Integrative genetic analysis of allergic inflammation in the murine lung.
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.
1 National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland.
Samir N P
SN
Kelada
Danielle E
DE
Carpenter
David L
DL
Aylor
Peter
P
Chines
Holly
H
Rutledge
Elissa J
EJ
Chesler
Gary A
GA
Churchill
Fernando
F
Pardo-Manuel de Villena
David A
DA
Schwartz
Francis S
FS
Collins
D000818:Animals; D039741:Antigens, Dermatophagoides / Q000276:immunology; D016535:Bronchial Hyperreactivity / Q000276:immunology*; D040002:Dermatophagoides pteronyssinus / Q000378:metabolism; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D005823:Genetics; D006967:Hypersensitivity / Q000276:immunology / Q000378:metabolism*; D007073:Immunoglobulin E / Q000097:blood; D007249:Inflammation; D008168:Lung / Q000276:immunology* / Q000378:metabolism; D008297:Male; D051379:Mice; D010641:Phenotype; D040641:Quantitative Trait Loci; D012130:Respiratory Hypersensitivity / Q000276:immunology
D039741:Antigens, Dermatophagoides; D007073:Immunoglobulin E
allergic airway disease; gene expression quantitative trait loci; systems genetics