A genome-wide association study of bronchodilator response in Latinos implicates rare variants

Katherine A. Drake, Dara G. Torgerson, Christopher R. Gignoux, Joshua M. Galanter, Lindsey A. Roth, Scott Huntsman, Celeste Eng, Sam S. Oh, Sook Wah Yee, Lawrence Lin, Carlos D. Bustamante, Andrés Moreno-Estrada, Karla Sandoval, Adam Davis, Luisa N. Borrell, Harold J. Farber, Rajesh Kumar, Pedro C. Avila, Emerita Brigino-Buenaventura, Rocio Chapela & 12 others Jean G. Ford, Michael A. Lenoir, Fred Lurmann, Kelley Meade, Denise Serebrisky, Shannon Thyne, William Rodríguez-Cintrón, Saunak Sen, José R. Rodríguez-Santana, Ryan D. Hernandez, Kathleen M. Giacomini, Esteban G. Burchard

Research output: Contribution to journalArticle

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Abstract

Background The primary rescue medication to treat acute asthma exacerbation is the short-acting β2-adrenergic receptor agonist; however, there is variation in how well a patient responds to treatment. Although these differences might be due to environmental factors, there is mounting evidence for a genetic contribution to variability in bronchodilator response (BDR). Objective To identify genetic variation associated with bronchodilator drug response in Latino children with asthma. Methods We performed a genome-wide association study (GWAS) for BDR in 1782 Latino children with asthma using standard linear regression, adjusting for genetic ancestry and ethnicity, and performed replication studies in an additional 531 Latinos. We also performed admixture mapping across the genome by testing for an association between local European, African, and Native American ancestry and BDR, adjusting for genomic ancestry and ethnicity. Results We identified 7 genetic variants associated with BDR at a genome-wide significant threshold (P < 5 × 10-8), all of which had frequencies of less than 5%. Furthermore, we observed an excess of small P values driven by rare variants (frequency, <5%) and by variants in the proximity of solute carrier (SLC) genes. Admixture mapping identified 5 significant peaks; fine mapping within these peaks identified 2 rare variants in SLC22A15 as being associated with increased BDR in Mexicans. Quantitative PCR and immunohistochemistry identified SLC22A15 as being expressed in the lung and bronchial epithelial cells. Conclusion Our results suggest that rare variation contributes to individual differences in response to albuterol in Latinos, notably in SLC genes that include membrane transport proteins involved in the transport of endogenous metabolites and xenobiotics. Resequencing in larger, multiethnic population samples and additional functional studies are required to further understand the role of rare variation in BDR.

Original languageEnglish (US)
JournalJournal of Allergy and Clinical Immunology
Volume133
Issue number2
DOIs
StatePublished - Jan 1 2014

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Genome-Wide Association Study
Bronchodilator Agents
Hispanic Americans
Asthma
Adrenergic Agonists
Membrane Transport Proteins
North American Indians
Albuterol
Chromosome Mapping
Xenobiotics
Individuality
African Americans
Genes
Linear Models
Epithelial Cells
Immunohistochemistry
Genome
Polymerase Chain Reaction
Lung
Pharmaceutical Preparations

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology

Cite this

Drake, K. A., Torgerson, D. G., Gignoux, C. R., Galanter, J. M., Roth, L. A., Huntsman, S., ... Burchard, E. G. (2014). A genome-wide association study of bronchodilator response in Latinos implicates rare variants. Journal of Allergy and Clinical Immunology, 133(2). https://doi.org/10.1016/j.jaci.2013.06.043

A genome-wide association study of bronchodilator response in Latinos implicates rare variants. / Drake, Katherine A.; Torgerson, Dara G.; Gignoux, Christopher R.; Galanter, Joshua M.; Roth, Lindsey A.; Huntsman, Scott; Eng, Celeste; Oh, Sam S.; Yee, Sook Wah; Lin, Lawrence; Bustamante, Carlos D.; Moreno-Estrada, Andrés; Sandoval, Karla; Davis, Adam; Borrell, Luisa N.; Farber, Harold J.; Kumar, Rajesh; Avila, Pedro C.; Brigino-Buenaventura, Emerita; Chapela, Rocio; Ford, Jean G.; Lenoir, Michael A.; Lurmann, Fred; Meade, Kelley; Serebrisky, Denise; Thyne, Shannon; Rodríguez-Cintrón, William; Sen, Saunak; Rodríguez-Santana, José R.; Hernandez, Ryan D.; Giacomini, Kathleen M.; Burchard, Esteban G.

In: Journal of Allergy and Clinical Immunology, Vol. 133, No. 2, 01.01.2014.

