Pharmacogenetics of inhaled corticosteroids in obesity-related childhood asthma

Asthma is a multifactorial disease driven by genetic and environmental factors that influence pathogenesis and therapeutic response. Obesity and asthma share overlapping inflammatory pathways that worsen disease severity and impair medication response. Inhaled corticosteroids (ICS) are the cornerstone of long-term persistent asthma management, yet 25-30% of patients exhibit poor response. Genetic variants in the T, GLCCI1, and CRHR1 genes have been associated with differential ICS response; however, whether obesity modifies these pharmacogenetic relationships remains unexplored. We conducted a candidate gene analysis in the Caucasian Childhood Asthma Management Program cohort to examine whether obesity status (BMI > 95th percentile; obesity: n = 24, no obesity: n = 176) modifies pharmacogenetic associations with ICS response. The primary outcome was the 2-month change in forced expiratory volume in the first second percentage predicted (FEV1PP) following ICS treatment, evaluated for single-nucleotide polymorphisms (SNPs) rs6456042, rs37972, and rs242941. The overall cohort demonstrated a 5.7% improvement in FEV1PP (P = 0.003). The no-obesity group showed a 6.6% increase (P = 0.001), while the obesity group experienced a -6.2% change (P = 0.26). Significant pharmacogenetic associations with ICS response were identified in the no-obesity group, whereas the obesity group exhibited attenuated or reversed effects for all three SNPs, most notably rs37972.These findings demonstrate for the first time that established pharmacogenetic associations with ICS response are differentially expressed by obesity status. Obesity acts as a pharmacogenetic modifier and likely represents a distinct asthma endotype with unique genetic determinants of ICS response. Endotype-based stratification incorporating obesity is a necessary step toward precision pharmacogenomics in asthma and warrants dedicated pharmacogenomic investigation.