Whole-Genome sequencing of pharmacogenetic drug response in racially diverse children with asthma

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

Research output: Contribution to journalArticlepeer-review

51 Scopus citations

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 populationspecific and shared genetic variants associated with BDR, including genome-wide significant (P,3.5331027) and suggestive (P, 7.0631026) loci near genes previously associated with lung capacity (DNAH5), immunity (NFKB1 and PLCB1), and b-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 wholegenome 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.

Original languageEnglish (US)
Pages (from-to)1552-1564
Number of pages13
JournalAmerican journal of respiratory and critical care medicine
Volume197
Issue number12
DOIs
StatePublished - Jun 15 2018

All Science Journal Classification (ASJC) codes

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine

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