Belfield, G. | bioRxiv Science

bioRxiv2023

Translational mapping of spatially resolved transcriptomes in human and mouse pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with poor prognosis and limited treatment options. Efforts to identify effective treatments are thwarted by limited understanding of IPF pathogenesis and poor translatability of available preclinical models. To address these limitations, we generated spatially resolved transcriptome maps of human IPF and bleomycin-induced mouse lung fibrosis. We uncovered distinct fibrotic niches in the IPF lung, characterized by aberrant alveolar epithelial cells in a microenvironment dominated by TGF{beta} signaling alongside factors such as p53 and ApoE. We also identified a clear divergence between the arrested alveolar regeneration in the IPF fibrotic niches, and the active tissue repair in the acutely fibrotic mouse lung. Our study offers in-depth insights into the IPF transcriptional landscape and proposes alveolar regeneration as a promising therapeutic strategy for IPF.

molecular biology↗

bioRxiv2020

A broad exome study of the genetic architecture of asthma reveals novel patient subgroups

IntroductionAsthma risk is a complex interplay between genetic susceptibility and environment. Despite many significantly-associated common variants, the contribution of rarer variants with potentially greater effect sizes has not been as extensively studied. We present an exome-based study adopting 24,576 cases and 120,530 controls to assess the contribution of rare protein-coding variants to the risk of early-onset or all-comer asthma. MethodsWe performed case-control analyses on three genetic units: variant-, gene- and pathway-level, using sequence data from the Scandinavian Asthma Genetic Study and UK Biobank participants with asthma. Cases were defined as all-comer asthma (n=24,576) and early-onset asthma (n=5,962). Controls were 120,530 UK Biobank participants without reported history of respiratory illness. ResultsVariant-level analyses identified statistically significant variants at moderate-to-common allele frequency, including protein-truncating variants in FLG and IL33. Asthma risk was significantly increased not only by individual, common FLG protein-truncating variants, but also among the collection of rare-to-private FLG protein-truncating variants (p=6.8x10-7). This signal was driven by early-onset asthma and did not correlate with circulating eosinophil levels. In contrast, a single splice variant in IL33 was significantly protective (p=8.0x10-10), while the collection of remaining IL33 protein-truncating variants showed no class effect (p=0.54). A pathway-based analysis identified that protein-truncating variants in loss-of-function intolerant genes were significantly enriched among individuals with asthma. ConclusionsAccess to the full allele frequency spectrum of protein-coding variants provides additional clarity about the potential mechanisms of action for FLG and IL33. Beyond these two significant drivers, we detected a significant enrichment of protein-truncating variants in loss-of-function intolerant genes.

genomics↗