192-5.  Back to cited text no. 51
    
52.Yuan H, Pan HF, Li LH, Feng JB, Li WX, Li XP, et al. Meta analysis on the association between FcgammaRIIa-R/H131 polymorphisms and systemic lupus erythematosus. Mol Biol Rep 2009;36:1053-8.  Back to cited text no. 52
    
53.Barber RC, Chang LY, Arnoldo BD, Purdue GF, Hunt JL, Horton JW, et al. Innate immunity SNPs are associated with risk for severe sepsis after burn injury. Clin Med Res 2006;4:250-5.  Back to cited text no. 53
    
54.Endeman H, Cornips MC, Grutters JC, van den Bosch JM, Ruven HJ, van Velzen-Blad H, et al. The Fcgamma receptor IIA-R/R131 genotype is associated with severe sepsis in community-acquired pneumonia. Clin Vaccine Immunol 2009;16:1087-90.  Back to cited text no. 54
    
55.Nasr A, Iriemenam NC, Troye-Blomberg M, Giha HA, Balogun HA, Osman OF, et al. Fc gamma receptor IIa (CD32) polymorphism and antibody responses to asexual blood-stage antigens of Plasmodium falciparum malaria in Sudanese patients. Scand J Immunol 2007;66:87-96.  Back to cited text no. 55
    
56.Meziani R, Yamada R, Takahashi M, Ohigashi K, Morinobu A, Terao C, et al. A trans-ethnic genetic study of rheumatoid arthritis identified FCGR2A as a candidate common risk factor in Japanese and European populations. Mod Rheumatol 2012;22:52-8.  Back to cited text no. 56
    
57.Cardinal-Fernández P, Ferruelo A, El-Assar M, Santiago C, Gómez-Gallego F, Martín-Pellicer A, et al. Genetic predisposition to acute kidney injury induced by severe sepsis. J Crit Care 2013;28:365-70.  Back to cited text no. 57
    
58.Dong GH, Gong JP, Li JZ, Luo YH, Li ZD, Li PZ, et al. Association between gene polymorphisms of IRAK-M and the susceptibility of sepsis. Inflammation 2013;36:1087-93.  Back to cited text no. 58
    
59.Fang Y, Zhang L, Zhou GQ, Wang ZF, Zeng ZS, Luo ZY, et al. Functional polymorphism in exon 5 and variant haplotype of the interleukin-1 receptor-associated kinase 1 gene are associated with susceptibility to and severity of sepsis in the Chinese population. Chin Med J (Engl) 2011;124:2248-53.  Back to cited text no. 59
    
60.Zhao Y, Tao L, Jiang D, Chen X, Li P, Ning Y, et al. The −144C/A polymorphism in the promoter of HSP90beta is associated with multiple organ dysfunction scores. PLoS One 2013;8:e58646.  Back to cited text no. 60
    
61.Cardinal-Fernández P, Ferruelo A, El-Assar M, Santiago C, Gómez-Gallego F, Martín-Pellicer A, et al. Genetic predisposition to acute respiratory distress syndrome in patients with severe sepsis. Shock 2013;39:255-60.  Back to cited text no. 61
    
62.Adamzik M, Schäfer S, Frey UH, Becker A, Kreuzer M, Winning S, et al. The NFKB1 promoter polymorphism (-94ins/delATTG) alters nuclear translocation of NF-êB1 in monocytes after lipopolysaccharide stimulation and is associated with increased mortality in sepsis. Anesthesiology 2013;118:123-33.  Back to cited text no. 62
    
63.Wang Z, Feng K, Yue M, Lu X, Zheng Q, Zhang H, et al. A non-synonymous SNP in the NOS2 associated with septic shock in patients with sepsis in Chinese populations. Hum Genet 2013;132:337-46.  Back to cited text no. 63
    
64.Paludo FJ, Picanço JB, Fallavena PR, Fraga Lda R, Graebin P, Nóbrega Ode T, et al. Higher frequency of septic shock in septic patients with the 47C allele (rs4880) of the SOD2 gene. Gene 2013;517:106-11.  Back to cited text no. 64
    
