title: Genetic analysis of lung function in inbred mice suggests vitamin D receptor as a candidate gene.
abstract: Vitamin D receptor (VDR) polymorphisms are associated with an increased asthma incidence in human populations; however, observations in Vdr knockout mice are unclear. The aim of our study was to determine the influence of the genetic variation in Vdr among inbred strains on lung resistance (i.e., dynamic and airway resistance). In an intercross between the strains C57BL/6J (B6) and KK/HlJ (KK), we identified that a significant QTL for dynamic resistance on Chr X was interacting with a QTL on Chr 15. The Chr 15 QTL peak was located in close proximity to the Vdr locus. We further examined if phenotypes of several inbred strains with varying Vdr genotypes differed. Strains with a B6-like genotype on the Vdr locus had significantly lower airway resistance than strains with a KK-like genotype. Vdr knockout mice were examined for dynamic resistance and showed significantly higher resistance than mice with one (i.e., heterozygous) or both copies (i.e., wild-type) of the Vdr. In comparison to B6, the strain A/J is more resistant but carries the same genotype at the Vdr locus. Dietary vitamin D manipulation in the strain A/J did not rescue the high airway resistance phenotype. Finally, we observed that serum vitamin D does not correlate significantly with lung resistance parameters in a survey of 18 strains. Conclusively, Vdr contributes to the phenotypic variation of lung resistance in inbred mice but other molecules in the Vdr pathway and extended network [i.e., Chr X gene(s)] may contribute as well.
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME, USA. anb128@pitt.edu
authors.forename: Annerose
authors.initials: A
authors.lastname: Berndt
authors.forename: H S
authors.initials: HS
authors.lastname: Savage
authors.forename: T M
authors.initials: TM
authors.lastname: Stearns
authors.forename: B
authors.initials: B
authors.lastname: Paigen
mesh_terms: D000403:Airway Resistance / Q000235:genetics / Q000502:physiology; D000818:Animals; D005260:Female; D056726:Genetic Association Studies; D006801:Humans; D006824:Hybridization, Genetic; D008168:Lung / Q000502:physiology*; D008297:Male; D051379:Mice; D008805:Mice, Inbred A; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci; D018167:Receptors, Calcitriol / Q000172:deficiency / Q000235:genetics* / Q000502:physiology; D014807:Vitamin D / Q000008:administration & dosage / Q000097:blood
chemical_list: D018167:Receptors, Calcitriol; D014807:Vitamin D