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Title: Plethysmography Phenotype QTL in Mice Before and After Allergen Sensitization and Challenge

Allergic asthma is common airway disease that is characterized in part by enhanced airway constriction in response to nonspecific stimuli. Genome-wide association studies have identified multiple loci associated with asthma risk in humans, but these studies have not accounted for gene–environment interactions, which are thought to be important factors in asthma. To identify quantitative trait loci (QTL) that regulate responses to a common human allergen, we applied a house dust mite mouse (HDM) model of allergic airway disease (AAD) to 146 incipient lines of the Collaborative Cross (CC) and the CC founder strains. We employed a longitudinal study design in which mice were phenotyped for response to the bronchoconstrictor methacholine both before and after HDM sensitization and challenge using whole body plethysmography (WBP). There was significant variation in methacholine responsiveness due to both strain and HDM treatment, as reflected by changes in the WBP parameter enhanced pause. We also found that distinct QTL regulate baseline [chromosome (Chr) 18] and post-HDM (Chr 19) methacholine responsiveness and that post-HDM airway responsiveness was correlated with other features of AAD. Finally, using invasive measurements of airway mechanics, we tested whether the Chr 19 QTL affects lung resistance per se using C57BL/6J mice and amore » consomic strain but found that QTL haplotype did not affect lung resistance. We conclude that aspects of baseline and allergen-induced methacholine responsiveness are associated with genetic variation, and that robust detection of airway resistance QTL in genetically diverse mice will be facilitated by direct measurement of airway mechanics.« less
Authors:
 [1]
  1. Univ. of North Carolina, Chapel Hill, NC (United States)
Publication Date:
Type:
Accepted Manuscript
Journal Name:
G3
Additional Journal Information:
Journal Volume: 6; Journal Issue: 9; Journal ID: ISSN 2160-1836
Publisher:
Genetics Society of America
Research Org:
Univ. of North Carolina, Chapel Hill, NC (United States)
Sponsoring Org:
USDOE Office of Science (SC), Biological and Environmental Research (BER) (SC-23)
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES
OSTI Identifier:
1378559

Kelada, Samir N. P.. Plethysmography Phenotype QTL in Mice Before and After Allergen Sensitization and Challenge. United States: N. p., Web. doi:10.1534/g3.116.032912.
Kelada, Samir N. P.. Plethysmography Phenotype QTL in Mice Before and After Allergen Sensitization and Challenge. United States. doi:10.1534/g3.116.032912.
Kelada, Samir N. P.. 2016. "Plethysmography Phenotype QTL in Mice Before and After Allergen Sensitization and Challenge". United States. doi:10.1534/g3.116.032912. https://www.osti.gov/servlets/purl/1378559.
@article{osti_1378559,
title = {Plethysmography Phenotype QTL in Mice Before and After Allergen Sensitization and Challenge},
author = {Kelada, Samir N. P.},
abstractNote = {Allergic asthma is common airway disease that is characterized in part by enhanced airway constriction in response to nonspecific stimuli. Genome-wide association studies have identified multiple loci associated with asthma risk in humans, but these studies have not accounted for gene–environment interactions, which are thought to be important factors in asthma. To identify quantitative trait loci (QTL) that regulate responses to a common human allergen, we applied a house dust mite mouse (HDM) model of allergic airway disease (AAD) to 146 incipient lines of the Collaborative Cross (CC) and the CC founder strains. We employed a longitudinal study design in which mice were phenotyped for response to the bronchoconstrictor methacholine both before and after HDM sensitization and challenge using whole body plethysmography (WBP). There was significant variation in methacholine responsiveness due to both strain and HDM treatment, as reflected by changes in the WBP parameter enhanced pause. We also found that distinct QTL regulate baseline [chromosome (Chr) 18] and post-HDM (Chr 19) methacholine responsiveness and that post-HDM airway responsiveness was correlated with other features of AAD. Finally, using invasive measurements of airway mechanics, we tested whether the Chr 19 QTL affects lung resistance per se using C57BL/6J mice and a consomic strain but found that QTL haplotype did not affect lung resistance. We conclude that aspects of baseline and allergen-induced methacholine responsiveness are associated with genetic variation, and that robust detection of airway resistance QTL in genetically diverse mice will be facilitated by direct measurement of airway mechanics.},
doi = {10.1534/g3.116.032912},
journal = {G3},
number = 9,
volume = 6,
place = {United States},
year = {2016},
month = {7}
}