65.Sponholz C, Huse K, Kramer M, Giamarellos-Bourboulis EJ, Claus RA, Kern A, et al. Gene polymorphisms in the heme degradation pathway and outcome of severe human sepsis. Shock 2012;38:459-65.  Back to cited text no. 65
    
66.Liu Y, Shao Y, Yu B, Sun L, Lv F. Association of PBEF gene polymorphisms with acute lung injury, sepsis, and pneumonia in a northeastern Chinese population. Clin Chem Lab Med 2012;50:1917-22.  Back to cited text no. 66
    
67.Song Z, Yao C, Yin J, Tong C, Zhu D, Sun Z, et al. Genetic variation in the TNF receptor-associated factor 6 gene is associated with susceptibility to sepsis-induced acute lung injury. J Transl Med 2012;10:166.  Back to cited text no. 67
    
68.Su L, Liu C, Li C, Jiang Z, Xiao K, Zhang X, et al. Dynamic changes in serum soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) and its gene polymorphisms are associated with sepsis prognosis. Inflammation 2012;35:1833-43.  Back to cited text no. 68
    
69.Frank AJ, Sheu CC, Zhao Y, Chen F, Su L, Gong MN, et al. BCL2 genetic variants are associated with acute kidney injury in septic shock. Crit Care Med 2012;40:2116-23.  Back to cited text no. 69
    
70.Weiss SL, Yu M, Jennings L, Haymond S, Zhang G, Wainwright MS. Pilot study of the association of the DDAH2 −449G polymorphism with asymmetric dimethylarginine and hemodynamic shock in pediatric sepsis. PLoS One 2012;7:e33355.  Back to cited text no. 70
    
71.Tekin D, Dalgic N, Kayaalti Z, Soylemezoglu T, Diler B, Kutlubay BI. Importance of NOD2/CARD15 gene variants for susceptibility to and outcome of sepsis in Turkish children. Pediatr Crit Care Med 2012;13:e73-7.  Back to cited text no. 71
    
72.Zeng L, Gu W, Zhang AQ, Zhang M, Zhang LY, Du DY, et al. A functional variant of lipopolysaccharide binding protein predisposes to sepsis and organ dysfunction in patients with major trauma. Ann Surg 2012;255:147-57.  Back to cited text no. 72
    
73.Zeng L, Zhang AQ, Gu W, Chen KH, Jiang DP, Zhang LY, et al. Clinical relevance of single nucleotide polymorphisms of the high mobility group box 1 protein gene in patients with major trauma in southwest China. Surgery 2012;151:427-36.  Back to cited text no. 73
    
74.Özkan H, Köksal N, Çetinkaya M, Kiliç ª, Çelebi S, Oral B, et al . Serum mannose-binding lectin (MBL) gene polymorphism and low MBL levels are associated with neonatal sepsis and pneumonia. J Perinatol 2012;32:210-7.  Back to cited text no. 74
    
75.Zhang AQ, Zeng L, Gu W, Zhang LY, Zhou J, Jiang DP, et al. Clinical relevance of single nucleotide polymorphisms within the entire NLRP3 gene in patients with major blunt trauma. Crit Care 2011;15:R280.  Back to cited text no. 75
    
76.Adamzik M, Frey UH, Möhlenkamp S, Scherag A, Waydhas C, Marggraf G, et al. Aquaporin 5 gene promoter −1364A/C polymorphism associated with 30-day survival in severe sepsis. Anesthesiology 2011;114:912-7.  Back to cited text no. 76
    
77.Nakada TA, Russell JA, Boyd JH, McLaughlin L, Nakada E, Thair SA, et al. Association of angiotensin II type 1 receptor-associated protein gene polymorphism with increased mortality in septic shock. Crit Care Med 2011;39:1641-8.  Back to cited text no. 77
    
78.Tiancha H, Huiqin W, Jiyong J, Jingfen J, Wei C. Association between lymphotoxin-α intron +252 polymorphism and sepsis: A meta-analysis. Scand J Infect Dis 2011;43:436-47.  Back to cited text no. 78
    
