Immunity, 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.
Biostatistics & Computational Biology Branch, Division of Intramural Research, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA.
Lung. 2024 Oct;202(5):659-672. doi: 10.1007/s00408-024-00738-7. Epub 2024 Aug 17.
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 (ADAM19) are consistently related to pulmonary function in GWAS. Thus, we used a mouse model to investigate the causal link between Adam19 and pulmonary function.
We created an Adam19 knockout (KO) mouse model and validated the gene targeting using RNA-Seq and RT-qPCR. Mouse body composition was assessed using dual-energy X-ray absorptiometry. Mouse lung function was measured using flexiVent.
Contrary to prior publications, the KO was not neonatal lethal. KO mice had lower body weight and shorter tibial length than wild-type (WT) mice. Their body composition revealed lower soft weight, fat weight, and bone mineral content. Adam19 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. Adam19 KO had attenuated tissue damping and tissue elastance in response to methacholine following LPS exposure. Adam19 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 (Cd300lg, Kpna2, and Pttg1) implicated in lung biology and pathogenesis. Gene set enrichment analysis identified negative enrichment for TNF pathways.
Our murine findings support a causal role of ADAM19, implicated in human GWAS, in regulating pulmonary function.
全基因组关联研究（GWAS）已经发现了超过 550 个与人类肺功能相关的基因位点；然而，大多数基因的因果作用仍不确定。在 GWAS 中，解整合素金属蛋白酶域 19（ADAM19）的单核苷酸多态性与肺功能始终相关。因此，我们使用小鼠模型来研究 Adam19 与肺功能之间的因果关系。
我们构建了 Adam19 敲除（KO）小鼠模型，并通过 RNA-Seq 和 RT-qPCR 验证了基因靶向。使用双能 X 射线吸收仪评估小鼠的身体成分。使用 flexiVent 测量小鼠的肺功能。
与之前的出版物相反，KO 并不具有新生致死性。KO 小鼠的体重和胫骨长度均低于野生型（WT）小鼠。它们的身体成分显示出较低的软组织重量、脂肪重量和骨矿物质含量。Adam19 KO 小鼠的基础呼吸系统弹性、呼吸功、组织阻尼、组织弹性和 50%用力肺活量时的强制呼气流量降低，但 FEV 和 FVC 增加。在 LPS 暴露后，Adam19 KO 小鼠对乙酰甲胆碱的反应中，组织阻尼和组织弹性降低。与 WT 相比，KO 小鼠在给予 LPS 后，气道中的中性粒细胞渗出也减少。KO 和 WT 肺的 RNA-Seq 分析确定了几个差异表达的基因（Cd300lg、Kpna2 和 Pttg1），这些基因与肺生物学和发病机制有关。基因集富集分析发现 TNF 途径呈负富集。
我们的小鼠研究结果支持 ADAM19 在调节肺功能方面的因果作用，ADAM19 是人类 GWAS 中发现的一个基因。
