Genetic polymorphisms of peptidase inhibitor 3 (elafin) are associated with acute respiratory distress syndrome

Paula Tejera, Zhaoxi Wang, Rihong Zhai, Li Su, Chau Chyun Sheu, Deanne M. Taylor, Feng Chen, Michelle Ng Gong, B. Taylor Thompson, David C. Christiani

Research output: Contribution to journalArticle

33 Citations (Scopus)

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 case-control 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 = 0.006; false discovery rate adjusted P = 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 = 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 = 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.

Original languageEnglish (US)
Pages (from-to)696-704
Number of pages9
JournalAmerican Journal of Respiratory Cell and Molecular Biology
Volume41
Issue number6
DOIs
StatePublished - Dec 1 2009
Externally publishedYes

Fingerprint

Elafin
Adult Respiratory Distress Syndrome
Genetic Polymorphisms
Protease Inhibitors
Polymorphism
Genes
Alleles
Leukocyte Elastase
Odds Ratio
Gene expression
Haplotypes
Nucleotides
Confidence Intervals
Plasmas
Critical Illness
Single Nucleotide Polymorphism
Case-Control Studies
Multivariate Analysis

Keywords

  • Acute respiratory distress syndrome
  • Elafin
  • Genetic susceptibility
  • Haplotypes
  • Tagging SNP

ASJC Scopus subject areas

  • Cell Biology
  • Pulmonary and Respiratory Medicine
  • Molecular Biology
  • Clinical Biochemistry

Cite this

Genetic polymorphisms of peptidase inhibitor 3 (elafin) are associated with acute respiratory distress syndrome. / Tejera, Paula; Wang, Zhaoxi; Zhai, Rihong; Su, Li; Sheu, Chau Chyun; Taylor, Deanne M.; Chen, Feng; Gong, Michelle Ng; Thompson, B. Taylor; Christiani, David C.

In: American Journal of Respiratory Cell and Molecular Biology, Vol. 41, No. 6, 01.12.2009, p. 696-704.

Research output: Contribution to journalArticle

Tejera, Paula ; Wang, Zhaoxi ; Zhai, Rihong ; Su, Li ; Sheu, Chau Chyun ; Taylor, Deanne M. ; Chen, Feng ; Gong, Michelle Ng ; Thompson, B. Taylor ; Christiani, David C. / Genetic polymorphisms of peptidase inhibitor 3 (elafin) are associated with acute respiratory distress syndrome. In: American Journal of Respiratory Cell and Molecular Biology. 2009 ; Vol. 41, No. 6. pp. 696-704.
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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 case-control 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 = 0.006; false discovery rate adjusted P = 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 = 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 = 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.",
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AU - Wang, Zhaoxi

AU - Zhai, Rihong

AU - Su, Li

AU - Sheu, Chau Chyun

AU - Taylor, Deanne M.

AU - Chen, Feng

AU - Gong, Michelle Ng

AU - Thompson, B. Taylor

AU - Christiani, David C.

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