79.Ma P, Zhu Y, Qiu H, Liu J, Wang Y, Zeng L. Endothelial nitric oxide synthase 894G→T but not −786T→C gene polymorphism is associated with organ dysfunction and increased mortality in patients with severe sepsis. J Trauma 2011;71:872-7.  Back to cited text no. 79
    
80.Nakada TA, Russell JA, Wellman H, Boyd JH, Nakada E, Thain KR, et al. Leucyl/cystinyl aminopeptidase gene variants in septic shock. Chest 2011;139:1042-9.  Back to cited text no. 80
    
81.Zeng L, Zhang AQ, Gu W, Zhou J, Zhang LY, Du DY, et al. Identification of haplotype tag SNPs within the whole myeloid differentiation 2 gene and their clinical relevance in patients with major trauma. Shock 2012;37:366-72.  Back to cited text no. 81
    
82.Chen KH, Gu W, Zeng L, Jiang DP, Zhang LY, Zhou J, et al. Identification of haplotype tag SNPs within the entire TLR2 gene and their clinical relevance in patients with major trauma. Shock 2011;35:35-41.  Back to cited text no. 82
    
83.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;123:281-7.  Back to cited text no. 83
    
84.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;8:439-43.  Back to cited text no. 84
    
85.Manocha S, Russell JA, Sutherland AM, Wattanathum A, Walley KR. Fibrinogen-beta gene haplotype is associated with mortality in sepsis. J Infect 2007;54:572-7.  Back to cited text no. 85
    
86.Wattanathum A, Manocha S, Groshaus H, Russell JA, Walley KR. Interleukin-10 haplotype associated with increased mortality in critically ill patients with sepsis from pneumonia but not in patients with extrapulmonary sepsis. Chest 2005;128:1690-8.  Back to cited text no. 86
    
87.Yang Y, Zhang P, Lv R, He Q, Zhu Y, Yang X, et al. Mitochondrial DNA haplogroup R in the Han population and recovery from septic encephalopathy. Intensive Care Med 2011;37:1613-9.  Back to cited text no. 87
    
88.Yang Y, Shou Z, Zhang P, He Q, Xiao H, Xu Y, et al. Mitochondrial DNA haplogroup R predicts survival advantage in severe sepsis in the Han population. Genet Med 2008;10:187-92.  Back to cited text no. 88
    
89.Aladzsity I, Madách K, Szilágyi A, Gál J, Pénzes I, Prohászka Z, et al. Analysis of the 8.1 ancestral MHC haplotype in severe, pneumonia-related sepsis. Clin Immunol 2011;139:282-9.  Back to cited text no. 89
    
90.Baudouin SV, Saunders D, Tiangyou W, Elson JL, Poynter J, Pyle A, et al. Mitochondrial DNA and survival after sepsis: A prospective study. Lancet 2005;366:2118-21.  Back to cited text no. 90
    
91.Benatti P, Gafà R, Barana D, Marino M, Scarselli A, Pedroni M, et al. Microsatellite instability and colorectal cancer prognosis. Clin Cancer Res 2005;11:8332-40.  Back to cited text no. 91
    
92.Cao F, Zhang H, Feng J, Gao C, Li S. Association study of three microsatellite polymorphisms located in introns 1, 8, and 9 of DISC1 with schizophrenia in the Chinese Han population. Genet Test Mol Biomarkers 2013;17:407-11.  Back to cited text no. 92
    
93.Shu Q, Fang X, Frank S. Association of tumor necrosis factor microsatellites TNF with the susceptibility to and outcome of postoperative severe sepsis. Zhonghua Yi Xue Za Zhi 2002;82:903-6.  Back to cited text no. 93
    
94.Celik U, Yildizdaº D, Alhan E, Celik T, Attila G, Sertdemir Y, et al . Genetic dilemma: eNOS gene intron 4a/b VNTR polymorphism in sepsis and its clinical features in Turkish children. Turk J Pediatr 2008;50:114-9.  Back to cited text no. 94
    
