This Article Full Text Full Text (PDF) Online Supplement All Versions of this Article: 2008-0410OCv1 41/6/696    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Tejera, P. Articles by Christiani, D. C. PubMed PubMed Citation Articles by Tejera, P. Articles by Christiani, D. C.

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

¹ Department of Environmental Health, ² Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts; ³ Division of Pulmonary and Critical Care Medicine, Mount Sinai School of Medicine, New York, New York; and ⁴ Pulmonary and Critical Care Unit, Department of Medicine, Massachusetts General Hospital/Harvard Medical School, Boston, Massachusetts

Correspondence and requests for reprints should be addressed to David C. Christiani, M.D., M.P.H., Department of Environmental Health, Harvard School of Public Health, 665 Huntington Avenue, Room I-1407, Boston, MA 02115. E-mail: dchris{at}hsph.harvard.edu

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.

Key Words: acute respiratory distress syndrome • elafin • genetic susceptibility • haplotypes • tagging SNP

CLINICAL RELEVANCE The present study demonstrates a significant association between peptidase inhibitor 3 (PI3) polymorphisms and risk for acute respiratory distress syndrome (ARDS). The single-nucleotide polymorphisms in PI3 gene may be important in controlling the PI3 plasma levels and the capability to protect from neutrophil elastase–induced lung injury. Our findings may have significant implications for risk assessment and treatment of patients with ARDS.