Genetic Polymorphisms of Peptidase Inhibitor 3 (Elafin) Are Associated with Acute Respiratory Distress Syndrome

Abstract

Peptidase inhibitor 3 (PI3, elafin) is a protease inhibitor produced locally in the lung, where it plays a central role in controlling excessive activity of neutrophil elastase. Our previous study revealed that PI3 gene expression is down-regulated during the acute stage of acute respiratory distress syndrome (ARDS). We conducted a casecontrol study to investigate whether genetic variants in PI3 gene are associated with ARDS development. Based on resequencing data from 29 unrelated white subjects, three tagging single-nucleotide polymorphisms were selected and genotyped in a prospective cohort consisting of 449 white patients with ARDS (cases) and 1,031 critically ill patients (at-risk control subjects). We found that the variant allele of rs2664581 (T34P) was significantly associated with increased ARDS risk (odds ratio [OR], 1.35; 95% confidence interval [CI], 1.09-1.67; P 5 0.006; false discovery rate adjusted P 5 0.018). Moreover, this association was stronger among subjects with extrapulmonary injury. The common haplotype Hap2 (TTC), containing the variant allele of rs2664581, was also identified as a risk haplotype for ARDS (OR, 1.31; 95% CI, 1.05-1.64; P 5 0.015). Furthermore, the rs2664581 polymorphism was associated with circulating PI3 levels in multivariate analyses. Patients with ARDS homozygous for the wild-type A allele of rs2664581 showed significant lower PI3 plasma level (P 5 0.019) at ARDS onset as compared with those homozygous or heterozygous for the variant C allele. Our data suggest that polymorphisms in PI3 gene are significantly associated with ARDS risk and with circulating PI3 levels.

Functional Characterization of Polymorphisms in the Peptidase Inhibitor 3 (Elafin) Gene and Validation of Their Contribution to Risk of Acute Respiratory Distress Syndrome

“…Assuming dominant and additive models of inheritance, and after adjustment by age, sex, and APACHE III score, we observed a significant association between the minor allele of rs2664581 (C allele) and an increased risk of ARDS (OR = 1.50, 95% CI = 1.07-2.12, P = 0.0198 and OR = 1.35; 95% CI = 1.01-1.80, P = 0.0426, for the dominant and additive models, respectively). The direction and magnitude of association was the same as previously observed (21). Stratified analyses showed a stronger effect of PI3 variants on ARDS susceptibility among the subjects with sepsis (OR = 1.51, 95% CI = 1.04-2.18, P = 0.0297 and OR = 1.44, 95% CI = 1.04-1.99, P = 0.0276, for the dominant and additive models, respectively; Table 3 (29), was validated in the current study using a cohort including mild to severe ARDS (Pa O 2 /FI O 2 < 300 mm Hg with PEEP > 5 cm H 2 O, formerly ALI).…”

“…Our previous genome-wide expression analysis showed that PI3 gene expression is downregulated during the acute stage of ARDS, and this correlates well with plasma preelafin levels (20). Recently, we found that single-nucleotide polymorphism (SNP) rs2664581, located in exon 2 of PI3 gene, is associated with increased ARDS risk and pre-elafin circulating levels (21). This SNP results in an amino acid substitution (Thr34Pro) within the N-terminal (cementoin) domain of pre-elafin, which anchors the molecule to extracellular matrix (ECM) proteins (22)(23)(24)(25).…”

“…Polymorphisms in PI3 promoter gene were identified by sequencing 2 kb of the 59 untranslated regions using DNA samples from 29 nonrelated, healthy white subjects, as previously described (21). Resequencing data were used to determine the LD structure of the PI3 promoter as described previously (30,31).…”

Endogeous sulfur dioxide protects against oleic acid-induced acute lung injury in association with inhibition of oxidative stress in rats

“…1,2 Since the first description of ALI/ARDS, in 1967, numerous studies have been conducted to better understand the pathogenesis. 3,4 Exposure to hazardous factors such as acid, lipopolysaccharide, hyperoxia, or overinflation generates excessive levels of reactive oxygen species (ROS) and recruitment of considerable amounts of neutrophils in lung tissue, thus resulting in proinflammatory processes and eventually cellular, and tissue dysfunction, which contributes to increased vascular permeability, leukocyte infiltration, plasma exudation and impaired arterial oxygenation. 5,6 The canonical role of oxidative stress in the development of ALI has been established.…”

Update on Acute Lung Injury and Critical Care Medicine 2009

“…In pediatric patients with ALI, higher plasma levels of PAI-1 were associated with increased mortality and fewer ventilator-free days in ALI (10). Another study reported that genetic polymorphisms of peptidase inhibitor 3 (elafin) were associated with increased risk of developing ARDS, especially with extrapulmonary injury (11). Patients with these single nucleotide polymorphisms had lower elafin levels in the plasma, which might reduce host defense against neutrophil elastasemediated injury.…”