| Title: | Multiomics analysis identifies BIRC3 as a novel glucocorticoid response-associated gene |
| Journal: | Journal of Allergy and Clinical Immunology |
| Published: | 28 Dec 2021 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/34971648/ |
| DOI: | https://doi.org/10.1016/j.jaci.2021.11.025 |
| URL: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9177524 |
| Citations: | 7 (6 in last 2 years) as of 8 Aug 2024 |
Publication 12636
WARNING: the interactive features of this website use CSS3, which your browser does not support. To use the full features of this website, please update your browser.
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.</p>
OBJECTIVE: We sought to identify functionally relevant ICS-response genetic associations by integrating complementary multiomics data sets.</p>
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.</p>
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.</p>
CONCLUSIONS: BIRC3 should be prioritized for further functional studies of ICS response.</p>
10 Keywords
- Adrenal Cortex Hormones
- Asthma
- Baculoviral IAP Repeat-Containing 3 Protein
- Genome-Wide Association Study
- Glucocorticoids
- Humans
- Lung
- Polymorphism, Single Nucleotide
- RNA Polymerase II
- Receptors, Glucocorticoid
17 Authors
- Mengyuan Kan
- Avantika R Diwadkar
- Haoyue Shuai
- Jaehyun Joo
- Alberta L Wang
- Mei-Sing Ong
- Joanne E Sordillo
- Carlos Iribarren
- Meng X Lu
- Natalia Hernandez-Pacheco
- Javier Perez-Garcia
- Mario Gorenjak
- Uroš Potočnik
- Esteban G Burchard
- Maria Pino-Yanes
- Ann Chen Wu
- Blanca E Himes
1 Application
| Application ID | Title |
|---|---|
| 40375 | Genome-wide association study of acute respiratory failure in UK Biobank |
Enabling scientific discoveries that improve human health