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Enhancer RNA transcription pinpoints functional genetic variants linked to asthma

Author

Listed:
  • Sarah K. Sasse

    (National Jewish Health)

  • Amber Dahlin

    (Brigham and Women’s Hospital and Harvard Medical School)

  • Lynn Sanford

    (University of Colorado)

  • Margaret A. Gruca

    (University of Colorado)

  • Arnav Gupta

    (National Jewish Health
    University of Colorado)

  • Fabienne Gally

    (University of Colorado
    National Jewish Health)

  • Ann Chen Wu

    (Harvard Medical School and Harvard Pilgrim Health Care Institute)

  • Carlos Iribarren

    (Kaiser Permanente)

  • Robin D. Dowell

    (University of Colorado
    University of Colorado
    University of Colorado)

  • Scott T. Weiss

    (Brigham and Women’s Hospital and Harvard Medical School)

  • Anthony N. Gerber

    (National Jewish Health
    University of Colorado
    National Jewish Health)

Abstract

Bidirectional enhancer RNA (eRNA) transcription is a widespread response to environmental signals and glucocorticoids. We investigated whether single nucleotide polymorphisms (SNPs) within dynamically regulated eRNA-transcribing regions contribute to genetic variation in asthma. Through applying multivariate regression modeling with permutation-based significance thresholding to a large clinical cohort, we identified novel associations between asthma and 35 SNPs located in eRNA-transcribing regions implicated in regulating cellular processes relevant to asthma, including rs258760 (mean allele frequency = 0.34, asthma odds ratio = 0.95; P = 5.04E-03). We show that rs258760 disrupts an active aryl hydrocarbon receptor (AHR) response element linked to transcriptional regulation of the glucocorticoid receptor gene by AHR ligands, which are commonly found in combusted air pollution. The role of rs258760 as a protective variant for asthma was independently validated using UK Biobank data. Our findings establish eRNA signatures as a tool for discovery of functional genetic variants and define a novel association between air pollution, glucocorticoid signaling and asthma.

Suggested Citation

  • Sarah K. Sasse & Amber Dahlin & Lynn Sanford & Margaret A. Gruca & Arnav Gupta & Fabienne Gally & Ann Chen Wu & Carlos Iribarren & Robin D. Dowell & Scott T. Weiss & Anthony N. Gerber, 2025. "Enhancer RNA transcription pinpoints functional genetic variants linked to asthma," Nature Communications, Nature, vol. 16(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-57693-x
    DOI: 10.1038/s41467-025-57693-x
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