Immunity, Inflammation, and Disease Laboratory.
Biostatistics and Computational Biology Branch.
Am J Respir Cell Mol Biol. 2021 Mar;64(3):368-378. doi: 10.1165/rcmb.2019-0444OC.
Human genome-wide association studies (GWASs) have identified more than 270 loci associated with pulmonary function; however, follow-up studies to determine causal genes at these loci are few. SNPs in low-density lipoprotein receptor-related protein 1 (LRP1) are associated with human pulmonary function in GWASs. Using murine models, we investigated the effect of genetic disruption of the gene in smooth muscle cells on pulmonary function in naive animals and after exposure to bacterial LPS or house dust mite extract. Disruption of in smooth muscle cells leads to an increase in tissue resistance, elastance, and tissue elastance at baseline. Furthermore, disruption of in smooth muscle increases airway responsiveness as measured by increased total lung resistance and airway resistance after methacholine. Immune cell counts in BAL fluid were increased in animals with disruption. The difference in airway responsiveness by genotype observed in naive animals was not observed after LPS or house dust mite extract exposure. To further explore the mechanisms contributing to changes in pulmonary function, we identified several ligands dysregulated with disruption in smooth muscle cells. These data suggest that dysregulation of LRP1 in smooth muscle cells affects baseline pulmonary function and airway responsiveness and helps establish as the causal gene at this GWAS locus.
人类全基因组关联研究（GWAS）已经确定了 270 多个与肺功能相关的基因位点；然而，针对这些基因座确定因果基因的后续研究很少。低密度脂蛋白受体相关蛋白 1（LRP1）基因的 SNP 与 GWAS 中的人类肺功能有关。使用小鼠模型，我们研究了基因敲除平滑肌细胞中的 基因对未暴露于细菌 LPS 或屋尘螨提取物的动物的肺功能的影响。在平滑肌细胞中敲除 基因会导致组织阻力、弹性和基线时的组织弹性增加。此外，平滑肌细胞中的 基因敲除会增加气道反应性，表现为乙酰甲胆碱后总肺阻力和气道阻力增加。BAL 液中的免疫细胞计数在 基因敲除的动物中增加。在未暴露于 LPS 或屋尘螨提取物的动物中，观察到的基因型引起的气道反应性差异不存在。为了进一步探讨导致肺功能变化的机制，我们鉴定了平滑肌细胞中与 基因敲除失调的几种配体。这些数据表明，平滑肌细胞中 LRP1 的失调会影响基础肺功能和气道反应性，并有助于将 LRP1 确定为该 GWAS 基因座的因果基因。
