1. Genetics and Genomics
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Identification of an emphysema-associated genetic variant near TGFB2 with regulatory effects in lung fibroblasts

  1. Margaret M Parker
  2. Yuan Hao
  3. Feng Guo
  4. Betty Pham
  5. Robert Chase
  6. John Platig
  7. Michael H Cho
  8. Craig P Hersh
  9. Victor J Thannickal
  10. James Crapo
  11. George Washko
  12. Scott H Randell
  13. Edwin K Silverman
  14. Raúl San José Estépar
  15. Xiaobo Zhou  Is a corresponding author
  16. Peter J Castaldi  Is a corresponding author
  1. Brigham and Women's Hospital, United States
  2. University of Alabama at Birmingham, United States
  3. National Jewish Health, United States
  4. University of North Carolina at Chapel Hill, United States
Research Article
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Cite this article as: eLife 2019;8:e42720 doi: 10.7554/eLife.42720

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/).

The following data sets were generated
The following previously published data sets were used

Article and author information

Author details

  1. Margaret M Parker

    Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, United States
    Competing interests
    No competing interests declared.
  2. Yuan Hao

    Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, United States
    Competing interests
    No competing interests declared.
  3. Feng Guo

    Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, United States
    Competing interests
    No competing interests declared.
  4. Betty Pham

    Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, United States
    Competing interests
    No competing interests declared.
  5. Robert Chase

    Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, United States
    Competing interests
    No competing interests declared.
  6. John Platig

    Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, United States
    Competing interests
    No competing interests declared.
  7. Michael H Cho

    Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, United States
    Competing interests
    Michael H Cho, reports grants from GSK and personal fees from Genentech.
  8. Craig P Hersh

    Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, United States
    Competing interests
    Craig P Hersh, reports personal fees from Mylan, personal fees from AstraZeneca, Concert Pharmaceuticals, 23andMe, grants from Novartis, and Boehringer-Ingelheim.
  9. Victor J Thannickal

    Department of Medicine, University of Alabama at Birmingham, Birmingham, United States
    Competing interests
    No competing interests declared.
  10. James Crapo

    National Jewish Health, Denver, United States
    Competing interests
    No competing interests declared.
  11. George Washko

    Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Boston, United States
    Competing interests
    George Washko, reports grants and other support from Boehringer Ingelheim, PulmonX, BTG Interventional Medicine, Janssen Pharmaceuticals, and GSK.
  12. Scott H Randell

    Marsico Lung Institute, University of North Carolina at Chapel Hill, Chapel Hill, United States
    Competing interests
    Scott H Randell, reports receiving personal fees from Amgen.
  13. Edwin K Silverman

    Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, United States
    Competing interests
    Edwin K Silverman, received honoraria from Novartis for Continuing Medical Education Seminars and grant and travel support from GlaxoSmithKline.
  14. Raúl San José Estépar

    Applied Chest Imaging Laboratory, Brigham and Women's Hospital, Boston, United States
    Competing interests
    Raúl San José Estépar, reports personal fees from Boehringer Ingelheim, Eolo Medical, and Toshiba.
  15. Xiaobo Zhou

    Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, United States
    For correspondence
    xiaobo.zhou@channing.harvard.edu
    Competing interests
    No competing interests declared.
  16. Peter J Castaldi

    Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, United States
    For correspondence
    peter.castaldi@channing.harvard.edu
    Competing interests
    Peter J Castaldi, has received research support and consulting fees from GSK and Novartis.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9920-4713

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.

Reviewing Editor

  1. Andrew P Morris, University of Liverpool, United Kingdom

Publication history

  1. Received: October 9, 2018
  2. Accepted: July 25, 2019
  3. Accepted Manuscript published: July 25, 2019 (version 1)
  4. Version of Record published: August 14, 2019 (version 2)

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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