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Am J Respir Crit Care Med. 2018 Jun 15;197(12):1552-1564. doi: 10.1164/rccm.201712-2529OC.

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

Author information

1
1 Department of Medicine.
2
2 Department of Bioengineering and Therapeutic Sciences.
3
3 Research Unit, Hospital Universitario N. S. de Candelaria, Universidad de La Laguna, Santa Cruz de Tenerife, Spain.
4
4 CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain.
5
5 Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
6
6 Precision Medicine Translational Research (PRoMoTeR) Center, Department of Population Medicine, Harvard Medical School and Pilgrim Health Care Institute, Boston, Massachusetts.
7
7 Department of Biostatistics, Epidemiology and Informatics and.
8
8 New York Genome Center, New York, New York.
9
9 Department of Pediatrics.
10
10 Cardiovascular Research Institute.
11
11 Institute for Human Genetics, and.
12
12 Department of Public Health Sciences.
13
13 Division of Pediatric Pulmonary Medicine, Allergy and Immunology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
14
15 Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
15
14 Center for Applied Genomics, The Children's Hospital of Philadelphia Research Institute, Philadelphia, Pennsylvania.
16
16 Pediatric Pulmonary Division, Jacobi Medical Center, Bronx, New York.
17
17 Department of Allergy and Immunology, Kaiser Permanente Vallejo Medical Center, Vallejo, California.
18
18 Department of Pediatrics, Baylor College of Medicine and Texas Children's Hospital, Houston, Texas.
19
19 Children's Hospital and Research Center, Oakland, California.
20
20 Bay Area Pediatrics, Oakland, California.
21
21 Department of Medicine, Northwestern University, Chicago, Illinois.
22
22 Department of Pediatrics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California.
23
23 Veterans Caribbean Health Care System, San Juan, Puerto Rico.
24
24 Basic Science Laboratory, Center for Cancer Research, National Cancer Institute, Leidos Biomedical Research, Frederick National Laboratory, Frederick, Maryland.
25
25 National Laboratory of Genomics for Biodiversity (UGA-LANGEBIO), CINVESTAV, Irapuato, Guanajuato, Mexico.
26
26 Centro de Neumologia Pediatrica, San Juan, Puerto Rico.
27
27 Division of Allergy and Immunology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
28
28 Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois.
29
29 Department of Internal Medicine, and.
30
30 Center for Health Policy and Health Services Research, Henry Ford Health System, Detroit, Michigan.
31
31 Center for Genes, Environment and Health, Department of Pediatrics, National Jewish Health, Denver, Colorado; and.
32
32 Laboratory of Molecular Neuro-Oncology and.
33
33 Howard Hughes Medical Institute, The Rockefeller University, New York, New York.
34
34 Quantitative Biosciences Institute, University of California San Francisco, San Francisco, California.

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.

KEYWORDS:

Latinos; NFKB1; albuterol; asthma; minority

PMID:
29509491
PMCID:
PMC6006403
[Available on 2019-06-15]
DOI:
10.1164/rccm.201712-2529OC

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