Single-cell RNA sequencing reveals profibrotic roles of distinct epithelial and mesenchymal lineages in pulmonary fibrosis.

Pulmonary fibrosis (PF) is a form of chronic lung disease characterized by pathologic epithelial remodeling and accumulation of extracellular matrix (ECM). To comprehensively define the cell types, mechanisms, and mediators driving fibrotic remodeling in lungs with PF, we performed single-cell RNA sequencing of single-cell suspensions from 10 nonfibrotic control and 20 PF lungs. Analysis of 114,396 cells identified 31 distinct cell subsets/states. We report that a remarkable shift in epithelial cell phenotypes occurs in the peripheral lung in PF and identify several previously unrecognized epithelial cell phenotypes, including a KRT5- /KRT17 + pathologic, ECM-producing epithelial cell population that was highly enriched in PF lungs. Multiple fibroblast subtypes were observed to contribute to ECM expansion in a spatially discrete manner. Together, these data provide high-resolution insights into the complexity and plasticity of the distal lung epithelium in human disease and indicate a diversity of epithelial and mesenchymal cells contribute to pathologic lung fibrosis.

Characterization of the Metabochip in diverse populations from the International HapMap Project in the Epidemiologic Architecture for Genes Linked to Environment (EAGLE) project.

Genome-wide association studies (GWAS) have identified hundreds of genomic regions associated with common human disease and quantitative traits. A major research avenue for mature genotype-phenotype associations is the identification of the true risk or functional variant for downstream molecular studies or personalized medicine applications. As part of the Population Architecture using Genomics and Epidemiology (PAGE) study, we as Epidemiologic Architecture for Genes Linked to Environment (EAGLE) are fine-mapping GWAS-identified genomic regions for common diseases and quantitative traits. We are currently genotyping the Metabochip, a custom content BeadChip designed for fine-mapping metabolic diseases and traits, in∼15,000 DNA samples from patients of African, Hispanic, and Asian ancestry linked to de-identified electronic medical records from the Vanderbilt University biorepository (BioVU). As an initial study of quality control, we report here the genotyping data for 360 samples of European, African, Asian, and Mexican descent from the International HapMap Project. In addition to quality control metrics, we report the overall allele frequency distribution, overall population differentiation (as measured by FST), and linkage disequilibrium patterns for a select GWAS-identified region associated with low-density lipoprotein cholesterol levels to illustrate the utility of the Metabochip for fine-mapping studies in the diverse populations expected in EAGLE, the PAGE study, and other efforts underway designed to characterize the complex genetic architecture underlying common human disease and quantitative traits.