Genome wide association studies of asthma have not explained environmental risk or variable clinical efficacy of glucocorticoids. Bidirectional enhancer RNA (eRNA) transcription is a widespread response to environmental signals and glucocorticoids. Therefore, we investigated whether single nucleotide polymorphisms (SNPs) within dynamically regulated enhancer RNA (eRNA)-transcribing regions contribute to genetic variation in asthma. Through applying machine-learning methods to a large clinical cohort, we identified novel associations between asthma and 36 SNPs located in eRNA-transcribing regions implicated in regulating diverse cellular processes relevant to asthma. Functional validation established that rs258760 (mean allele frequency = 0.35, asthma odds ratio 0.95; P<0.005) eliminates an active aryl hydrocarbon receptor (AHR) response element linked to transcriptional regulation of the glucocorticoid receptor by AHR ligands commonly found in air pollution. Our findings establish eRNA signatures as a tool for discovery of functional genetic variants and define a novel link between air pollution, glucocorticoid signaling and asthma.

ANG and SKS own shares in Psammiad Therapeutics; RDD is a cofounder of Arpeggio Biosciences; STW receives royalties from UpToDate and is on the Scientific Board of Histolix.

NHLBI R01 HL109557 (to A.G.); NHLBI R01 HL152244 (to A.D.); NIH R01 GM125871 (to R.D.)

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