Multiomics analysis identifies BIRC3 as a novel glucocorticoid response–associated gene - 03/06/22
Abstract |
Background |
Inhaled corticosteroid (ICS) response among patients with asthma is influenced by genetics, but biologically actionable insights based on associations have not been found. Various glucocorticoid response omics data sets are available to interrogate their biological effects.
Objective |
We sought to identify functionally relevant ICS-response genetic associations by integrating complementary multiomics data sets.
Methods |
Variants with P values less than 10−4 from a previous ICS-response genome-wide association study were reranked on the basis of integrative scores determined from (1) glucocorticoid receptor– and (2) RNA polymerase II–binding regions inferred from ChIP-Seq data for 3 airway cell types, (3) glucocorticoid response element motifs, (4) differentially expressed genes in response to glucocorticoid exposure according to 20 transcriptomic data sets, and (5) expression quantitative trait loci from GTEx. Candidate variants were tested for association with ICS response and asthma in 6 independent studies.
Results |
Four variants had significant (q value < 0.05) multiomics integrative scores. These variants were in a locus consisting of 52 variants in high linkage disequilibrium (r2 ≥ 0.8) near glucocorticoid receptor–binding sites by the gene BIRC3. Variants were also BIRC3 expression quantitative trait loci in lung, and 2 were within/near putative glucocorticoid response element motifs. BIRC3 had increased RNA polymerase II occupancy and gene expression, with glucocorticoid exposure in 2 ChIP-Seq and 13 transcriptomic data sets. Some BIRC3 variants in the 52-variant locus were associated (P < .05) with ICS response in 3 independent studies and others with asthma in 1 study.
Conclusions |
BIRC3 should be prioritized for further functional studies of ICS response.
Le texte complet de cet article est disponible en PDF.Key words : Asthma, ChIP-Seq, genome-wide association study, glucocorticoid response, glucocorticoid receptor, inhaled corticosteroids, integrative analysis, multiomics, transcriptomics
Abbreviations used : 1000G, ASM, eQTL, EUR, ICS, GALA II, GERA, GR, GRE, GSK, GWAS, LD, RNAP II, SAGE, SNP, TSS
Plan
| Funding was provided by the National Institutes of Health awards (grant nos. R01 HL133433, R01 HL141992, P30ES013508, K23HL151819, R01 HL117004, X01HL134589, R01HL155024, R01MD010443, and R01ES015794), the Spanish Ministry of Science and Innovation grant (grant no. RYC-2015-17205) and fellowship (grant no. FPU19/02175), the European Academy of Allergy and Clinical Immunology Medium-Term Research Fellowship 2021, the Sandler Family Foundation, the American Asthma Foundation, the RWJF Amos Medical Faculty Development Program, and Harry Wm. and Diana V. Hind Distinguished in Pharmaceutical Sciences II. |
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| Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest. |
Vol 149 - N° 6
P. 1981-1991 - juin 2022 Retour au numéro
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