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<p>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 <i>rs258760</i> (mean allele frequency = 0.34, asthma odds ratio = 0.95; P = 5.04E-03). We show that <i>rs258760</i> 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 <i>rs258760</i> 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.</p>

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Enhancer RNA transcription pinpoints functional genetic variants linked to asthma

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年3月31日

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  • 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

摘要

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.