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Adam19 Deficiency Impacts Pulmonary Function: Human GWAS Follow-up in a Mouse Knockout Model
Huiling Li1, John S House2, Cody E Nichols3
1Immunity, Inflammation and Disease Laboratory, Division of Intramural Research, National Institute of Environmental Health Sciences, 111 TW Alexander Drive, MD A3-05, PO Box 12233, Research Triangle Park, North Carolina, 27709, USA.
Lung
|August 17, 2024
Summary
The study investigated the role of ADAM19 in lung function using a mouse model. Adam19 knockout mice showed altered body composition and lung mechanics, suggesting ADAM19 regulates pulmonary function.
Area of Science:
- Genetics
- Pulmonary Medicine
- Animal Models
Background:
- Genome-wide association studies (GWAS) have identified over 550 loci linked to human pulmonary function, but causal genes remain largely unknown.
- Single nucleotide polymorphisms in a disintegrin and metalloprotease domain 19 (ADAM19) are consistently associated with pulmonary function in GWAS.
Purpose of the Study:
- To investigate the causal role of Adam19 in pulmonary function using a genetically modified mouse model.
- To determine if Adam19 deficiency impacts lung mechanics, inflammation, and gene expression.
Main Methods:
- Generated Adam19 knockout (KO) mice and validated gene targeting via RNA-Seq and RT-qPCR.
- Assessed mouse body composition using dual-energy X-ray absorptiometry and lung function with flexiVent.
- Analyzed gene expression profiles in KO and wild-type (WT) lungs and evaluated inflammatory responses post-LPS exposure.
Main Results:
- Adam19 KO mice exhibited reduced body weight, tibial length, soft weight, fat weight, and bone mineral content compared to WT.
- KO mice showed altered lung function, including decreased respiratory system elastance and increased FEV0.1 and FVC.
- Adam19 deficiency attenuated lung inflammation, neutrophil extravasation, and altered gene expression, with negative enrichment for TNF pathways.
Conclusions:
- Murine findings support a causal role for ADAM19 in regulating pulmonary function, consistent with human GWAS data.
- ADAM19 influences lung mechanics, inflammation, and overall body composition.
