This study investigated whether the insertion/deletion polymorphism in the promoter of NFKB1 is associated with severity and/or mortality in ARDS.
Prospective study in a mixed anesthesiological ICU of the University Hospital Essen.
103 adult patients with ARDS (white Germans).
Patients with ARDS were genotyped for the insertion/deletion polymorphism in the promoter of NFKB1 (-94ins/delATTG). In ARDS patients genotypes differed significantly between those with severe ARDS [Lung Injury Score (LIS)>or=3; 23 homozygote deletion (DD), heterozygote (ID) 31, and homozygote insertion wildtype (II) 23], and those with LIS below 3 (1 DD, 9 ID, 16 II). Likewise, the frequency of the D allele was significantly less in patients with higher LIS (50% D) than lower LIS (21% D). Using these values produces a significantly higher OR of 16.0 (95% CI 1.96-130.9) for DD than for II, while the OR for ID vs. II was 2.4 (95% CI 0.9-6.4). Genotypes of the NFKB1 promoter polymorphism were associated neither with 30-day survival nor with duration of ICU stay.
The insertion/deletion polymorphism in the promoter of NFKB1 influences the severity but not the mortality of ARDS.
"In addition, this polymorphism is an independent risk factor for 30-day mortality in patients with severe sepsis . In another study, the deletion allele of this NFKB1 polymorphism was associated with increased illness severity in patients suffering from the acute respiratory distress syndrome . Thus, we could show, that the NFKB1 promoter polymorphism is functionally active and associated with hyperinflammation . "
[Show abstract][Hide abstract] ABSTRACT: Background
Previous investigations and meta-analyses on the effect of glucocorticoids on mortality in septic shock revealed mixed results. This heterogeneity might be evoked by genetic variations. Such candidate is a promoter polymorphism (-94ins/delATTG) of the gene encoding the ubiquitous transcription-factor nuclear-factor-κB (NF-κB) which binds to recognition elements in the promoter of several genes encoding for the innate immune-system. In turn, hydrocortisone inhibits NF-κB nuclear translocation and thus transcription of key immune-response regulators. Accordingly, we tested the hypotheses that hydrocortisone has a NFKB1 genotype dependent effect on 1) NF-κB1 nuclear translocation evoked by lipopolysaccharide (LPS) in monocytes in vitro, and 2) mortality in septic shock.
Monocytes of volunteers with the homozygous insertion (II; n = 5) or deletion (DD; n = 6) NFKB1 genotype were incubated with 10 µgml-1 LPS ± hydrocortisone (10-5M), and NF-κB1 nuclear translocation was assessed (immunofluorescence). Furthermore, we analyzed 30-day-mortality in 160 patients with septic shock stratified for both genotype and hydrocortisone therapy.
Hydrocortisone inhibited LPS induced nuclear translocation of NF-κB1 in II (25%±11;p = 0.0001) but not in DD genotypes (51%±15;p = n.s.). Onehundredandfour of 160 patients with septic shock received hydrocortisone, at the discretion of the intensivist. NFKB1 deletion allele carriers (ID/DD) receiving hydrocortisone had a much greater 30-day-mortality (57.6%) than II genotypes (24.4%; HR:3.18, 95%-CI:1.61-6.28;p = 0.001). In contrast, 30-day mortality was 22.2% in ID/DD and 25.0% in II genotypes without hydrocortisone therapy. Results were similar when using propensity score matching to account for possible bias in the intensivists' decision to administer hydrocortisone.
Hydrocortisone fails to inhibit LPS induced nuclear NF-κB1 translocation in deletion allele carriers of the NFKB1 promoter polymorphism (-94ins/delATTG). In septic shock, hydrocortisone treatment is associated with markedly increased 30-day-mortality only in such carriers. Accordingly, previous heterogeneous results regarding the benefit of hydrocortisone in septic shock may be reconciled by genetic variation of the NFKB1 promoter polymorphism.
