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Functional characterization of polymorphisms in the peptidase inhibitor 3 (elafin) gene and validation of their contribution to risk of acute respiratory distress syndrome.

ABSTRACT: Elafin (peptidase inhibitor 3 [PI3]) and its biologically active precursor, pre-elafin, are neutrophil serine proteinase inhibitors with an important role in preventing excessive tissue injury during inflammatory events. Recently, we reported an association between single-nucleotide polymorphism (SNP) rs2664581 in the PI3 gene, increased risk of acute respiratory distress syndrome (ARDS) and pre-elafin circulating levels. This study aims to validate the legitimacy of this association by using a cohort of patients who met the criteria for systemic inflammatory response syndrome and were at risk of developing ARDS (n = 840). A comprehensive functional study of SNPs in PI3 gene was also performed. Luciferase assays and electrophoretic mobility shift assays were conducted to determine the functional relevance of promoter region variants. The effect of the coding SNP rs2664581 on the neutrophil elastase inhibitory activity and transglutaminase binding properties of pre-elafin was also investigated. The variant allele of rs2664581 (C) was significantly associated with increased ARDS risk, mainly among subjects with sepsis (odds ratio = 1.44; 95% confidence interval = 1.04-1.99; P = 0.0276, adjusted by age, sex, and Acute Physiology and Chronic Health Evaluation III). Pre-elafin recombinant protein carrying the amino acid change associated with rs2664581 (Thr34Pro, mutant protein [MT]) had greater capacity to undergo transglutaminase-mediated cross-linking to immobilized fibronectin than wild-type protein in vitro (P < 0.003). No differences were observed in the neutrophil elastase inhibitory activities of wild-type versus MT proteins. In addition, the risk allele-promoter construct had significantly lower cytokine-induced transcriptional activity. Electrophoretic mobility shift assay results indicated a differential binding of nuclear proteins to the G and A alleles of SNP -338G > A. Our results confirm the association between SNP rs2664581 and enhanced risk of ARDS, further supporting the role of PI3 in ARDS development. SNPs in the PI3 locus may act synergistically by regulating PI3 gene expression and pre-elafin biological functions.

SUBMITTER: Tejera P

PROVIDER: S-EPMC4148037 | biostudies-literature | 2014 Aug

REPOSITORIES: biostudies-literature

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Functional characterization of polymorphisms in the peptidase inhibitor 3 (elafin) gene and validation of their contribution to risk of acute respiratory distress syndrome.

Tejera Paula P O'Mahony D Shane DS Owen Caroline A CA Wei Yongyue Y Wang Zhaoxi Z Gupta Kushagra K Su Li L Villar Jesus J Wurfel Mark M Christiani David C DC

American journal of respiratory cell and molecular biology 20140801 2

Elafin (peptidase inhibitor 3 [PI3]) and its biologically active precursor, pre-elafin, are neutrophil serine proteinase inhibitors with an important role in preventing excessive tissue injury during inflammatory events. Recently, we reported an association between single-nucleotide polymorphism (SNP) rs2664581 in the PI3 gene, increased risk of acute respiratory distress syndrome (ARDS) and pre-elafin circulating levels. This study aims to validate the legitimacy of this association by using a ...[more]

PMID: 24617927

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Project description:RationaleAdiponectin is an anti-inflammatory adipokine that is the most abundant gene product of adipose tissue. Lower levels have been observed in obesity, insulin resistance, and in critical illness. However, elevated levels early in acute respiratory failure have been associated with mortality. Polymorphisms in adiponectin-related genes (ADIPOQ, ADIPOR1, ADIPOR2) have been examined for relationships with obesity, insulin resistance and diabetes, cardiovascular disease, and to circulating adipokine levels, but many gaps in knowledge remain. The current study aims to assess the association between potentially functional polymorphisms in adiponectin-related genes with acute respiratory distress syndrome (ARDS) risk and mortality.MethodsConsecutive patients with risk factors for ARDS admitted to the ICU were enrolled and followed prospectively for development of ARDS. ARDS cases were followed through day 60 for all-cause mortality. 2067 patients were successfully genotyped using the Illumina CVD BeadChip high-density platform. Of these, 567 patients developed ARDS. Forty-four single nucleotide polymorphisms (SNPs) on ADIPOQ, ADIPOR1 and ADIPOR2 were successfully genotyped. Of these, 9 SNPs were hypothesized to be functional based on their location (promoter, exon, or 3' untranslated region). These 9 SNPs were analyzed for association with ARDS case status and mortality among ARDS cases.ResultsAfter multivariable analysis and adjustment for multiple comparisons, no SNPs were significantly associated with ARDS case status. Among ARDS cases, homozygotes for the minor allele of rs2082940 (ADIPOQ) had increased mortality (hazard ratio 2.61, 95% confidence interval 1.36-5.00, p = 0.0039) after adjustment for significant covariates. The significance of this association persisted after adjustment for multiple comparisons (FDR_q = 0.029).ConclusionsA common and potentially functional polymorphism in ADIPOQ may impact survival in ARDS. Further studies are required to replicate these results and to correlate genotype with circulating adiponectin levels.

Dataset Information

Functional characterization of polymorphisms in the peptidase inhibitor 3 (elafin) gene and validation of their contribution to risk of acute respiratory distress syndrome.

Publications

Functional characterization of polymorphisms in the peptidase inhibitor 3 (elafin) gene and validation of their contribution to risk of acute respiratory distress syndrome.

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