Research output: Contribution to journalArticle

Drake, KA, Torgerson, DG, Gignoux, CR, Galanter, JM, Roth, LA, Huntsman, S, Eng, C, Oh, SS, Yee, SW, Lin, L, Bustamante, CD, Moreno-Estrada, A, Sandoval, K, Davis, A, Borrell, LN, Farber, HJ, Kumar, R, Avila, PC, Brigino-Buenaventura, E, Chapela, R, Ford, JG, Lenoir, MA, Lurmann, F, Meade, K, Serebrisky, D, Thyne, S, Rodríguez-Cintrón, W, Sen, S, Rodríguez-Santana, JR, Hernandez, RD, Giacomini, KM & Burchard, EG 2014, 'A genome-wide association study of bronchodilator response in Latinos implicates rare variants', Journal of Allergy and Clinical Immunology, vol. 133, no. 2. https://doi.org/10.1016/j.jaci.2013.06.043
Drake, Katherine A. ; Torgerson, Dara G. ; Gignoux, Christopher R. ; Galanter, Joshua M. ; Roth, Lindsey A. ; Huntsman, Scott ; Eng, Celeste ; Oh, Sam S. ; Yee, Sook Wah ; Lin, Lawrence ; Bustamante, Carlos D. ; Moreno-Estrada, Andrés ; Sandoval, Karla ; Davis, Adam ; Borrell, Luisa N. ; Farber, Harold J. ; Kumar, Rajesh ; Avila, Pedro C. ; Brigino-Buenaventura, Emerita ; Chapela, Rocio ; Ford, Jean G. ; Lenoir, Michael A. ; Lurmann, Fred ; Meade, Kelley ; Serebrisky, Denise ; Thyne, Shannon ; Rodríguez-Cintrón, William ; Sen, Saunak ; Rodríguez-Santana, José R. ; Hernandez, Ryan D. ; Giacomini, Kathleen M. ; Burchard, Esteban G. / A genome-wide association study of bronchodilator response in Latinos implicates rare variants. In: Journal of Allergy and Clinical Immunology. 2014 ; Vol. 133, No. 2.
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abstract = "Background The primary rescue medication to treat acute asthma exacerbation is the short-acting β2-adrenergic receptor agonist; however, there is variation in how well a patient responds to treatment. Although these differences might be due to environmental factors, there is mounting evidence for a genetic contribution to variability in bronchodilator response (BDR). Objective To identify genetic variation associated with bronchodilator drug response in Latino children with asthma. Methods We performed a genome-wide association study (GWAS) for BDR in 1782 Latino children with asthma using standard linear regression, adjusting for genetic ancestry and ethnicity, and performed replication studies in an additional 531 Latinos. We also performed admixture mapping across the genome by testing for an association between local European, African, and Native American ancestry and BDR, adjusting for genomic ancestry and ethnicity. Results We identified 7 genetic variants associated with BDR at a genome-wide significant threshold (P < 5 × 10-8), all of which had frequencies of less than 5{\%}. Furthermore, we observed an excess of small P values driven by rare variants (frequency, <5{\%}) and by variants in the proximity of solute carrier (SLC) genes. Admixture mapping identified 5 significant peaks; fine mapping within these peaks identified 2 rare variants in SLC22A15 as being associated with increased BDR in Mexicans. Quantitative PCR and immunohistochemistry identified SLC22A15 as being expressed in the lung and bronchial epithelial cells. Conclusion Our results suggest that rare variation contributes to individual differences in response to albuterol in Latinos, notably in SLC genes that include membrane transport proteins involved in the transport of endogenous metabolites and xenobiotics. Resequencing in larger, multiethnic population samples and additional functional studies are required to further understand the role of rare variation in BDR.",
author = "Drake, {Katherine A.} and Torgerson, {Dara G.} and Gignoux, {Christopher R.} and Galanter, {Joshua M.} and Roth, {Lindsey A.} and Scott Huntsman and Celeste Eng and Oh, {Sam S.} and Yee, {Sook Wah} and Lawrence Lin and Bustamante, {Carlos D.} and Andr{\'e}s Moreno-Estrada and Karla Sandoval and Adam Davis and Borrell, {Luisa N.} and Farber, {Harold J.} and Rajesh Kumar and Avila, {Pedro C.} and Emerita Brigino-Buenaventura and Rocio Chapela and Ford, {Jean G.} and Lenoir, {Michael A.} and Fred Lurmann and Kelley Meade and Denise Serebrisky and Shannon Thyne and William Rodr{\'i}guez-Cintr{\'o}n and Saunak Sen and Rodr{\'i}guez-Santana, {Jos{\'e} R.} and Hernandez, {Ryan D.} and Giacomini, {Kathleen M.} and Burchard, {Esteban G.}",
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T1 - A genome-wide association study of bronchodilator response in Latinos implicates rare variants

AU - Drake, Katherine A.

