Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2019
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
_version_ 1783443751783366656
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
work_keys_str_mv AT parkermargaretm identificationofanemphysemaassociatedgeneticvariantneartgfb2withregulatoryeffectsinlungfibroblasts
AT haoyuan identificationofanemphysemaassociatedgeneticvariantneartgfb2withregulatoryeffectsinlungfibroblasts
AT guofeng identificationofanemphysemaassociatedgeneticvariantneartgfb2withregulatoryeffectsinlungfibroblasts
AT phambetty identificationofanemphysemaassociatedgeneticvariantneartgfb2withregulatoryeffectsinlungfibroblasts
AT chaserobert identificationofanemphysemaassociatedgeneticvariantneartgfb2withregulatoryeffectsinlungfibroblasts
AT platigjohn identificationofanemphysemaassociatedgeneticvariantneartgfb2withregulatoryeffectsinlungfibroblasts
AT chomichaelh identificationofanemphysemaassociatedgeneticvariantneartgfb2withregulatoryeffectsinlungfibroblasts
AT hershcraigp identificationofanemphysemaassociatedgeneticvariantneartgfb2withregulatoryeffectsinlungfibroblasts
AT thannickalvictorj identificationofanemphysemaassociatedgeneticvariantneartgfb2withregulatoryeffectsinlungfibroblasts
AT crapojames identificationofanemphysemaassociatedgeneticvariantneartgfb2withregulatoryeffectsinlungfibroblasts
AT washkogeorge identificationofanemphysemaassociatedgeneticvariantneartgfb2withregulatoryeffectsinlungfibroblasts
AT randellscotth identificationofanemphysemaassociatedgeneticvariantneartgfb2withregulatoryeffectsinlungfibroblasts
AT silvermanedwink identificationofanemphysemaassociatedgeneticvariantneartgfb2withregulatoryeffectsinlungfibroblasts
AT sanjoseesteparraul identificationofanemphysemaassociatedgeneticvariantneartgfb2withregulatoryeffectsinlungfibroblasts
AT zhouxiaobo identificationofanemphysemaassociatedgeneticvariantneartgfb2withregulatoryeffectsinlungfibroblasts
AT castaldipeterj identificationofanemphysemaassociatedgeneticvariantneartgfb2withregulatoryeffectsinlungfibroblasts