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

Mak, A. C. Y.; White, M. J.; Eckalbar, W. L.; Szpiech, Z. A.; Oh, S. S.; Pino-Yanes, M.; Hu, D.; Goddard, P.; Huntsman, S.; Galanter, J.; Wu, A. C.; Himes, B. E.; Germer, S.; Vogel, J. M.; Bunting, K. L.; Eng, C.; Salazar, S.; Keys, K. L.; Liberto, J.; Nuckton, T. J.; Nguyen, T. A.; Torgerson, D. G.; Kwok, P. Y.; Levin, A. M.; Celedon, J. C.; Forno, E.; Hakonarson, H.; Sleiman, P. M.; Dahlin, A.; Tantisira, K. G.; Weiss, S. T.; Serebrisky, D.; Brigino-Buenaventura, E.; Farber, H. J.; Meade, K.; Lenoir, M. A.; Avila, P. C.; Sen, S.; Thyne, S. M.; Rodriguez-Cintron, W.; Winkler, C. A.; Moreno-Estrada, A.; Sandoval, K.; Rodriguez-Santana, J. R.; Kumar, R.; Williams, L. K.; Ahituv, N.; Ziv, E.; Seibold, M. A.; Darnell, R. B.; Zaitlen, N.; Hernandez, R. D.; Burchard, E. G.

Am J Respir Crit Care Med. 2018 Mar 7; 197(12):1552-1564

Abstract

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 x 10(-7)) and suggestive (P < 7.06 x 10(-6)) loci near genes previously associated with lung capacity (DNAH5), immunity (NFKB1 and PLCB1), and beta-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. CONCLUSIONS: 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.

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