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

Mak ACY, White MJ, Eckalbar WL, et al. Am J Respir Crit Care Med. 2018 Jun 15;197(12):1552-64. [CrossRef] [PubMed]

Albuterol, a bronchodilator medication, is the first-line therapy for asthma worldwide. However, there are significant racial/ethnic differences in albuterol drug response. The authors performed whole-genome sequencing pharmacogenetics study from 1,441 children with asthma to identify genetic association with bronchodilator response (BDR). They 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 neighboring gene, SLC39A8. This study demonstrates that a set of genetic mutations found mostly in children of African-American or Puerto Rican descent may make them less likely to respond to albuterol. This research suggests that a genetic test could be developed to help identify patients who are resistant to albuterol and could benefit from alternative treatments.