%0 Journal Article %J Am J Respir Crit Care Med %D 2018 %T Whole-Genome Sequencing of Pharmacogenetic Drug Response in Racially Diverse Children with Asthma. %A Mak, Angel C Y %A White, Marquitta J %A Eckalbar, Walter L %A Szpiech, Zachary A %A Oh, Sam S %A Pino-Yanes, Maria %A Hu, Donglei %A Goddard, Pagé %A Huntsman, Scott %A Galanter, Joshua %A Wu, Ann Chen %A Himes, Blanca E %A Germer, Soren %A Vogel, Julia M %A Bunting, Karen L %A Eng, Celeste %A Salazar, Sandra %A Keys, Kevin L %A Liberto, Jennifer %A Nuckton, Thomas J %A Nguyen, Thomas A %A Torgerson, Dara G %A Kwok, Pui-Yan %A Levin, Albert M %A Celedón, Juan C %A Forno, Erick %A Hakonarson, Hakon %A Sleiman, Patrick M %A Dahlin, Amber %A Tantisira, Kelan G %A Weiss, Scott T %A Serebrisky, Denise %A Brigino-Buenaventura, Emerita %A Farber, Harold J %A Meade, Kelley %A Lenoir, Michael A %A Avila, Pedro C %A Sen, Saunak %A Thyne, Shannon M %A Rodriguez-Cintron, William %A Winkler, Cheryl A %A Moreno-Estrada, Andrés %A Sandoval, Karla %A Rodriguez-Santana, Jose R %A Kumar, Rajesh %A Williams, L Keoki %A Ahituv, Nadav %A Ziv, Elad %A Seibold, Max A %A Darnell, Robert B %A Zaitlen, Noah %A Hernandez, Ryan D %A Burchard, Esteban G %X

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) and suggestive (P < 7.06 × 10) 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.

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.

%B Am J Respir Crit Care Med %V 197 %P 1552-1564 %8 2018 Jun 15 %G eng %N 12 %1 http://www.ncbi.nlm.nih.gov/pubmed/29509491?dopt=Abstract %R 10.1164/rccm.201712-2529OC