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- Title
Whole-Genome Sequencing of Pharmacogenetic Drug Response in Racially Diverse Children with Asthma.
- Authors
Mak, Angel C. Y.; White, Marquitta J.; Eckalbar, Walter L.; Szpiech, Zachary A.; Oh, Sam S.; Pino-Yanes, Maria; Donglei Hu; Goddard, Pagé; Huntsman, Scott; Galanter, Joshua; Chen Wu, Ann; Himes, Blanca E.; Germer, Soren; Vogel, Julia M.; Bunting, Karen L.; Eng, Celeste; Salazar, Sandra; Keys, Kevin L.; Liberto, Jennifer; Nuckton, Thomas J.
- Abstract
<bold>Rationale: </bold>Albuterol, a bronchodilator medication, is the first-line therapy for asthma worldwide. There are significant racial/ethnic differences in albuterol drug response.<bold>Objectives: </bold>To identify genetic variants important for bronchodilator drug response (BDR) in racially diverse children.<bold>Methods: </bold>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.<bold>Measurements and Main Results: </bold>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 neighboring gene, SLC39A8. The lack of other asthma study populations with BDR and whole-genome sequencing data on minority children makes it impossible to perform replication of our rare variant associations. Minority underrepresentation also poses significant challenges to identify age-matched and population-matched cohorts of sufficient sample size for replication of our common variant findings.<bold>Conclusions: </bold>The lack of minority data, despite a collaboration of eight universities and 13 individual laboratories, highlights the urgent need for a dedicated national effort to prioritize diversity in research. Our study expands the understanding of pharmacogenetic analyses in racially/ethnically diverse populations and advances the foundation for precision medicine in at-risk and understudied minority populations.
- Publication
American Journal of Respiratory & Critical Care Medicine, 2018, Vol 197, Issue 12, p1552
- ISSN
1073-449X
- Publication type
journal article
- DOI
10.1164/rccm.201712-2529OC