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

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY

卷:133

Article

Drake, Katherine A.¹  Torgerson, Dara G.¹  Gignoux, Christopher R.¹  Galanter, Joshua M.¹  Roth, Lindsey A.¹  Huntsman, Scott¹  Eng, Celeste¹  Oh, Sam S.¹  Yee, Sook Wah²  Lin, Lawrence²  Bustamante, Carlos D.⁵  Moreno-Estrada, Andres⁵  Sandoval, Karla⁵  Davis, Adam⁶  Borrell, Luisa N.⁷  Farber, Harold J.^8,9  Kumar, Rajesh^10,11  Avila, Pedro C.¹²  Brigino-Buenaventura, Emerita¹³  Chapela, Rocio¹⁴  Ford, Jean G.¹⁵  LeNoir, Michael A.¹⁶  Lurmann, Fred¹⁷  Meade, Kelley⁶  Serebrisky, Denise¹⁸  Thyne, Shannon³  Rodriguez-Cintron, William¹⁹  Sen, Saunak⁴  Rodriguez-Santana, Jose R.²⁰  Hernandez, Ryan D.²  Giacomini, Kathleen M.²  Burchard, Esteban G.^1,2 

[1] Univ Calif San Francisco, Dept Med, San Francisco, CA 94158 USA

[2] Univ Calif San Francisco, Dept Bioengn & Therapeut Sci, San Francisco, CA 94158 USA

[3] Univ Calif San Francisco, Dept Pediat, San Francisco, CA 94158 USA

[4] Univ Calif San Francisco, Dept Biostat, San Francisco, CA 94158 USA

[5] Stanford Univ, Dept Genet, Stanford, CA 94305 USA

[6] Childrens Hosp & Res Ctr Oakland, Oakland, CA USA

[7] CUNY Herbert H Lehman Coll, Dept Hlth Sci, Grad Program Publ Hlth, Bronx, NY 10468 USA

[8] Baylor Coll Med, Dept Pediat, Sect Pulmonol, Houston, TX 77030 USA

[9] Texas Childrens Hosp, Houston, TX 77030 USA

[10] Northwestern Univ, Childrens Mem Hosp, Chicago, IL 60614 USA

[11] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA

[12] Northwestern Univ, Feinberg Sch Med, Div Allergy Immunol, Chicago, IL 60611 USA

[13] Kaiser Permanente Vallejo Med Ctr, Dept Allergy & Immunol, Vallejo, CA USA

[14] INER, Mexico City, DF, Mexico

[15] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA

[16] Bay Area Pediat, Oakland, CA USA

[17] Sonoma Technol, Petaluma, CA USA

[18] Jacobi Med Ctr, Pediat Pulm Div, Bronx, NY USA

[19] Vet Caribbean Hlth Care Syst, San Juan, PR USA

[20] Ctr Neumol Pediat, San Juan, PR USA

关键词: Bronchodilator response;    genome-wide association study;    admixture mapping;    Latinos;    asthma;    rare variants;   

DOI  :  10.1016/j.jaci.2013.06.043

来源: Elsevier

【 摘 要 】

Background: The primary rescue medication to treat acute asthma exacerbation is the short-acting beta(2)-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<5x10(-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.

【 授权许可】

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