Abstract
In a previous study we determined that BcA86 mice, a strain belonging to a panel of AcB/BcA recombinant congenic strains, have an airway responsiveness phenotype resembling mice from the airway hyperresponsive A/J strain. The majority of the BcA86 genome is however from the hyporesponsive C57BL/6J strain. The aim of this study was to identify candidate regions and genes associated with airway hyperresponsiveness (AHR) by quantitative trait locus (QTL) analysis using the BcA86 strain. Airway responsiveness of 205 F2 mice generated from backcrossing BcA86 strain to C57BL/6J strain was measured and used for QTL analysis to identify genomic regions in linkage with AHR. Consomic mice for the QTL containing chromosomes were phenotyped to study the contribution of each chromosome to lung responsiveness. Candidate genes within the QTL were selected based on expression differences in mRNA from whole lungs, and the presence of coding non-synonymous mutations that were predicted to have a functional effect by amino acid substitution prediction tools. One QTL for AHR was identified on Chromosome 12 with its 95% confidence interval ranging from 54.6 to 82.6 Mbp and a maximum LOD score of 5.11 (p = 3.68×10−3). We confirmed that the genotype of mouse Chromosome 12 is an important determinant of lung responsiveness using a Chromosome 12 substitution strain. Mice with an A/J Chromosome 12 on a C57BL/6J background have an AHR phenotype similar to hyperresponsive strains A/J and BcA86. Within the QTL, genes with deleterious coding variants, such as Foxa1, and genes with expression differences, such as Mettl21d and Snapc1, were selected as possible candidates for the AHR phenotype. Overall, through QTL analysis of a recombinant congenic strain, microarray analysis and coding variant analysis we identified Chromosome 12 and three potential candidate genes to be in linkage with airway responsiveness.
Highlights
The assessment of airway responsiveness to methacholine is one of the key tests for diagnosing asthma
This paper reports quantitative trait locus (QTL) mapping results using a unique inbred strain generated as part of a panel of AcB/BcA recombinant congenic strains (RCS)
The results presented in this paper describe in detail our strategy that allowed us to identify, a QTL on Chromosome 12 that is linked to airway hyperresponsiveness (AHR)
Summary
The assessment of airway responsiveness to methacholine is one of the key tests for diagnosing asthma. Airways naturally respond to stimuli such as methacholine by constricting, resulting in decreased airflow to the lungs. In asthmatic patients, this response occurs more quickly and forcefully, and at lower doses of the airway constricting agent. Studies involving murine models have shown that mice have an airway responsiveness phenotype comparable to humans [1]. Certain inbred strains, such as the A/J strain, have an airway hyperresponsive phenotype when exposed to methacholine and can be used as a model to study the phenotype observed in asthmatic individuals. Other strains, such as the C57BL/6J and C3H/HeJ strains, are relatively less responsive to methacholine [2]
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