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

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

  2. Author Address

    University of California San Francisco, Department of Medicine, San Francisco, California, United States ; angelcymak@gmail.com., University of California San Francisco, Department of Medicine, San Francisco, California, United States., University of California San Francisco, Department of Bioengineering and Therapeutic Sciences, San Francisco, California, United States., Hospital Universitario N.S. de Candelaria, Universidad de La Laguna, Research Unit, Santa Cruz de Tenerife, Spain., Instituto de Salud Carlos III, 38176, CIBER de Enfermedades Respiratorias, Madrid, Spain., Genentech Inc, 7412, South San Francisco, California, United States., Brigham and Women 39;s Hospital and Harvard Medical School, Channing Division of Network Medicine, Department of Medicine, Boston, Massachusetts, United States., Harvard Medical School and Pilgrim Health Care Institute, Precision Medicine Translational Research (PRoMoTeR) Center, Department of Population Medicine, Boston, Massachusetts, United States., University of Pennsylvania , Department of Biostatistics, Epidemiology and Informatics, Philadelphia , Pennsylvania, United States., New York Genome Center, New York, New York, United States., The Scripps Research Institute, La Jolla, California, United States., New York Genome Center, 377591, New York, New York, United States., University of California San Francisco, Department of Pediatrics, San Francisco, California, United States., University of California San Francisco, Cardiovascular Research Institute, San Francisco, California, United States., University of California San Francisco, Institute for Human Genetics, San Francisco, California, United States., Henry Ford Health System, Department of Public Health Sciences, Detroit, Michigan, United States., University of Pittsburgh School of Medicine, Division of Pediatric Pulmonary Medicine, Allergy and Immunology, Pittsburgh, Pennsylvania, United States., The Children 39;s Hospital of Philadelphia Research Institute, Center for Applied Genomics, Philadelphia, Pennsylvania, United States., Perelman School of Medicine, University of Pennsylvania, Department of Pediatrics, Philadelphia, Pennsylvania, United States., Jacobi Medical Center, 24502, Pediatric Pulmonary Division, Bronx, New York, United States., Kaiser Permanente-Vallejo Medical Center, Department of Allergy and Immunology, Vallejo, California, United States., Baylor College of Medicine and Texas Children 39;s Hospital, Department of Pediatrics, Houston, Texas, United States., Children 39;s Hospital and Research Center, Oakland, California, United States., Bay Area Pediatrics, Oakland, California, United States., Northwestern University, Department of Medicine, Chicago, Illinois, United States., Allergy & ENT Associates, The Woodlands, Texas, United States., University of California, San Francisco, Department of Medicine, San Francisco, California, United States., University of Tennessee Health Science Center, Memphis, Tennessee, United States., David Geffen School of Medicine, University of California Los Angeles, Department of Pediatrics, Los Angeles, California, United States., Veterans Caribbean Health Care System, San Juan, Puerto Rico., Frederick National Laboratory, Basic Science Laboratory, Center for Cancer Research, National Cancer Institute, Leidos Biomedical Research, Frederick, Maryland, United States., National Laboratory of Genomics for Biodiversity (UGALANGEBIO), Irapuato, Mexico., Centro de Neumolog 237;a Pedi 225;trica, San Juan, Puerto Rico., Northwestern University, Feinberg School of Medicine 39;s Division of Allergy and Immunology, Chicago, Illinois, United States., Ann & Robert H. Lurie Children 39;s Hospital of Chicago, Chicago, Illinois, United States., Henry Ford Health System, Department of Internal Medicine, Detroit, Michigan, United States., Henry Ford Health System, 2971, Center for Health Policy and Health Services Research, Detroit, Michigan, United States., National Jewish Health, 2930, Center for Genes, Environment and Health, Department of Pediatrics, Denver, Colorado, United States., The Rockefeller University, Laboratory of Molecular Neuro-Oncology, New York, New York, United States., The Rockefeller University, Howard Hughes Medical Institute, New York, New York, United States., University of California San Francisco, Quantitative Biosciences Institute, San Francisco, California, United States.,
    1. Year: 2018
    2. Date: Jun 15
    3. Epub Date: 2018 03 06
  2. Journal: American Journal of Respiratory and Critical Care Medicine
    1. 197
    2. 12
    3. Pages: 1552-1564
  4. Type of Article: Article
  1. Abstract:

    Rationale Albuterol, a bronchodilator medication, is the first-line therapy for asthma worldwide. There are significant racial/ethnic differences in albuterol drug response. Objective To identify genetic variants important for bronchodilator drug response (BDR) in racially diverse children. Methods We performed the first whole genome sequencing (WGS) 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 < 3.53x10-7) and suggestive (p < 7.06x10-6) loci near genes previously associated with lung capacity (DNAH5), immunity (NFKB1 and PLCB1), and ß-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 (eQTL) for a neighboring gene, SLC39A8. The lack of other asthma study populations with BDR and WGS 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. Conclusion The lack of minority data, despite a collaboration of 8 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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External Sources

  1. View Full Text
  2. DOI: 10.1164/rccm.201712-2529OC
  3. PMID: 29509491
  4. PMCID: PMC6006403
  5. View record in Web of Science®
  6. WOS: 000435459000011

Library Notes

  1. Fiscal Year: FY2017-2018
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