GSDMB/ORMDL3 Rare/Common Variants Are Associated with Inhaled Corticosteroid Response among Children with Asthma.

Area of Science:

• Genomics
• Pediatric Asthma Research
• Pharmacogenomics

Background:

• Asthma affects over 300 million globally, with inhaled corticosteroids (ICS) as a primary treatment.
• Genome-wide association studies have identified some genes linked to ICS response, but the combined effect of rare and common variants is less understood.
• Pediatric populations and diverse ancestries are crucial for comprehensive asthma genetic research.

Purpose of the Study:

• To investigate the combined effect of rare and common genetic variants on ICS treatment response in children with asthma.
• To identify specific genes and genomic regions associated with differential ICS response.
• To validate findings in an independent cohort and demonstrate the utility of pediatric biobanks.

Main Methods:

• Whole exome sequencing (WES) data from pediatric asthma patients in the PrecisionLink Biobank.
• Sequence Kernel Association Test (SKAT) using a combined sum test for 12 pre-selected genomic regions.
• Analysis adjusted for age, sex, BMI, and stratified by race.
• Replication analysis in the Biorepository and Integrative Genomics (BIG) Initiative cohort.

Main Results:

• The GSDMB/ORMDL3 genomic region showed a significant association with ICS response when considering the combined effect of rare and common variants (p=0.003) in White children from the PrecisionLink Biobank.
• This association was successfully replicated in the BIG Initiative cohort (p=0.02).
• No other tested regions reached statistical significance after Bonferroni correction.

Conclusions:

• The combined effect of rare and common variants in GSDMB/ORMDL3 is associated with ICS response in pediatric asthma.
• This study underscores the value of pediatric biobanks for genetic research in asthma.
• Integrating rare and common variant analysis provides a more comprehensive understanding of genetic contributions to ICS response.