Integrative Genetic Analysis of Allergic Inflammation in the Murine Lung

Abstract

Airway allergen exposure induces inflammation among individuals with atopy that is characterized by altered airway gene expression, elevated levels of T helper type 2 cytokines, mucus hypersecretion, and airflow obstruction. To identify the genetic determinants of the airway allergen response, we employed a systems genetics approach. We applied a house dust mite mouse model of allergic airway disease to 151 incipient lines of the Collaborative Cross, a new mouse genetic reference population, and measured serum IgE, airway eosinophilia, and gene expression in the lung. Allergen-induced serum IgE and airway eosinophilia were not correlated. We detected quantitative trait loci (QTL) for airway eosinophilia on chromosome (Chr) 11 (71.802-87.098 megabases [Mb]) and allergen-induced IgE on Chr 4 (13.950-31.660 Mb). More than 4,500 genes expressed in the lung had gene expression QTL (eQTL), the majority of which were located near the gene itself. However, we also detected approximately 1,700 trans-eQTL, and many of these trans-eQTL clustered into two regions on Chr 2. We show that one of these loci (at 147.6 Mb) is associated with the expression of more than 100 genes, and, using bioinformatics resources, fine-map this locus to a 53 kb-long interval. We also use the gene expression and eQTL data to identify a candidate gene, Tlcd2, for the eosinophil QTL. Our results demonstrate that hallmark allergic airway disease phenotypes are associated with distinct genetic loci on Chrs 4 and 11, and that gene expression in the allergically inflamed lung is controlled by both cis and trans regulatory factors.

Genetic Regulation ofZfp30, CXCL1, and Neutrophilic Inflammation in Murine Lung

“…We obtained 151 male preCC mice (ages 10-14 weeks) from Oak Ridge National Laboratory (Chesler et al 2008;Kelada et al 2012;Kelada et al 2014). Each mouse was from an independent CC line that had undergone 5-14 generations of inbreeding.…”

“…On day 14, mice were challenged with 50 mg of Der p 1, administered by orotracheal aspiration (Kelada et al 2011;Kelada et al 2014). Mice were phenotyped on day 17 by performing lavage followed by differential cell counts.…”

“…We previously identified eQTL from whole lung RNA using data from a subset of the same mice described here (n = 131) (Kelada et al 2014). We used these data to identify genes with eQTL in the QTL region on chromosome 7.…”

“…We used these data to identify genes with eQTL in the QTL region on chromosome 7. We included genes whose eQTL peak resided in the confidence interval for the PMN and CXCL1 QTL, spanning 26-30 Mb, and limited the analysis to local eQTL, which we defined as within 10 Mb upstream or downstream of the gene's position (Kelada et al 2014).…”

“…The genomes of the CC founder strains Yalcin et al 2011) and the features of the CC population have been described recently (Collaborative Cross Consortium 2012). Results obtained using incipient CC lines that were partially inbred (referred to as "preCC" mice) have been notable in terms of phenotypic diversity and identification of new QTL (Aylor et al 2011;Bottomly et al 2012;Kelada et al 2012;Ferris et al 2013;Kelada et al 2014).…”