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Genetic Variation in LRP1 and Pulmonary Function: Follow-Up of Human GWAS in the Mouse
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A3949 - Genetic Variation in LRP1 and Pulmonary Function: Follow-Up of Human GWAS in the Mouse
Author Block: C. Nichols1, H. Li1, J. S. House2, L. M. Degraff1, D. C. Zeldin3, S. J. London4; 1IIDL, NIEHS, Research Triangle Park, NC, United States, 2IIDL, NIEHS, RTP, NC, United States, 3IIDL, Div of Intramural Research, Research Triangle Park, NC, United States, 4Epidemiology, NIEHS, Research Triangle Park, NC, United States.
Human genome-wide association studies (GWAS) have identified over 100 loci associated with pulmonary function and related phenotypes, yet follow-up studies to determine causal genes or variants are few. Single nucleotide polymorphisms (SNPs) in the low density lipoprotein receptor-related protein 1 (LRP1) are associated with human pulmonary function in GWAS; there are no studies following up this locus. We investigated the effect of genetic disruption of the Lrp1 gene in specific pulmonary cell types on lung function (measured using flexiVenttm) in naïve and after lipopolysaccharide (LPS) exposure in murine models. Disrupting Lrp1 in either endothelial and epithelial cells does not alter baseline pulmonary function but induces a significant increase in airway responsiveness to methacholine (MCH). With disruption of Lrp1 in smooth muscle cells, there is a significant increase in tissue resistance, elastance, and tissue elastance at baseline. Further, disruption of Lrp1 in smooth muscle significantly increases airway responsiveness as measured by increased total lung resistance and airway resistance to MCH. To explore mechanisms leading to increased airway responsiveness, we analyzed the presence of immune cells in the lung collected by bronchoalveolar lavage, and observed no difference between animals with disruption of Lrp1 in endothelial, epithelial or smooth muscle cells and their respective wild type controls. After LPS exposure, the increased airway responsiveness with Lrp1 disruption in epithelial and endothelial cells was attenuated. Animals with Lrp1 disruption in smooth muscle cells have decreased airway responsiveness to MCH following LPS exposure. Collectively, disruption of Lrp1 in endothelial and epithelial cells leads to increased airway responsiveness to MCH, whereas disruption in smooth muscle cells additionally impacts baseline pulmonary function. This work helps to establish LRP1 as a causal gene at this GWAS locus. Further analyses will help to determine the precise molecular mechanisms contributing to this pulmonary phenotype.
Author Block: C. Nichols1, H. Li1, J. S. House2, L. M. Degraff1, D. C. Zeldin3, S. J. London4; 1IIDL, NIEHS, Research Triangle Park, NC, United States, 2IIDL, NIEHS, RTP, NC, United States, 3IIDL, Div of Intramural Research, Research Triangle Park, NC, United States, 4Epidemiology, NIEHS, Research Triangle Park, NC, United States.
Human genome-wide association studies (GWAS) have identified over 100 loci associated with pulmonary function and related phenotypes, yet follow-up studies to determine causal genes or variants are few. Single nucleotide polymorphisms (SNPs) in the low density lipoprotein receptor-related protein 1 (LRP1) are associated with human pulmonary function in GWAS; there are no studies following up this locus. We investigated the effect of genetic disruption of the Lrp1 gene in specific pulmonary cell types on lung function (measured using flexiVenttm) in naïve and after lipopolysaccharide (LPS) exposure in murine models. Disrupting Lrp1 in either endothelial and epithelial cells does not alter baseline pulmonary function but induces a significant increase in airway responsiveness to methacholine (MCH). With disruption of Lrp1 in smooth muscle cells, there is a significant increase in tissue resistance, elastance, and tissue elastance at baseline. Further, disruption of Lrp1 in smooth muscle significantly increases airway responsiveness as measured by increased total lung resistance and airway resistance to MCH. To explore mechanisms leading to increased airway responsiveness, we analyzed the presence of immune cells in the lung collected by bronchoalveolar lavage, and observed no difference between animals with disruption of Lrp1 in endothelial, epithelial or smooth muscle cells and their respective wild type controls. After LPS exposure, the increased airway responsiveness with Lrp1 disruption in epithelial and endothelial cells was attenuated. Animals with Lrp1 disruption in smooth muscle cells have decreased airway responsiveness to MCH following LPS exposure. Collectively, disruption of Lrp1 in endothelial and epithelial cells leads to increased airway responsiveness to MCH, whereas disruption in smooth muscle cells additionally impacts baseline pulmonary function. This work helps to establish LRP1 as a causal gene at this GWAS locus. Further analyses will help to determine the precise molecular mechanisms contributing to this pulmonary phenotype.
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