95.Shu Q, Shi CC, Zhang XH, Shi Z, Shi SS, Fang XM, et al. Interleukin 10.G microsatellite in the promoter region of the interleukin-10 gene in severe sepsis. Chin Med J (Engl) 2006;119:197-201.  Back to cited text no. 95
    
96.Flores C, Maca-Meyer N, Pérez-Méndez L, Sangüesa R, Espinosa E, Muriel A, et al. A CXCL2 tandem repeat promoter polymorphism is associated with susceptibility to severe sepsis in the Spanish population. Genes Immun 2006;7:141-9.  Back to cited text no. 96
    
97.Gonzalez E, Kulkarni H, Bolivar H, Mangano A, Sanchez R, Catano G, et al. The influence of CCL3L1 gene-containing segmental duplications on HIV-1/AIDS susceptibility. Science 2005;307:1434-40.  Back to cited text no. 97
    
98.Chen Q, Hakimi M, Wu S, Jin Y, Cheng B, Wang H, et al. Increased genomic copy number of DEFA1/DEFA3 is associated with susceptibility to severe sepsis in Chinese Han population. Anesthesiology 2010;112:1428-34.  Back to cited text no. 98
    
99.Fode P, Larsen AR, Feenstra B, Jespersgaard C, Skov RL, Stegger M, et al.; Danish SAB Study Group Consortium. Genetic variability in beta-defensins is not associated with susceptibility to Staphylococcus aureus bacteremia. PLoS One 2012;7:e32315.  Back to cited text no. 99
    
100.Carson WF 4 th , Cavassani KA, Ito T, Schaller M, Ishii M, Dou Y, et al. Impaired CD4+ T-cell proliferation and effector function correlates with repressive histone methylation events in a mouse model of severe sepsis. Eur J Immunol 2010;40:998-1010.  Back to cited text no. 100
    
101.Li Y, Alam HB. Creating a pro-survival and anti-inflammatory phenotype by modulation of acetylation in models of hemorrhagic and septic shock. Adv Exp Med Biol 2012;710:107-33.  Back to cited text no. 101
    
102.El Gazzar M, Yoza BK, Chen X, Hu J, Hawkins GA, McCall CE. G9a and HP1 couple histone and DNA methylation to TNFalpha transcription silencing during endotoxin tolerance. J Biol Chem 2008;283:32198-208.  Back to cited text no. 102
    
103.Wang L, Wang HC, Chen C, Zeng J, Wang Q, Zheng L, et al. Differential expression of plasma miR-146a in sepsis patients compared with non-sepsis-SIRS patients. Exp Ther Med 2013;5:1101-4.  Back to cited text no. 103
    
104.Wang JF, Yu ML, Yu G, Bian JJ, Deng XM, Wan XJ, et al. Serum miR-146a and miR-223 as potential new biomarkers for sepsis. Biochem Biophys Res Commun 2010;394:184-8.  Back to cited text no. 104
    
105.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:e7405.  Back to cited text no. 105
    
106.Wang HJ, Zhang PJ, Chen WJ, Feng D, Jia YH, Xie LX. Four serum microRNAs identified as diagnostic biomarkers of sepsis. J Trauma Acute Care Surg 2012;73:850-4.  Back to cited text no. 106
    
107.Wang H, Zhang P, Chen W, Feng D, Jia Y, Xie LX. Evidence for serum miR-15a and miR-16 levels as biomarkers that distinguish sepsis from systemic inflammatory response syndrome in human subjects. Clin Chem Lab Med 2012;50:1423-8.  Back to cited text no. 107
    



 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]



 

Top
 
 
  Search
 
Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
Access Statistics
Email Alert *
Add to My List *
* Registration required (free)

 
  In this article
Abstract
Introduction
References
Article Tables

 Article Access Statistics
    Viewed3268    
    Printed284    
    Emailed0    
    PDF Downloaded370    
    Comments [Add]    

Recommend this journal


[TAG2]
[TAG3]
[TAG4]