Whole Genome Sequencing of Pharmacogenetic Drug Response in Racially Diverse Children with Asthma

Rationale: Albuterol, a bronchodilator medication, is the first-line therapy for asthma worldwide. There are significant racial/ethnic differences in albuterol drug response.Objectives: To identify genetic variants important for bronchodilator drug response (BDR) in racially diverse children.Methods: We performed the first whole-genome sequencing pharmacogenetics study from 1,441 children with asthma from the tails of the BDR distribution to identify genetic association with BDR.Measurements and Main Results: We identified population-specific and shared genetic variants associated with BDR, including genome-wide significant (P < 3.53 × 10−7) and suggestive (P < 7.06 × 10−6) loci near genes previously associated with lung capacity (DNAH5), immunity (NFKB1 and PLCB1), and β-adrenergic signaling (ADAMTS3 and COX18). Functional analyses of the BDR-associated SNP in NFKB1 revealed potential regulatory function in bronchial smooth muscle cells. The SNP is also an expression quantitative trait locus for a neighb...