Asthma and lower airway diseaseA genome-wide association study of bronchodilator response in Latinos implicates rare variants
Section snippets
Genes-Environments & Admixture in Latino Americans study
Patients with asthma in the discovery phase were recruited from the Genes-Environments & Admixture in Latino Americans (GALA II) study, which began in 2006 and is an ongoing clinical study of children between the ages of 8 and 21 years both with and without asthma. A total of 4045 subjects, including 1976 asthmatic patients, were recruited from urban study centers across the mainland United States and Puerto Rico through June 2011 (see Table E1 in this article's Online Repository at //www.jacionline.org
Allelic association tests
After QC, we tested for an association of BDR at a total of 568,037 SNPs in 1,782 asthmatic children in all Latino subjects regardless of self-reported ethnicity and also separately in subsets of 823 Puerto Ricans and 572 Mexicans. In all 3 analyses we observed an excess of small P values compared with those expected by chance (Fig 1 and see Fig E2 in this article's Online Repository at www.jacionline.org). However, this excess disappeared after removing SNPs with a minor allele frequency (MAF)
Discussion
We performed genome-wide tests for allelic and local ancestry associations with BDR in 1782 Latino children with asthma from across the United States and Puerto Rico and found 16 rare variants to be significantly associated with BDR in either Puerto Ricans, Mexicans, or all of the GALA II population combined (including Puerto Ricans, Mexicans, and other Latinos; P < 5 × 10−8). All of the associated variants had frequencies of 5% or less, and no common variants were significantly associated with
References (36)
- et al.
Family-based association analysis of beta2-adrenergic receptor polymorphisms in the childhood asthma management program
J Allergy Clin Immunol
(2003) - et al.
Population pharmacodynamic model of bronchodilator response to inhaled albuterol in children and adults with asthma
Chest
(2008) - et al.
Case-control admixture mapping in Latino populations enriches for known asthma-associated genes
J Allergy Clin Immunol
(2012) - et al.
Estimating local ancestry in admixed populations
Am J Hum Genet
(2008) Multilocus association mapping using variable-length markov chains
Am J Hum Genet
(2006)- et al.
Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method
Methods
(2001) - et al.
Novel human cDNAs homologous to Drosophila Orct and mammalian carnitine transporters
Biochem Biophys Res Commun
(2002) - et al.
Design and coverage of high throughput genotyping arrays optimized for individuals of East Asian, African American, and Latino race/ethnicity using imputation and a novel hybrid SNP selection algorithm
Genomics
(2011) - et al.
Role of insulin-like growth factor-I in allergen-induced airway inflammation and remodeling
Cell Immunol
(2005) Beta-adrenergic bronchodilators
N Engl J Med
(1995)
Pharmacogenetics of asthma
Am J Respir Crit Care Med
Heterogeneity of therapeutic responses in asthma
Br Med Bull
Association between genetic polymorphisms of the beta2-adrenoceptor and response to albuterol in children with and without a history of wheezing
J Clin Invest
Pharmacogenetic differences in response to albuterol between Puerto Ricans and Mexicans with asthma
Am J Respir Crit Care Med
Association of corticotropin-releasing hormone receptor-2 genetic variants with acute bronchodilator response in asthma
Pharmacogenet Genomics
Molecular properties and pharmacogenetics of a polymorphism of adenylyl cyclase type 9 in asthma: interaction between beta-agonist and corticosteroid pathways
Hum Mol Genet
ARG1 is a novel bronchodilator response gene: screening and replication in four asthma cohorts
Am J Respir Crit Care Med
A polymorphism in the thyroid hormone receptor gene is associated with bronchodilator response in asthmatics
Pharmacogenomics J
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Supported by grants from the National Institute of Health (HL088133 and HL078885 to E.G.B. and M01-RR00188 to Texas Children's Hospital General Clinical Research Center), the National Institute on Minority Health and Health Disparities (P60MD006902), the National Institutes of Environmental Health Sciences (ES015794 to E.G.B.), the National Institutes of Health Training Grant (T32 GM07175), the Flight Attendant Medical Research Institute (FAMRI), the Sandler Foundation, and an Ernest Bazley Grant (to P.C.A.).
Disclosure of potential conflict of interest: K. A. Drake has received grants from the National Institutes of Health (NIH) and has received support for travel to meetings for study or other purposes from the American Thoracic Society. C. R. Gignoux has received grants from the NIH and has stock/stock options in 23andMe. S. Huntsman has received grants from the NIH. C. Eng and E. G. Burchard have received grants from the National Heart, Lung, and Blood Institute (NHLBI) and have grants/grants pending with the NIH. S. W. Yee, L. Lin, L. N. Borrell, and K. M. Giacomini have received grants from the NIH. C. D. Bustamante has consultant arrangements with Ancestry.com, Personalis, and InVitae and has grants/grants pending from the NIH. A. Davis has received grants from the University of California San Francisco (UCSF) for work recruiting patients. H. J. Farber has received grants from the NIH, is employed by Texas Children's Health Plan, has provided expert testimony for Serpe Jones Andrews Callender and Bell, has received payment for lectures, including service on speakers’ bureaus, from the American Academy of Pediatrics and Astra Zeneca, and has served as Journal Editor for Mary Anne Liebert. R. Kumar has received grants from the NHLBI. P. C. Avila has received grants from and has grants/grants pending with the NIH. E. Brigno-Buenaventura has received grants, consulting feed or honorarium, support for travel to meetings for study or other purposes, and provision of writing assistance, medicines, equipment, or administrative support from the Sandler Foundation and is employed by the Kaiser Permanente Medical Group. J. G. Ford has consultant arrangements with GlaxoSmithKline and has received monetary reward for a patent. F. Lurmann has received grants from NIH/UCSF. K. Meade has received a grant from UCSF and subcontracted support for study. D. Serebrisky and S. Sen have received grants from the NIH. W. Rodriguez-Cintron has received grants in the form of money to his institution. The rest of the authors declare that they have no relevant conflicts of interest.