Lrp1 Regulation of Pulmonary Function: Follow-up of Human GWAS in Mouse.

Human genome-wide association studies (GWAS) have identified over 270 loci associated with pulmonary function; however, follow-up studies to determine causal genes at these loci are few. Single nucleotide polymorphisms (SNPs) in low-density lipoprotein receptor-related protein 1 (LRP1) are associated with human pulmonary function in GWAS. Using murine models, we investigated the effect of genetic disruption of the Lrp1 gene in smooth muscle cells on pulmonary function in naïve animals and after exposure to bacterial lipopolysaccharide (LPS) or house dust mite extract (HDME). Disruption of Lrp1 in smooth muscle cells leads to an increase in tissue resistance, elastance, and tissue elastance at baseline. Further, disruption of Lrp1 in smooth muscle increases airway responsiveness as measured by increased total lung resistance and airway resistance after methacholine. Immune cell counts in bronchoalveolar lavage fluid were increased in animals with Lrp1 disruption. The difference in airway responsiveness by genotype observed in naïve animals was not observed following LPS or HDME exposure. To further explore the mechanisms contributing to changes in pulmonary function, we identified several ligands dysregulated with Lrp1 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 LRP1 as the causal gene at this GWAS locus.