AU - Torgerson, Dara G.

AU - Gignoux, Christopher R.

AU - Galanter, Joshua M.

AU - Roth, Lindsey A.

AU - Huntsman, Scott

AU - Eng, Celeste

AU - Oh, Sam S.

AU - Yee, Sook Wah

AU - Lin, Lawrence

AU - Bustamante, Carlos D.

AU - Moreno-Estrada, Andrés

AU - Sandoval, Karla

AU - Davis, Adam

AU - Borrell, Luisa N.

AU - Farber, Harold J.

AU - Kumar, Rajesh

AU - Avila, Pedro C.

AU - Brigino-Buenaventura, Emerita

AU - Chapela, Rocio

AU - Ford, Jean G.

AU - Lenoir, Michael A.

AU - Lurmann, Fred

AU - Meade, Kelley

AU - Serebrisky, Denise

AU - Thyne, Shannon

AU - Rodríguez-Cintrón, William

AU - Sen, Saunak

AU - Rodríguez-Santana, José R.

AU - Hernandez, Ryan D.

AU - Giacomini, Kathleen M.

AU - Burchard, Esteban G.

PY - 2014/1/1

Y1 - 2014/1/1

N2 - Background The primary rescue medication to treat acute asthma exacerbation is the short-acting β2-adrenergic receptor agonist; however, there is variation in how well a patient responds to treatment. Although these differences might be due to environmental factors, there is mounting evidence for a genetic contribution to variability in bronchodilator response (BDR). Objective To identify genetic variation associated with bronchodilator drug response in Latino children with asthma. Methods We performed a genome-wide association study (GWAS) for BDR in 1782 Latino children with asthma using standard linear regression, adjusting for genetic ancestry and ethnicity, and performed replication studies in an additional 531 Latinos. We also performed admixture mapping across the genome by testing for an association between local European, African, and Native American ancestry and BDR, adjusting for genomic ancestry and ethnicity. Results We identified 7 genetic variants associated with BDR at a genome-wide significant threshold (P < 5 × 10-8), all of which had frequencies of less than 5%. Furthermore, we observed an excess of small P values driven by rare variants (frequency, <5%) and by variants in the proximity of solute carrier (SLC) genes. Admixture mapping identified 5 significant peaks; fine mapping within these peaks identified 2 rare variants in SLC22A15 as being associated with increased BDR in Mexicans. Quantitative PCR and immunohistochemistry identified SLC22A15 as being expressed in the lung and bronchial epithelial cells. Conclusion Our results suggest that rare variation contributes to individual differences in response to albuterol in Latinos, notably in SLC genes that include membrane transport proteins involved in the transport of endogenous metabolites and xenobiotics. Resequencing in larger, multiethnic population samples and additional functional studies are required to further understand the role of rare variation in BDR.

AB - Background The primary rescue medication to treat acute asthma exacerbation is the short-acting β2-adrenergic receptor agonist; however, there is variation in how well a patient responds to treatment. Although these differences might be due to environmental factors, there is mounting evidence for a genetic contribution to variability in bronchodilator response (BDR). Objective To identify genetic variation associated with bronchodilator drug response in Latino children with asthma. Methods We performed a genome-wide association study (GWAS) for BDR in 1782 Latino children with asthma using standard linear regression, adjusting for genetic ancestry and ethnicity, and performed replication studies in an additional 531 Latinos. We also performed admixture mapping across the genome by testing for an association between local European, African, and Native American ancestry and BDR, adjusting for genomic ancestry and ethnicity. Results We identified 7 genetic variants associated with BDR at a genome-wide significant threshold (P < 5 × 10-8), all of which had frequencies of less than 5%. Furthermore, we observed an excess of small P values driven by rare variants (frequency, <5%) and by variants in the proximity of solute carrier (SLC) genes. Admixture mapping identified 5 significant peaks; fine mapping within these peaks identified 2 rare variants in SLC22A15 as being associated with increased BDR in Mexicans. Quantitative PCR and immunohistochemistry identified SLC22A15 as being expressed in the lung and bronchial epithelial cells. Conclusion Our results suggest that rare variation contributes to individual differences in response to albuterol in Latinos, notably in SLC genes that include membrane transport proteins involved in the transport of endogenous metabolites and xenobiotics. Resequencing in larger, multiethnic population samples and additional functional studies are required to further understand the role of rare variation in BDR.

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