Adam19 Deficiency Impacts Pulmonary Function: Human GWAS Follow-up in Mouse.

Purpose: Over 550 loci have been associated with human pulmonary function in genome-wide association studies (GWAS); however, the causal role of most remains uncertain. Single nucleotide polymorphisms in a disintegrin and metalloprotease domain 19 () are consistently related to pulmonary function in GWAS. Thus, we used a mouse model to investigate the causal link between and pulmonary function.

Methods: We created an knockout (KO) mouse model and validated the gene targeting using RNA-Seq and RT-qPCR. Contrary to prior publications, the KO was not neonatal lethal. Thus, we phenotyped the KO.

Results: KO mice had lower body weight and shorter tibial length than wild type (WT). Dual-energy X-ray Absorptiometry indicated lower soft weight, fat weight, and bone mineral content in KO mice. In lung function analyses using flexiVent, compared to WT, KO had decreased baseline respiratory system elastance, minute work of breathing, tissue damping, tissue elastance, and forced expiratory flow at 50% forced vital capacity but higher FEV and FVC. KO had attenuated tissue damping and tissue elastance in response to methacholine following LPS exposure. KO also exhibited attenuated neutrophil extravasation into the airway after LPS administration compared to WT. RNA-Seq analysis of KO and WT lungs identified several differentially expressed genes () implicated in lung biology and pathogenesis. Gene set enrichment analysis identified negative enrichment for TNF pathways.

Conclusion: Our murine findings support a causal role of ADAM19, implicated in human GWAS, in regulating pulmonary function.