Multiomics analysis identifies BIRC3 as a novel glucocorticoid response-associated gene

Area of Science:

• Genomics
• Pharmacogenomics
• Molecular Biology

Background:

• Genetic factors influence inhaled corticosteroid (ICS) effectiveness in asthma.
• Previous studies have not identified actionable biological insights from these genetic associations.
• Multiomics data offer a pathway to explore glucocorticoid response mechanisms.

Purpose of the Study:

• To identify functionally relevant genetic associations with ICS response.
• To integrate multiomics data for a deeper understanding of genetic influences on ICS treatment.

Main Methods:

• Genome-wide association study (GWAS) variants were reranked using integrative multiomics scores.
• Data included ChIP-Seq for glucocorticoid receptor and RNA polymerase II binding, motifs, gene expression, and eQTLs.
• Candidate variants were tested for association with ICS response and asthma in independent cohorts.

Main Results:

• Four variants achieved significant multiomics integrative scores near the BIRC3 gene.
• These variants are located in a linkage disequilibrium block near glucocorticoid receptor binding sites.
• BIRC3 variants showed associations with ICS response and asthma in independent studies, with evidence of altered gene expression and regulation.

Conclusions:

• The BIRC3 gene locus is a priority for functional studies investigating inhaled corticosteroid response.
• These findings highlight BIRC3 as a potential key player in asthma pharmacogenomics.