Published ahead of print on January 7, 2005, doi:10.1164/rccm.200409-1204OC Am. J. Respir. Crit. Care Med., Volume 171, Number 8, April 2005, 880-888 A more recent version of this article appeared on April 15, 2005
Submitted on September 14, 2004 Genomewide Linkage Analysis Identifies Novel Genetic Loci for Lung Function in MiceClaudia Reinhard1*,1 Institute for Inhalation Biology, GSF-National Research Center for Environment and Health, Neuherberg/Munich, Germany, 2 Gene Mapping Center, Max-Delbrueck-Centrum, Berlin, Germany, 3 Institute of Experimental Genetics, GSF-National Research Center for Environment and Health, Neuherberg/Munich, Germany, 4 Gene Mapping Center, Max-Delbrueck-Centrum, Berlin, Germany; Institute for Medical Biometrics, Informatics, and Epidemiology, Friedrich-Wilhelms-University, Bonn, Germany * To whom correspondence should be addressed. E-mail: reinhard{at}gsf.de.
Rationale: Pulmonary function including lung volumes and compliance may be genetically determined, but few genetic polymorphisms have been identified that control these traits. We used an experimental approach and carried out the first whole genome scan for pulmonary function in mice. Objectives and Methods: To identify novel chromosomal regions contributing to lung function, quantitative trait locus linkage analysis was applied in N2 backcross and F2 intercross mice derived from two inbred strains - C3H/HeJ and JF1/Msf - with extremely divergent phenotypes. Main results: Significant linkages to total lung capacity with LOD (logarithm of the odds) scores up to 6.0 were detected on chromosomes 15 and 17, to dead space volume and lung compliance on chromosomes 5 and 15 (LOD scores above 4.0), to lung compliance also on chromosome 19 (LOD score of 5.8), and to diffusing capacity on chromosomes 15 and 17 (LOD scores up to 5.0). The region of interest on chromosome 17 near D17Mit133 contains a syntenic region to human chromosome 6q27, which was recently identified to be linked to lung function in humans. The identified intervals harbour valuable candidate genes, like the relaxin1 and transforming growth factor beta receptor3 gene, which revealed missense polymorphisms between the parental strains. Conclusion: The study provides evidence for linkage of different measures of lung function on murine chromosomes 5, 15, 17, and 19 and suggests novel candidate genes that may also affect the expression of human pulmonary function. Key words: Linkage mapping, murine lung function, genetics, pulmonary diseases
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