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1 Inst. of Inhalation Biology, GSF-National Research Center for Environment and Health, Munich, Bavaria, Germany
2 Inst. of Inhalation Biology, GSF-National Research Center for Environment and Health, Germany
3 Center for Environmental Genetics, Department of Environmental Health, University of Cincinnati, Ohio, United States
4 GSF - Institute of Inhalation Biology, United States
* To whom correspondence should be addressed. E-mail: schulz{at}gsf.de.
Rationale: Impaired development and reduced lung capacity are risk factors of asthma and chronic obstructive pulmonary disease (COPD). Previously, our genome-wide linkage analysis of C3H/HeJ (C3H) and JF1/Msf (JF1) mouse strains identified quantitative trait loci (QTL) associated with the complex traits of dead space volume (VD), total lung capacity (TLC), lung compliance (CL), and diffusing capacity (DCO). Method/Findings: We assessed positional candidate genes by comparing C3H with JF1 lung transcript levels using microarray and by comparing C3H, BALB/cByJ, C57BL/6J, A/J, PWD/PhJ, and JF1 using exon sequencing to predict protein structure. Microarray identified >900 transcripts differing in C3H and JF1 lungs related to lung development, function, and remodeling. Of these, 3 genes localized to QTLs associated with differences in lung function. C3H and JF1 strains differed in transcript and protein levels of superoxide dismutase 3, extracellular (SOD3; mCh5: VD) and transcript of trefoil factor 2 (TFF2; mCh17: TLC&DCO), and ectonucleotide pyrophosphatase/phosphordiesterase 2 (ENPP2; mCh15: TLC&CL). Nucleotide sequencing of Sod3, Tff2, and previously identified relaxin 1 (Rln1; mCh19: CL) uncovered polymorphisms that could lead to nonsynonymous amino acid changes and altered predicted protein structure. Gene-targeted Sod3(-/-) mice had increased conducting airway volume (VD/TLC) compared to strain-matched control Sod3(+/+) mice, consistent with the QTL on mCh 5. Conclusions: Two novel genes (Tff2 and Enpp2) have been identified and two suspected genes (Sod3 and Rln1) have been supported as determinants of lung function in mice. Findings with gene-targeted mice suggest that SOD3 is a contributing factor defining the complex trait of conducting airway volume.
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