title: Genetic regulation of expression of leukotriene A4 hydrolase.
abstract: In chronic inflammatory lung disorders such as chronic obstructive pulmonary disease (COPD), the concurrent organ-specific and systemic inflammatory responses lead to airway remodelling and vascular dysfunction. Although a major common risk factor for COPD, cigarette smoke alone cannot explain the progression of this disease; there is increasing evidence that genetic predisposition also plays a role in COPD susceptibility and progression. A key enzyme in chronic lung inflammation is leukotriene A4 hydrolase (LTA4H). With its aminopeptidase activity, LTA4H degrades the neutrophil chemoattractant tripeptide PGP. In this study, we used the luciferase reporter gene analysis system and quantitative trait locus analysis to explore the impact of single-nucleotide polymorphisms (SNPs) in the putative promoter region ofLTA4Hon LTA4H expression. We show that not only is the putative promoter ofLTA4Hlarger than previously reported but also that SNPs in the expanded promoter region regulate expression of LTA4H both in cell-based systems and in peripheral blood samples from human subjects. These findings provide significant evidence for an active region upstream of the previously reportedLTA4Hpromoter, which may have implications related to ongoing inflammatory processes in chronic lung disease.
authors.affiliation: Dept of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, University of Alabama at Birmingham, Birmingham, AL, USA; Program in Protease and Matrix Biology, University of Alabama at Birmingham, Birmingham, AL, USA; Gregory Fleming James Cystic Fibrosis Research Center, University of Alabama at Birmingham, Birmingham, AL, USA; Lung Health Center, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Tomasz
authors.initials: T
authors.lastname: Szul
authors.affiliation: Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA; Division of General Internal Medicine and Primary Care, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Castaldi
authors.affiliation: Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA; Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Boston, MA, USA.
authors.forename: Michael H
authors.initials: MH
authors.lastname: Cho
authors.affiliation: Dept of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, University of Alabama at Birmingham, Birmingham, AL, USA; Program in Protease and Matrix Biology, University of Alabama at Birmingham, Birmingham, AL, USA; Gregory Fleming James Cystic Fibrosis Research Center, University of Alabama at Birmingham, Birmingham, AL, USA; Lung Health Center, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: J Edwin
authors.initials: JE
authors.lastname: Blalock
authors.affiliation: Dept of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, University of Alabama at Birmingham, Birmingham, AL, USA; Program in Protease and Matrix Biology, University of Alabama at Birmingham, Birmingham, AL, USA; Gregory Fleming James Cystic Fibrosis Research Center, University of Alabama at Birmingham, Birmingham, AL, USA; Lung Health Center, University of Alabama at Birmingham, Birmingham, AL, USA; Medicine Service, United States Department of Veterans Affairs Medical Center, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Amit
authors.initials: A
authors.lastname: Gaggar