title: A genome-wide association study of bronchodilator response in Latinos implicates rare variants.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Medicine, University of California, San Francisco, Calif.
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Drake
authors.affiliation: Department of Medicine, University of California, San Francisco, Calif. Electronic address: dara.torgerson@ucsf.edu.
authors.forename: Dara G
authors.initials: DG
authors.lastname: Torgerson
authors.affiliation: Department of Medicine, University of California, San Francisco, Calif.
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Gignoux
authors.affiliation: Department of Medicine, University of California, San Francisco, Calif.
authors.forename: Joshua M
authors.initials: JM
authors.lastname: Galanter
authors.affiliation: Department of Medicine, University of California, San Francisco, Calif.
authors.forename: Lindsey A
authors.initials: LA
authors.lastname: Roth
authors.affiliation: Department of Medicine, University of California, San Francisco, Calif.
authors.forename: Scott
authors.initials: S
authors.lastname: Huntsman
authors.affiliation: Department of Medicine, University of California, San Francisco, Calif.
authors.forename: Celeste
authors.initials: C
authors.lastname: Eng
authors.affiliation: Department of Medicine, University of California, San Francisco, Calif.
authors.forename: Sam S
authors.initials: SS
authors.lastname: Oh
authors.affiliation: Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, Calif.
authors.forename: Sook Wah
authors.initials: SW
authors.lastname: Yee
authors.affiliation: Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, Calif.
authors.forename: Lawrence
authors.initials: L
authors.lastname: Lin
authors.affiliation: Department of Genetics, Stanford University, Stanford, Calif.
authors.forename: Carlos D
authors.initials: CD
authors.lastname: Bustamante
authors.affiliation: Department of Genetics, Stanford University, Stanford, Calif.
authors.forename: Andrés
authors.initials: A
authors.lastname: Moreno-Estrada
authors.affiliation: Department of Genetics, Stanford University, Stanford, Calif.
authors.forename: Karla
authors.initials: K
authors.lastname: Sandoval
authors.affiliation: Children's Hospital and Research Center Oakland, Oakland, Calif.
authors.forename: Adam
authors.initials: A
authors.lastname: Davis
authors.affiliation: Department of Health Sciences, Graduate Program in Public Health, Lehman College, City University of New York, Bronx, New York.
authors.forename: Luisa N
authors.initials: LN
authors.lastname: Borrell
authors.affiliation: Department of Pediatrics, Section of Pulmonology, Baylor College of Medicine and Texas Children's Hospital, Houston, Tex.
authors.forename: Harold J
authors.initials: HJ
authors.lastname: Farber
authors.affiliation: Children's Memorial Hospital, and the Feinberg School of Medicine, Northwestern University, Chicago, Ill.
authors.forename: Rajesh
authors.initials: R
authors.lastname: Kumar
authors.affiliation: Division of Allergy-Immunology, Feinberg School of Medicine, Northwestern University, Chicago, Ill.
authors.forename: Pedro C
authors.initials: PC
authors.lastname: Avila
authors.affiliation: Department of Allergy and Immunology, Kaiser Permanente-Vallejo Medical Center, Vallejo, Calif.
authors.forename: Emerita
authors.initials: E
authors.lastname: Brigino-Buenaventura
authors.affiliation: Instituto Nacional de Enfermedades Respiratorias (INER), Mexico City, Mexico.
authors.forename: Rocio
authors.initials: R
authors.lastname: Chapela
authors.affiliation: Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Md.
authors.forename: Jean G
authors.initials: JG
authors.lastname: Ford
authors.affiliation: Bay Area Pediatrics, Oakland, Calif.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Lenoir
authors.affiliation: Sonoma Technologies, Petaluma, Calif.
authors.forename: Fred
authors.initials: F
authors.lastname: Lurmann
authors.affiliation: Children's Hospital and Research Center Oakland, Oakland, Calif.
authors.forename: Kelley
authors.initials: K
authors.lastname: Meade
authors.affiliation: Pediatric Pulmonary Division, Jacobi Medical Center, Bronx, New York.
authors.forename: Denise
authors.initials: D
authors.lastname: Serebrisky
authors.affiliation: Department of Pediatrics, University of California, San Francisco, Calif.
authors.forename: Shannon
authors.initials: S
authors.lastname: Thyne
authors.affiliation: Veterans Caribbean Health Care System, San Juan, Puerto Rico.
authors.forename: William
authors.initials: W
authors.lastname: Rodríguez-Cintrón
authors.affiliation: Department of Biostatistics, University of California, San Francisco, Calif.
authors.forename: Saunak
authors.initials: S
authors.lastname: Sen
authors.affiliation: Centro de Neumologia Pediatrica, San Juan, Puerto Rico.
authors.forename: José R
authors.initials: JR
authors.lastname: Rodríguez-Santana
authors.affiliation: Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, Calif.
authors.forename: Ryan D
authors.initials: RD
authors.lastname: Hernandez
authors.affiliation: Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, Calif.
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Giacomini
authors.affiliation: Department of Medicine, University of California, San Francisco, Calif; Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, Calif.
authors.forename: Esteban G
authors.initials: EG
authors.lastname: Burchard
mesh_terms: D000293:Adolescent; D000328:Adult; D000420:Albuterol / Q000627:therapeutic use*; D001249:Asthma / Q000188:drug therapy* / Q000235:genetics* / Q000503:physiopathology; D001993:Bronchodilator Agents / Q000627:therapeutic use*; D002648:Child; D005541:Forced Expiratory Volume; D055106:Genome-Wide Association Study; D005838:Genotype; D006630:Hispanic or Latino / Q000235:genetics*; D006801:Humans; D020641:Polymorphism, Single Nucleotide; D055815:Young Adult
chemical_list: D001993:Bronchodilator Agents; D000420:Albuterol
keywords: BDR; Bronchodilator response; GALA I; GALA II; GWAS; Genes-Environments & Admixture in Latino Americans; Genetics of Asthma in Latino Americans; Genome-wide association study; IGF; Insulin-like growth factor; LD; Latinos; Linkage disequilibrium; MAF; Minor allele frequency; QC; Quality control; SABA; SLC; SNP; Short-acting β(2)-adrenergic receptor agonist; Single nucleotide polymorphism; Solute carrier; admixture mapping; asthma; genome-wide association study; rare variants; β(2)-Adrenergic receptor; β(2)AR