Asthma and lower airway disease
A genome-wide association study of bronchodilator response in Latinos implicates rare variants

https://doi.org/10.1016/j.jaci.2013.06.043Get rights and content

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.

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

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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.

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