Journal Article

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

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

2018

Overview

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 × 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. 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.

• Publisher: Oxford University Press,American Thoracic Society
• Subject: Adolescent / African Americans / Albuterol - therapeutic use / Asthma / Asthma - drug therapy / Black or African American - genetics / Bronchodilator Agents - therapeutic use / Bronchodilators / Child / Female / Genome-Wide Association Study / Genomics / Hispanic Americans / Hispanic or Latino - genetics / Humans / Male / Mexican Americans - genetics / Minority & ethnic groups / Mortality / Original / Pediatrics / Pharmacogenomic Variants - genetics / Polymorphism, Single Nucleotide / Race Factors / United States / Whole genome sequencing