title: 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 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.
authors.affiliation: Department of Environmental Health, Harvard School of Public Health, 665 Huntington Avenue, Room I-1407, Boston, MA 02115, USA.
authors.forename: Paula
authors.initials: P
authors.lastname: Tejera
authors.forename: Zhaoxi
authors.initials: Z
authors.lastname: Wang
authors.forename: Rihong
authors.initials: R
authors.lastname: Zhai
authors.forename: Li
authors.initials: L
authors.lastname: Su
authors.forename: Chau-Chyun
authors.initials: CC
authors.lastname: Sheu
authors.forename: Deanne M
authors.initials: DM
authors.lastname: Taylor
authors.forename: Feng
authors.initials: F
authors.lastname: Chen
authors.forename: Michelle N
authors.initials: MN
authors.lastname: Gong
authors.forename: B Taylor
authors.initials: BT
authors.lastname: Thompson
authors.forename: David C
authors.initials: DC
authors.lastname: Christiani
mesh_terms: D000328:Adult; D000368:Aged; D000483:Alleles; D016022:Case-Control Studies; D015331:Cohort Studies; D053492:Elafin / Q000097:blood / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D016254:Mutagenesis, Insertional; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D012128:Respiratory Distress Syndrome / Q000097:blood / Q000235:genetics* / Q000401:mortality; D012307:Risk Factors; D017384:Sequence Deletion
chemical_list: D053492:Elafin; C506806:PI3 protein, human