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. Nuckton & 33 others Thomas 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 journalArticle

19 Citations (Scopus)

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

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Pharmacogenetics
Bronchodilator Agents
Asthma
Genome
Pharmaceutical Preparations
Albuterol
Population
Single Nucleotide Polymorphism
Lung Volume Measurements
Precision Medicine
Quantitative Trait Loci
Adrenergic Agents
Sample Size
Genes
Smooth Muscle Myocytes
Immunity
Research

All Science Journal Classification (ASJC) codes

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

Cite this

Mak, A. C. Y., White, M. J., Eckalbar, W. L., Szpiech, Z. A., Oh, S. S., Pino-Yanes, M., ... Burchard, E. G. (2018). Whole-Genome sequencing of pharmacogenetic drug response in racially diverse children with asthma. American Journal of Respiratory and Critical Care Medicine, 197(12), 1552-1564. https://doi.org/10.1164/rccm.201712-2529OC

Whole-Genome sequencing of pharmacogenetic drug response in racially diverse children with asthma. / Mak, Angel C.Y.; White, Marquitta J.; Eckalbar, Walter L.; Szpiech, Zachary A.; Oh, Sam S.; Pino-Yanes, Maria; Hu, Donglei; Goddard, Paǵe; Huntsman, Scott; Galanter, Joshua; Chen Wu, Ann; 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; 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 A.; Moreno-Estrada, Andŕes; Sandoval, Karla; Rodriguez-Santana, Jose R.; Kumar, Rajesh; Keoki Williams, L.; Ahituv, Nadav; Ziv, Elad; Seibold, Max A.; Darnell, Robert B.; Zaitlen, Noah; Hernandez, Ryan D.; Burchard, Esteban G.

In: American Journal of Respiratory and Critical Care Medicine, Vol. 197, No. 12, 15.06.2018, p. 1552-1564.

Research output: Contribution to journalArticle

Mak, ACY, White, MJ, Eckalbar, WL, Szpiech, ZA, Oh, SS, Pino-Yanes, M, Hu, D, Goddard, P, Huntsman, S, Galanter, J, Chen Wu, A, Himes, BE, Germer, S, Vogel, JM, Bunting, KL, Eng, C, Salazar, S, Keys, KL, Liberto, J, Nuckton, TJ, Nguyen, TA, Torgerson, DG, Kwok, PY, Levin, AM, Celedón, JC, Forno, E, Hakonarson, H, Sleiman, PM, Dahlin, A, Tantisira, KG, Weiss, ST, Serebrisky, D, Brigino-Buenaventura, E, Farber, HJ, Meade, K, Lenoir, MA, Avila, PC, Sen, S, Thyne, SM, Rodriguez-Cintron, W, Winkler, CA, Moreno-Estrada, A, Sandoval, K, Rodriguez-Santana, JR, Kumar, R, Keoki Williams, L, Ahituv, N, Ziv, E, Seibold, MA, Darnell, RB, Zaitlen, N, Hernandez, RD & Burchard, EG 2018, 'Whole-Genome sequencing of pharmacogenetic drug response in racially diverse children with asthma', American Journal of Respiratory and Critical Care Medicine, vol. 197, no. 12, pp. 1552-1564. https://doi.org/10.1164/rccm.201712-2529OC
Mak, Angel C.Y. ; White, Marquitta J. ; Eckalbar, Walter L. ; Szpiech, Zachary A. ; Oh, Sam S. ; Pino-Yanes, Maria ; Hu, Donglei ; Goddard, Paǵe ; Huntsman, Scott ; Galanter, Joshua ; Chen Wu, Ann ; 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 ; 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 A. ; Moreno-Estrada, Andŕes ; Sandoval, Karla ; Rodriguez-Santana, Jose R. ; Kumar, Rajesh ; Keoki Williams, L. ; Ahituv, Nadav ; Ziv, Elad ; Seibold, Max A. ; Darnell, Robert B. ; Zaitlen, Noah ; Hernandez, Ryan D. ; Burchard, Esteban G. / Whole-Genome sequencing of pharmacogenetic drug response in racially diverse children with asthma. In: American Journal of Respiratory and Critical Care Medicine. 2018 ; Vol. 197, No. 12. pp. 1552-1564.
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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 Andŕes 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.}",
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TY - JOUR

T1 - Whole-Genome sequencing of pharmacogenetic drug response in racially diverse children with asthma

AU - Mak, Angel C.Y.

AU - White, Marquitta J.

AU - Eckalbar, Walter L.

AU - Szpiech, Zachary A.

AU - Oh, Sam S.

AU - Pino-Yanes, Maria

AU - Hu, Donglei

AU - Goddard, Paǵe

AU - Huntsman, Scott

AU - Galanter, Joshua

AU - Chen Wu, Ann

AU - Himes, Blanca E.

AU - Germer, Soren

AU - Vogel, Julia M.

AU - Bunting, Karen L.

AU - Eng, Celeste

AU - Salazar, Sandra

AU - Keys, Kevin L.

AU - Liberto, Jennifer

AU - Nuckton, Thomas J.

AU - Nguyen, Thomas A.

AU - Torgerson, Dara G.

AU - Kwok, Pui Yan

AU - Levin, Albert M.

AU - Celedón, Juan C.

AU - Forno, Erick

AU - Hakonarson, Hakon

AU - Sleiman, Patrick M.

AU - Dahlin, Amber

AU - Tantisira, Kelan G.

AU - Weiss, Scott T.

AU - Serebrisky, Denise

AU - Brigino-Buenaventura, Emerita

AU - Farber, Harold J.

AU - Meade, Kelley

AU - Lenoir, Michael A.

AU - Avila, Pedro C.

AU - Sen, Saunak

AU - Thyne, Shannon M.

AU - Rodriguez-Cintron, William

AU - Winkler, Cheryl A.

AU - Moreno-Estrada, Andŕes

AU - Sandoval, Karla

AU - Rodriguez-Santana, Jose R.

AU - Kumar, Rajesh

AU - Keoki Williams, L.

AU - Ahituv, Nadav

AU - Ziv, Elad

AU - Seibold, Max A.

AU - Darnell, Robert B.

AU - Zaitlen, Noah

AU - Hernandez, Ryan D.

AU - Burchard, Esteban G.

PY - 2018/6/15

Y1 - 2018/6/15

N2 - 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.

AB - 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.

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