TNF and TNFR polymorphisms in severe sepsis and septic shock: a prospective multicentre study

Abstract

Tumour necrosis factor (TNF) is an important pro-inflammatory cytokine produced in sepsis. Studies examining the association of individual TNF single nucleotide polymorphisms with sepsis have produced conflicting results. This study investigated whether common polymorphisms of the TNF locus and the two receptor genes, TNFRSF1A and TNFRSF1B, influence circulating levels of encoded proteins, and whether individual polymorphisms or extended haplotypes of these genes are associated with susceptibility, severity of illness or outcome in adult patients with severe sepsis or septic shock. A total of 213 Caucasian patients were recruited from eight intensive care units (ICU) in the UK and Australia. Plasma levels of TNF (P ¼ 0.02), sTNFRSF1A (P ¼ 0.005) and sTNFRSF1B (P ¼ 0.01) were significantly higher in those who died on ICU compared to those who survived. There was a positive correlation between increasing soluble receptor levels and organ dysfunction (increasing SOFA score) (sTNFRSF1A R ¼ 0.51, Po0.001; sTNFRSF1B R ¼ 0.53, Po0.001), and in particular with the degree of renal dysfunction. In this study, there were no significant associations between the selected candidate TNF or TNF receptor polymorphisms, or their haplotypes, and susceptibility to sepsis, illness severity or outcome. The influence of polymorphisms of the TNF locus on susceptibility to, and outcome from sepsis remains uncertain.

TNF -308G > a promoter polymorphism (rs1800629) and outcome from critical illness

“…In agreement with a recent epidemiological study in a Brazilian hospital in the state of Paraná, we found that the main medical cause for ICU admission was sepsis (35% against 40% in Kauss et al 29 recent study), and the mortality rates at ICU plus follow-up were 46% in our study compared to 42% in Kauss et al 29 Our study revealed no association between -308G > A TNF-α genotypes and adverse outcomes (sepsis, septic shock, higher organ dysfunction or mortality) from critical illness. Our results demonstrated that the -308A rare allele frequency was 15%, confirming the trend documented in Danish (22%), 24 English (20%), 23 French (18%), 17 and Spanish subjects (9%). 30 The -308A allele has higher level of inducible and constitutional TNF-α, 13,14 but its phenotypical effects in sepsis, septic shock, organ dysfunction, and mortality have been contradictory; 31 while it was perceived in some genetic association studies; 16,18 in other it was not present.…”

“…30 The -308A allele has higher level of inducible and constitutional TNF-α, 13,14 but its phenotypical effects in sepsis, septic shock, organ dysfunction, and mortality have been contradictory; 31 while it was perceived in some genetic association studies; 16,18 in other it was not present. [22][23][24] Specifically, in contrast to our study (n = 520, southern Brazilian population), positive associations between -308A allele and sepsis, septic shock, higher organ dysfunction, and/or mortality were found when Mira et al 17 (n = 89, France), Tang et al 18 (n = 112, China), O'Keefe et al…”

“…15 Systemic administration of TNF-α produces most of the symptoms and signs of sepsis, and although a number of studies have found associations of the -308A allele with a predisposition to septic shock and/ or outcome from sepsis, findings have been inconsistent. [16][17][18][19][20][21][22][23][24] In order to clarify the potential role of the -308G>A SNP we tested 520 patients for the presence of -308A allele influencing the outcome of critical illness, leading patients to sepsis, septic shock, higher organ dysfunction, and/or mortality. Patients were not eligible if they were diagnosed with HIV-infection, taking immunosuppressive drugs, pregnant or lactating, or of non-Caucasian ancestry.…”

Searching for Genes That Matter in Acute Kidney Injury

“…This has been seen in other complex diseases, such as the discovery of a single nucleotide polymorphism (SNP) in complement factor H as a risk factor for macular degeneration (13). In AKI, genetic variation in inflammatory cytokines such as Tumor Necrosis Factor-alpha (TNF-␣) and Interleukin-6 (IL-6) have recently been proposed as risk factors (11,(14)(15)(16)(17). This is due to the role of inflammatory mediators in the pathophysiology of AKI, especially with ischemia and sepsis (1,18,19).…”

Host Genetics and Pediatric Sepsis

“…Other studies demonstrating an association of "high-secretor" genotypes and more severe disease include children with meningococcal infections [95] and bacteremia [90], severe sepsis in adults [26,83,85,96], and community acquired pneumonia in adults [97,98]. However, these results have not been uniformly observed [28,[99][100][101][102][103], and further studies are needed. Thus, individuals in which genetic variations result in a hyper-response during sepsis (as with those with the TNF--308A allele) or hypo-response (as with those with the TNF--238A allele) may have worse outcomes with sepsis.…”