PLoS ONE 08/2014; 9(8):e104953. DOI:10.1371/journal.pone.0104953 · 3.23 Impact Factor
"The role of the NF-κB signaling in the host immune response to lung injury is increasingly well understood . NF-κB activation pathway gene polymorphisms alter the susceptibility to  and severity  of clinical ARDS. NF-κB is a dimer of a number of related proteins, including RelA (also known as P65), p50, p52, RelB, and cRel, with the RelA and p50 heterodimer, the most common form. "
[Show abstract][Hide abstract] ABSTRACT: Introduction
Nuclear factor (NF)-κB is central to the pathogenesis of inflammation in acute lung injury, but also to inflammation resolution and repair. We wished to determine whether overexpression of the NF-κB inhibitor IκBα could modulate the severity of acute and prolonged pneumonia-induced lung injury in a series of prospective randomized animal studies.
Adult male Sprague-Dawley rats were randomized to undergo intratracheal instillation of (a) 5 × 109 adenoassociated virus (AAV) vectors encoding the IκBα transgene (5 × 109 AAV-IκBα); (b) 1 × 1010 AAV-IκBα; (c) 5 × 1010 AAV-IκBα; or (d) vehicle alone. After intratracheal inoculation with Escherichia coli, the severity of the lung injury was measured in one series over a 4-hour period (acute pneumonia), and in a second series after 72 hours (prolonged pneumonia). Additional experiments examined the effects of IκBα and null-gene overexpression on E. coli-induced and sham pneumonia.
In acute pneumonia, IκBα dose-dependently decreased lung injury, improving arterial oxygenation and lung static compliance, reducing alveolar protein leak and histologic injury, and decreasing alveolar IL-1β concentrations. Benefit was maximal at the intermediate (1 × 1010) IκBα vector dose; however, efficacy was diminished at the higher (5 × 1010) IκBα vector dose. In contrast, IκBα worsened prolonged pneumonia-induced lung injury, increased lung bacterial load, decreased lung compliance, and delayed resolution of the acute inflammatory response.
Inhibition of pulmonary NF-κB activity reduces early pneumonia-induced injury, but worsens injury and bacterial load during prolonged pneumonia.
"We found significant heterogeneities among the ORs (Pallele < 0.0001, Pdominant = 0.003, and Precessive = 0.004) (Additional file 2: Figure S1, Additional file 3: Figure S2, Additional file 4: Figure S3). The pooled OR derived from the five studies [15,17,19,21,29] did not indicate significant association for any genotype model (Additional file 2: Figure S1, Additional file 3: Figure S2, Additional file 4: Figure S3). There was no significant publication bias using either the Egger test or the rank correlation test (data not shown). "
[Show abstract][Hide abstract] ABSTRACT: A previous meta-analysis reported a positive association between an insertion/deletion (I/D) polymorphism in the angiotensin-converting enzyme gene (ACE) and the risk of acute lung injury (ALI)/acute respiratory distress syndrome (ARDS). Here, we updated this meta-analysis and additionally assessed the association of this polymorphism with ALI/ARDS mortality.
We searched electronic databases through October 2011 for the terms "angiotensin-converting enzyme gene", "acute lung injury", and "acute respiratory distress syndrome," and reviewed all studies that reported the relationship of the I/D polymorphism in ACE with ALI/ARDS in humans. Seven studies met the inclusion criteria, comprising 532 ALI/ARDS patients, 3032 healthy controls, and 1432 patients without ALI/ARDS. We used three genetic models: the allele, dominant, and recessive models.
The ACE I/D polymorphism was not associated with susceptibility to ALI/ARDS for any genetic model. However, the ACE I/D polymorphism was associated with the mortality risk of ALI/ARDS in Asian subjects ( Pallele < 0.0001, Pdominant = 0.001, Precessive = 0.002). This finding remained significant after correction for multiple comparisons.
There is a possible association between the ACE I/D polymorphism genotype and the mortality risk of ALI/ARDS in Asians.
BMC Medical Genetics 08/2012; 13(1):76. DOI:10.1186/1471-2350-13-76 · 2.08 Impact Factor
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