An international research team co-led by Vanderbilt University Medical Center has revealed how variations in gene regulation in different cell types drive pulmonary fibrosis (PF), a progressive respiratory disorder characterized by scarring and loss of functional lung tissue.
The team’s findings, published March 28 in the journal Nature Genetics, may aid development of better treatments for the incurable disease, which currently leads to death or lung transplant within three to five years of diagnosis.
“It has become clear that genetic factors contribute substantially to a person’s risk of developing pulmonary fibrosis, but how these genetic variations lead to disease has not been well understood,” said Jonathan Kropski, MD, associate professor of Medicine at VUMC.
“Our work is focused on understanding the molecular mechanisms that drive the disease so that we can start to think about therapeutics that would treat those mechanisms rather than treating the end-stage fibrosis,” said Nicholas Banovich, PhD, from the Translational Genomics Research Institute (TGen) in Phoenix.
Kropski and Banovich, associate professor in the Integrated Cancer Genomics Division at TGen, part of Los Angeles-based City of Hope, are co-senior authors of the paper with Davis McCarthy, DPhil, head of Bioinformatics and Cellular Genomics at St. Vincent’s Institute of Medical Research in Melbourne, Australia.
The researchers performed single-cell RNA-sequencing of lung tissue taken from 116 people, 67 of whom had PF. Combining these findings with genome-wide genotype data, they mapped expression quantitative trait loci (eQTL), which reflect variations in the regulation of gene expression, across 38 cell types.
The researchers found that while most eQTL were shared across a cell lineage, a small fraction was specific to an individual cell type. For example, eQTL related to PF risk often were found in epithelial cells that line the lungs and airways.
“Seeing that a lot of the genetic risk for the disease was localizing to these cells strengthens a theory that this is where a lot of the action is happening in PF,” Banovich said.
Some eQTL had different effects on gene expression in healthy compared to PF lung tissue, often in a highly cell-type specific way. This suggests that the impact of certain variants on gene expression and cellular function evolves through the course of PF, the researchers explained.
“By understanding how these gene regulators contribute to chronic lung disease, we see an opportunity to develop new targeted treatments,” Kropski said.
Added McCarthy, “The success of this international collaboration is a tribute to the close integration of clinical, genomic, and computational researchers within the team.”
Other VUMC co-authors were Chase Taylor, David Flaherty, Brittany Matlock, Carla Calvi, Timothy Blackwell, MD, Lorraine Ware, MD, Matthew Bacchetta, MD, MBA, and Ciara Shaver, MD, PhD.
The research was supported in part by National Institutes of Health grants R01HL145372, P01HL092870, K08HL136888, and R01HG011886, the U.S. Department of Defense, the National Health and Medical Research Council of Australia, and the Doris Duke Charitable Foundation.