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Identification of an emphysema-associated genetic variant near TGFB2 with regulatory effects in lung fibroblasts
Murine studies have linked TGF-β 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-β superfamily. However, the functional regulatory mechanisms at these loci have not been identified. We...
Autores principales: | , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
eLife Sciences Publications, Ltd
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6693893/ https://www.ncbi.nlm.nih.gov/pubmed/31343404 http://dx.doi.org/10.7554/eLife.42720 |
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author | Parker, Margaret M Hao, Yuan Guo, Feng Pham, Betty Chase, Robert Platig, John Cho, Michael H Hersh, Craig P Thannickal, Victor J Crapo, James Washko, George Randell, Scott H Silverman, Edwin K San José Estépar, Raúl Zhou, Xiaobo Castaldi, Peter J |
author_facet | Parker, Margaret M Hao, Yuan Guo, Feng Pham, Betty Chase, Robert Platig, John Cho, Michael H Hersh, Craig P Thannickal, Victor J Crapo, James Washko, George Randell, Scott H Silverman, Edwin K San José Estépar, Raúl Zhou, Xiaobo Castaldi, Peter J |
author_sort | Parker, Margaret M |
collection | PubMed |
description | Murine studies have linked TGF-β 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-β superfamily. However, the functional regulatory mechanisms at these loci have not been identified. We performed the largest GWAS of emphysema patterns to date, identifying 10 GWAS loci including an association peak spanning a 200 kb 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 ~ 100 bp 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-β pathway to emphysema in humans. |
format | Online Article Text |
id | pubmed-6693893 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | eLife Sciences Publications, Ltd |
record_format | MEDLINE/PubMed |
spelling | pubmed-66938932019-08-16 Identification of an emphysema-associated genetic variant near TGFB2 with regulatory effects in lung fibroblasts Parker, Margaret M Hao, Yuan Guo, Feng Pham, Betty Chase, Robert Platig, John Cho, Michael H Hersh, Craig P Thannickal, Victor J Crapo, James Washko, George Randell, Scott H Silverman, Edwin K San José Estépar, Raúl Zhou, Xiaobo Castaldi, Peter J eLife Genetics and Genomics Murine studies have linked TGF-β 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-β superfamily. However, the functional regulatory mechanisms at these loci have not been identified. We performed the largest GWAS of emphysema patterns to date, identifying 10 GWAS loci including an association peak spanning a 200 kb 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 ~ 100 bp 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-β pathway to emphysema in humans. eLife Sciences Publications, Ltd 2019-07-25 /pmc/articles/PMC6693893/ /pubmed/31343404 http://dx.doi.org/10.7554/eLife.42720 Text en © 2019, Parker et al http://creativecommons.org/licenses/by/4.0/ http://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited. |
spellingShingle | Genetics and Genomics Parker, Margaret M Hao, Yuan Guo, Feng Pham, Betty Chase, Robert Platig, John Cho, Michael H Hersh, Craig P Thannickal, Victor J Crapo, James Washko, George Randell, Scott H Silverman, Edwin K San José Estépar, Raúl Zhou, Xiaobo Castaldi, Peter J Identification of an emphysema-associated genetic variant near TGFB2 with regulatory effects in lung fibroblasts |
title | Identification of an emphysema-associated genetic variant near TGFB2 with regulatory effects in lung fibroblasts |
title_full | Identification of an emphysema-associated genetic variant near TGFB2 with regulatory effects in lung fibroblasts |
title_fullStr | Identification of an emphysema-associated genetic variant near TGFB2 with regulatory effects in lung fibroblasts |
title_full_unstemmed | Identification of an emphysema-associated genetic variant near TGFB2 with regulatory effects in lung fibroblasts |
title_short | Identification of an emphysema-associated genetic variant near TGFB2 with regulatory effects in lung fibroblasts |
title_sort | identification of an emphysema-associated genetic variant near tgfb2 with regulatory effects in lung fibroblasts |
topic | Genetics and Genomics |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6693893/ https://www.ncbi.nlm.nih.gov/pubmed/31343404 http://dx.doi.org/10.7554/eLife.42720 |
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