title: Superoxide dismutase 3, extracellular (SOD3) variants and lung function.
abstract: Polymorphisms in Superoxide dismutase 3, extracellular (SOD3) have been associated with reduced lung function and susceptibility to chronic obstructive pulmonary disease (COPD) in adults. Previously, we identified SOD3 as a contributing factor to altered ventilation efficiency (dead space volume/total lung capacity) in mice. Because SOD3 protects the extracellular matrix of the lung, we hypothesized that SOD3 variants also may influence postnatal lung function development. In this study, SOD3 transcript and protein localization were examined in mouse strains with differing ventilation efficiency [C3H/HeJ (high), JF1/Msf (low)] during postnatal lung development. Compared with C3H/HeJ mice, JF1/Msf mice had Sod3 promoter single nucleotide polymorphisms (SNPs) that could affect transcription factor binding sites and a decline in total lung SOD3 mRNA during postnatal development. In adult JF1/Msf mice, total lung SOD3 activity as well as SOD3 transcript and protein in airway epithelial and alveolar type II cells and the associated matrix decreased. In children (n = 1,555; age 9-11 yr), two common SOD3 SNPs, one located in the promoter region [C/T affecting a predicted aryl hydrocarbon receptor-xenobiotic response element (AhR-XRE) binding motif] and the other in exon 2 (Thr/Ala missense mutation), were associated with decreased forced expiratory volume in 1 s (FEV(1)), and the promoter SNP was associated with decreased maximal expiratory flow at 25% volume (MEF(25)). In vitro, a SOD3 promoter region-derived oligonucleotide containing the C variant was more effective in competing with the nuclear protein-binding capacity of a labeled probe than that containing the T variant. Along with the previous associated risk of lung function decline in COPD, these findings support a possible role of SOD3 variants in determining lung function in children.
authors.affiliation: Institute of Lung Biology and Disease, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich, Germany.
authors.forename: Koustav
authors.initials: K
authors.lastname: Ganguly
authors.forename: Martin
authors.initials: M
authors.lastname: Depner
authors.forename: Cheryl
authors.initials: C
authors.lastname: Fattman
authors.forename: Kiflai
authors.initials: K
authors.lastname: Bein
authors.forename: Tim D
authors.initials: TD
authors.lastname: Oury
authors.forename: Scott C
authors.initials: SC
authors.lastname: Wesselkamper
authors.forename: Michael T
authors.initials: MT
authors.lastname: Borchers
authors.forename: Martina
authors.initials: M
authors.lastname: Schreiber
authors.forename: Fei
authors.initials: F
authors.lastname: Gao
authors.forename: Erika
authors.initials: E
authors.lastname: von Mutius
authors.forename: Michael
authors.initials: M
authors.lastname: Kabesch
authors.forename: George D
authors.initials: GD
authors.lastname: Leikauf
authors.forename: Holger
authors.initials: H
authors.lastname: Schulz