Identification of an emphysema-associated genetic variant near TGFB2 with regulatory effects in lung fibroblasts
- Brigham and Women's Hospital, United States
- University of Alabama at Birmingham, United States
- National Jewish Health, United States
- University of North Carolina at Chapel Hill, United States
Abstract
Murine studies have linked TGF-b signaling to emphysema, and human genome-wide association studies (GWAS) studies of lung function and COPD have identified associated regions near genes in the TGF-b superfamily. However, the functional regulatory mechanisms at these loci have not been identified. We performed the largest GWAS of emphysema patterns to date, identifying ten GWAS loci including an association peak spanning a 200kb region downstream from TGFB2. Integrative analysis of publicly available eQTL, DNaseI, and chromatin conformation data identified a putative functional variant, rs1690789, that may regulate TGFB2 expression in human fibroblasts. Using chromatin conformation capture, we confirmed that the region containing rs1690789 contacts the TGFB2 promoter in fibroblasts, and CRISPR/Cas-9 targeted deletion of a ~100bp region containing rs1690789 resulted in decreased TGFB2 expression in primary human lung fibroblasts. These data provide novel mechanistic evidence linking genetic variation affecting the TGF-b pathway to emphysema in humans.
Data availability
COPDGene genetic data and RNA-seq data have been deposited in dbGaP under accession code phs000765.v3.p2. To access these data users may apply for access to the dbGaP data repository (https://www.ncbi.nlm.nih.gov/books/NBK482114/).
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Blood RNA-seqNCBI dbGaP, phs000765.v3.p2.
Article and author information
Author details
Funding
National Heart, Lung, and Blood Institute (R01 HL124233)
- Peter J Castaldi
National Heart, Lung, and Blood Institute (R01 HL126596)
- Peter J Castaldi
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2019, Parker et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Identification of an emphysema-associated genetic variant near TGFB2 with regulatory effects in lung fibroblasts
eLife 8:e42720.
https://doi.org/10.7554/eLife.42720
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