Genetic influences on asthma susceptibility in the developing lung.
Asthma is the leading serious pediatric chronic illness in the United States, affecting 7.1 million children. The prevalence of asthma in children under 4 years of age has increased dramatically in the last 2 decades. Existing evidence suggests that this increase in prevalence derives from early environmental exposures acting on a pre-existing asthma-susceptible genotype. We studied the origins of asthma susceptibility in developing lung in rat strains that model the distinct phenotypes of airway hyperresponsiveness (Fisher rats) and atopy (brown Norway [BN] rats). Postnatal BN rat lungs showed increased epithelial proliferation and tracheal goblet cell hyperplasia. Fisher pups showed increased lung resistance at age 2 weeks, with elevated neutrophils throughout the postnatal period. Diverse transcriptomic signatures characterized the distinct respiratory phenotypes of developing lung in both rat models. Linear regression across age and strain identified developmental variation in expression of 1,376 genes, and confirmed both strain and temporal regulation of lung gene expression. Biological processes that were heavily represented included growth and development (including the T Box 1 transcription factor [Tbx5], the epidermal growth factor receptor [Egfr], the transforming growth factor beta-1-induced transcript 1 [Tgfbr1i1]), extracellular matrix and cell adhesion (including collagen and integrin genes), and immune function (including lymphocyte antigen 6 (Ly6) subunits, IL-17b, Toll-interacting protein, and Ficolin B). Genes validated by quantitative RT-PCR and protein analysis included collagen III alpha 1 Col3a1, Ly6b, glucocorticoid receptor and Importin-13 (specific to the BN rat lung), and Serpina1 and Ficolin B (specific to the Fisher lung). Innate differences in patterns of gene expression in developing lung that contribute to individual variation in respiratory phenotype are likely to contribute to the pathogenesis of asthma.
Carpe
Nicole
N
Department of Human Genetics, McGill University, 4060 Saint Catherine West, Montreal, PQ, Canada.
Mandeville
Isabel
I
Ribeiro
Leslie
L
Ponton
Andre
A
Martin
James G
JG
Kho
Alvin T
AT
Chu
Jen-Hwa
JH
Tantisira
Kelan
K
Weiss
Scott T
ST
Raby
Benjamin A
BA
Kaplan
Feige
F
D021581:Active Transport, Cell Nucleus / Q000235:genetics; D000818:Animals; D000831:Animals, Newborn; D000950:Antigens, Ly / Q000235:genetics / Q000378:metabolism; D001249:Asthma / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D005260:Female; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D020022:Genetic Predisposition to Disease; D020397:Goblet Cells / Q000378:metabolism / Q000473:pathology; D006965:Hyperplasia; D007113:Immunity, Innate / Q000235:genetics; D007958:Leukocyte Count; D008168:Lung / Q000201:enzymology / Q000254:growth & development* / Q000473:pathology* / Q000503:physiopathology; D008297:Male; D051381:Rats; D012129:Respiratory Function Tests; D013997:Time Factors; D015854:Up-Regulation / Q000235:genetics
D000950:Antigens, Ly; C526827:Ly6 protein, mouse