Insertion/deletion polymorphism in the promoter of NFKB1 influences severity but not mortality of acute respiratory distress syndrome
Institut für Pharmakogenetik, University Hospital Essen, University of Duisburg-Essen, Hufelandstrasse 55, 45147, Essen, Germany. Intensive Care Medicine
(Impact Factor: 7.21).
08/2007; 33(7):1199-203. DOI: 10.1007/s00134-007-0649-4
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.
Available from: Simon T Schäfer
- "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 . "
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ABSTRACT: 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.
Available from: John G Laffey
- "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. "
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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.
Available from: Taro Kishi
- "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). "
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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.
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