title: Genetic regulation of Zfp30, CXCL1, and neutrophilic inflammation in murine lung.
abstract: Allergic asthma is a complex disease characterized in part by granulocytic inflammation of the airways. In addition to eosinophils, neutrophils (PMN) are also present, particularly in cases of severe asthma. We sought to identify the genetic determinants of neutrophilic inflammation in a mouse model of house dust mite (HDM)-induced asthma. We applied an HDM model of allergic asthma to the eight founder strains of the Collaborative Cross (CC) and 151 incipient lines of the CC (preCC). Lung lavage fluid was analyzed for PMN count and the concentration of CXCL1, a hallmark PMN chemokine. PMN and CXCL1 were strongly correlated in preCC mice. We used quantitative trait locus (QTL) mapping to identify three variants affecting PMN, one of which colocalized with a QTL for CXCL1 on chromosome (Chr) 7. We used lung eQTL data to implicate a variant in the gene Zfp30 in the CXCL1/PMN response. This genetic variant regulates both CXCL1 and PMN by altering Zfp30 expression, and we model the relationships between the QTL and these three endophenotypes. We show that Zfp30 is expressed in airway epithelia in the normal mouse lung and that altering Zfp30 expression in vitro affects CXCL1 responses to an immune stimulus. Our results provide strong evidence that Zfp30 is a novel regulator of neutrophilic airway inflammation.
authors.affiliation: Department of Genetics, University of North Carolina, Chapel Hill, North Carolina 27599.
authors.forename: Holly
authors.initials: H
authors.lastname: Rutledge
authors.affiliation: Department of Biology, North Carolina State University, Raleigh, North Carolina 27695.
authors.forename: David L
authors.initials: DL
authors.lastname: Aylor
authors.affiliation: National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892.
authors.forename: Danielle E
authors.initials: DE
authors.lastname: Carpenter
authors.affiliation: National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892.
authors.forename: Bailey C
authors.initials: BC
authors.lastname: Peck
authors.affiliation: National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892.
authors.forename: Peter
authors.initials: P
authors.lastname: Chines
authors.affiliation: Marsico Lung Institute, University of North Carolina, Chapel Hill, North Carolina 27599.
authors.forename: Lawrence E
authors.initials: LE
authors.lastname: Ostrowski
authors.affiliation: The Jackson Laboratory, Bar Harbor, Maine 04609.
authors.forename: Elissa J
authors.initials: EJ
authors.lastname: Chesler
authors.affiliation: The Jackson Laboratory, Bar Harbor, Maine 04609.
authors.forename: Gary A
authors.initials: GA
authors.lastname: Churchill
authors.affiliation: Department of Genetics, University of North Carolina, Chapel Hill, North Carolina 27599 Department of Biology, North Carolina State University, Raleigh, North Carolina 27695.
authors.forename: Fernando Pardo-Manuel
authors.initials: FP
authors.lastname: de Villena
authors.affiliation: Department of Genetics, University of North Carolina, Chapel Hill, North Carolina 27599 Marsico Lung Institute, University of North Carolina, Chapel Hill, North Carolina 27599 samir_kelada@med.unc.edu.
authors.forename: Samir N P
authors.initials: SN
authors.lastname: Kelada
mesh_terms: D000818:Animals; D054360:Chemokine CXCL1 / Q000235:genetics* / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000502:physiology*; D015870:Gene Expression; D005786:Gene Expression Regulation / Q000276:immunology*; D008168:Lung / Q000276:immunology / Q000473:pathology; D008297:Male; D008822:Mice, Transgenic; D020556:Neutrophil Infiltration; D011014:Pneumonia / Q000235:genetics*; D040641:Quantitative Trait Loci; D014132:Trachea / Q000276:immunology / Q000473:pathology; D014157:Transcription Factors / Q000502:physiology*
chemical_list: D054360:Chemokine CXCL1; C475895:Cxcl1 protein, mouse; D004268:DNA-Binding Proteins; D014157:Transcription Factors; C000598643:Zfp30 protein, mouse
keywords: CXCL1; MPP; Multiparent Advanced Generation Inter-Cross (MAGIC); asthma; complex traits; expression quantitative trait locus (eQTL); multiparental populations; neutrophil; systems genetics
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