@article{7a90c17e5d49418f8f5eae091c3e04d2,
title = "Whole-Genome sequencing of pharmacogenetic drug response in racially diverse children with asthma",
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.",
author = "Mak, {Angel C.Y.} and White, {Marquitta J.} and Eckalbar, {Walter L.} and Szpiech, {Zachary A.} and Oh, {Sam S.} and Maria Pino-Yanes and Donglei Hu and Paǵe Goddard and Scott Huntsman and Joshua Galanter and {Chen Wu}, Ann and Himes, {Blanca E.} and Soren Germer and Vogel, {Julia M.} and Bunting, {Karen L.} and Celeste Eng and Sandra Salazar and Keys, {Kevin L.} and Jennifer Liberto and Nuckton, {Thomas J.} and Nguyen, {Thomas A.} and Torgerson, {Dara G.} and Kwok, {Pui Yan} and Levin, {Albert M.} and Celed{\'o}n, {Juan C.} and Erick Forno and Hakon Hakonarson and Sleiman, {Patrick M.} and Amber Dahlin and Tantisira, {Kelan G.} and Weiss, {Scott T.} and Denise Serebrisky and Emerita Brigino-Buenaventura and Farber, {Harold J.} and Kelley Meade and Lenoir, {Michael A.} and Avila, {Pedro C.} and Saunak Sen and Thyne, {Shannon M.} and William Rodriguez-Cintron and Winkler, {Cheryl A.} and And{\'r}es Moreno-Estrada and Karla Sandoval and Rodriguez-Santana, {Jose R.} and Rajesh Kumar and {Keoki Williams}, L. and Nadav Ahituv and Elad Ziv and Seibold, {Max A.} and Darnell, {Robert B.} and Noah Zaitlen and Hernandez, {Ryan D.} and Burchard, {Esteban G.}",
note = "Funding Information: *These authors contributed equally to this work. ‡Current affiliation: Genentech, South San Francisco, California. xCurrent affiliation: The Scripps Research Institute, La Jolla, California. ||Current affiliation: Allergy and ENT Associates, The Woodlands, Texas. ¶Current affiliation: Division of Biostatistics, Department of Preventive Medicine, University of Tennessee Health Science Center, Memphis, Tennessee. Whole-genome sequencing for the TOPMed (Trans-Omics in Precision Medicine) program was supported by the NHLBI. Whole-genome sequencing for GALA II (NHLBI TOPMed: Genes-environments and Admixture in Latino Americans) Study (phs000920) and SAGE (NHLBI TOPMed: Study of African Americans, Asthma, Genes and Environments) (phs000921) was performed at the New York Genome Center (3R01HL117004-01S3). Centralized read mapping and genotype calling, along with variant quality metrics and filtering, were provided by the TOPMed Informatics Research Center (3R01HL-117626-02S1). Phenotype harmonization, data management, sample-identity QC, and general study coordination were provided by the TOPMed Data Coordinating Center (3R01HL-120393-02S1). This work was supported in part by the Sandler Family Foundation, the American Asthma Foundation, the RWJF Amos Medical Faculty Development Program, the Harry Wm. and Diana V. Hind Distinguished Professor in Pharmaceutical Sciences II, the NHLBI (R01HL117004, R01HL128439, R01HL135156, and X01HL134589), the National Institute of Environmental Health Sciences (R01ES015794 and R21ES24844), the National Institute on Minority Health and Health Disparities (NIMHD; P60MD006902, RL5GM118984, and R01MD010443), and the Tobacco-Related Disease Research Program (Award Number 24RT-0025). M.J.W. was supported by a diversity supplement of NHLBI (R01HL117004) and an Institutional Research and Academic Career Development Award (K12GM081266). K.L.K. was supported by a diversity supplement of NHLBI (R01HL135156). W.L.E. was supported by NHLBI (K99HL135403-01A1). M.P.-Y. was supported by the grant AC15/00015 by Instituto de Salud Carlos III within the ERACoSysMed first Joint Transnational Call (SysPharmPedia) from the European Union, under the Horizon 2020. A.C.W. was supported by the National Institute of Child Health and Human Development (R01HD0855993). B.E.H. was supported by NHLBI (R01HL133433). R.B.D., S.G., K.L.B., and J.M.V. were supported by the National Human Genome Research Institute (NHGRI) of the NIH (Award Number UM1HG008901). H.H. was supported by NHGRI (U01HG008684). C.A.W. was funded in part with federal funds from the National Cancer Institute, NIH (contract HHSN26120080001E), and by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. L.K.W. was supported by the National Institute of Allergy and Infectious Diseases (R01AI079139), NHLBI (R01HL118267), and National Institute of Diabetes and Digestive and Kidney Diseases (R01DK113003), American Asthma Foundation, and Fund for Henry Ford Hospital. N.A. was supported in part by NHGRI and Division of Cancer Prevention, National Cancer Institute (1R01CA197139), and NHLBI (1R01HL138424). N.Z. was supported by the NHLBI (K25HL121295) and the NHGRI (R01HG006399). M.A.S. was supported by NHLBI (P01-HL132821-01A1, R01HL135156-01, and R01HL128439-03), NIMHD (R01MD010443-02), and the Department of Defense (W81WH-16-2-0018). C.A.W. declares that the content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. Publisher Copyright: Copyright {\textcopyright} 2018 by the American Thoracic Society.",
year = "2018",
month = jun,
day = "15",
doi = "10.1164/rccm.201712-2529OC",
language = "English (US)",
volume = "197",
pages = "1552--1564",
journal = "American Review of Respiratory Disease",
issn = "1073-449X",
publisher = "American Thoracic Society",
number = "12",
}