IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v12y2021i1d10.1038_s41467-021-26347-z.html
   My bibliography  Save this article

Asthma-associated genetic variants induce IL33 differential expression through an enhancer-blocking regulatory region

Author

Listed:
  • Ivy Aneas

    (University of Chicago)

  • Donna C. Decker

    (University of Chicago)

  • Chanie L. Howard

    (University of Chicago)

  • Débora R. Sobreira

    (University of Chicago)

  • Noboru J. Sakabe

    (University of Chicago)

  • Kelly M. Blaine

    (University of Chicago)

  • Michelle M. Stein

    (University of Chicago)

  • Cara L. Hrusch

    (University of Chicago)

  • Lindsey E. Montefiori

    (University of Chicago)

  • Juan Tena

    (Universidad Pablo de Olavide)

  • Kevin M. Magnaye

    (University of Chicago)

  • Selene M. Clay

    (University of Chicago)

  • James E. Gern

    (University of Wisconsin School of Medicine and Public Health)

  • Daniel J. Jackson

    (University of Wisconsin School of Medicine and Public Health)

  • Matthew C. Altman

    (University of Washington)

  • Edward T. Naureckas

    (University of Chicago)

  • Douglas K. Hogarth

    (University of Chicago)

  • Steven R. White

    (University of Chicago)

  • Jose Luis Gomez-Skarmeta

    (Universidad Pablo de Olavide)

  • Nathan Schoetler

    (University of Chicago)

  • Carole Ober

    (University of Chicago)

  • Anne I. Sperling

    (University of Chicago
    University of Chicago)

  • Marcelo A. Nóbrega

    (University of Chicago)

Abstract

Genome-wide association studies (GWAS) have implicated the IL33 locus in asthma, but the underlying mechanisms remain unclear. Here, we identify a 5 kb region within the GWAS-defined segment that acts as an enhancer-blocking element in vivo and in vitro. Chromatin conformation capture showed that this 5 kb region loops to the IL33 promoter, potentially regulating its expression. We show that the asthma-associated single nucleotide polymorphism (SNP) rs1888909, located within the 5 kb region, is associated with IL33 gene expression in human airway epithelial cells and IL-33 protein expression in human plasma, potentially through differential binding of OCT-1 (POU2F1) to the asthma-risk allele. Our data demonstrate that asthma-associated variants at the IL33 locus mediate allele-specific regulatory activity and IL33 expression, providing a mechanism through which a regulatory SNP contributes to genetic risk of asthma.

Suggested Citation

  • Ivy Aneas & Donna C. Decker & Chanie L. Howard & Débora R. Sobreira & Noboru J. Sakabe & Kelly M. Blaine & Michelle M. Stein & Cara L. Hrusch & Lindsey E. Montefiori & Juan Tena & Kevin M. Magnaye & S, 2021. "Asthma-associated genetic variants induce IL33 differential expression through an enhancer-blocking regulatory region," Nature Communications, Nature, vol. 12(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-26347-z
    DOI: 10.1038/s41467-021-26347-z
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-021-26347-z
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-021-26347-z?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Chris McKennan & Dan Nicolae, 2019. "Accounting for unobserved covariates with varying degrees of estimability in high-dimensional biological data," Biometrika, Biometrika Trust, vol. 106(4), pages 823-840.
    2. Michelle Daya & Nicholas Rafaels & Tonya M. Brunetti & Sameer Chavan & Albert M. Levin & Aniket Shetty & Christopher R. Gignoux & Meher Preethi Boorgula & Genevieve Wojcik & Monica Campbell & Candelar, 2019. "Author Correction: Association study in African-admixed populations across the Americas recapitulates asthma risk loci in non-African populations," Nature Communications, Nature, vol. 10(1), pages 1-2, December.
    3. Michelle Daya & Nicholas Rafaels & Tonya M. Brunetti & Sameer Chavan & Albert M. Levin & Aniket Shetty & Christopher R. Gignoux & Meher Preethi Boorgula & Genevieve Wojcik & Monica Campbell & Candelar, 2019. "Association study in African-admixed populations across the Americas recapitulates asthma risk loci in non-African populations," Nature Communications, Nature, vol. 10(1), pages 1-13, December.
    4. Scott Smemo & Juan J. Tena & Kyoung-Han Kim & Eric R. Gamazon & Noboru J. Sakabe & Carlos Gómez-Marín & Ivy Aneas & Flavia L. Credidio & Débora R. Sobreira & Nora F. Wasserman & Ju Hee Lee & Vijitha P, 2014. "Obesity-associated variants within FTO form long-range functional connections with IRX3," Nature, Nature, vol. 507(7492), pages 371-375, March.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Gerard Llimos & Vincent Gardeux & Ute Koch & Judith F. Kribelbauer & Antonina Hafner & Daniel Alpern & Joern Pezoldt & Maria Litovchenko & Julie Russeil & Riccardo Dainese & Riccardo Moia & Abdurraouf, 2022. "A leukemia-protective germline variant mediates chromatin module formation via transcription factor nucleation," Nature Communications, Nature, vol. 13(1), pages 1-21, December.
    2. Pereira, Rita & Biroli, Pietro & von hinke, stephanie & Van Kippersluis, Hans & Galama, Titus & Rietveld, Niels & Thom, Kevin, 2022. "Gene-Environment Interplay in the Social Sciences," OSF Preprints d96z3, Center for Open Science.
    3. Moshe Shay Ben-Haim & Yishay Pinto & Sharon Moshitch-Moshkovitz & Vera Hershkovitz & Nitzan Kol & Tammy Diamant-Levi & Michal Schnaider Beeri & Ninette Amariglio & Haim Y. Cohen & Gideon Rechavi, 2021. "Dynamic regulation of N6,2′-O-dimethyladenosine (m6Am) in obesity," Nature Communications, Nature, vol. 12(1), pages 1-12, December.
    4. Matthew C. Pahl & Claudia A. Doege & Kenyaita M. Hodge & Sheridan H. Littleton & Michelle E. Leonard & Sumei Lu & Rick Rausch & James A. Pippin & Maria Caterina Rosa & Alisha Basak & Jonathan P. Bradf, 2021. "Cis-regulatory architecture of human ESC-derived hypothalamic neuron differentiation aids in variant-to-gene mapping of relevant complex traits," Nature Communications, Nature, vol. 12(1), pages 1-12, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-26347-z. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.