A genome-wide association and admixture mapping study of bronchodilator drug response in African Americans with asthma

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Abstract

Short-acting β2-adrenergic receptor agonists (SABAs) are the most commonly prescribed asthma medications worldwide. Response to SABAs is measured as bronchodilator drug response (BDR), which varies among racial/ethnic groups in the United States. However, the genetic variation that contributes to BDR is largely undefined in African Americans with asthma. To identify genetic variants that may contribute to differences in BDR in African Americans with asthma, we performed a genome-wide association study (GWAS) of BDR in 949 African-American children with asthma, genotyped with the Axiom World Array 4 (Affymetrix, Santa Clara, CA) followed by imputation using 1000 Genomes phase III genotypes. We used linear regression models adjusting for age, sex, body mass index (BMI) and genetic ancestry to test for an association between BDR and genotype at single-nucleotide polymorphisms (SNPs). To increase power and distinguish between shared vs. population-specific associations with BDR in children with asthma, we performed a meta-analysis across 949 African Americans and 1830 Latinos (total = 2779). Finally, we performed genome-wide admixture mapping to identify regions whereby local African or European ancestry is associated with BDR in African Americans. We identified a population-specific association with an intergenic SNP on chromosome 9q21 that was significantly associated with BDR (rs73650726, p = 7.69 × 10−9). A trans-ethnic meta-analysis across African Americans and Latinos identified three additional SNPs within the intron of PRKG1 that were significantly associated with BDR (rs7903366, rs7070958 and rs7081864, p ≤ 5 × 10−8). Our results failed to replicate in three additional populations of 416 Latinos and 1615 African Americans. Our findings indicate that both population-specific and shared genetic variation contributes to differences in BDR in minority children with asthma, and that the genetic underpinnings of BDR may differ between racial/ethnic groups.

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Acknowledgements

This work was supported in part by the Sandler Family Foundation, the American Asthma Foundation, the RWJF Amos Medical Faculty Development Program, National Institutes of Health 1R01HL117004, R01Hl128439, National Institute of Health and Environmental Health Sciences R01 ES015794, R21ES24844, National Institute on Minority Health and Health Disparities 1P60 MD006902, U54MD009523, 1R01MD010443, and the National Institutes of Health National Heart, Lung, and Blood Institute K08 HL118128, U10 HL109164, HL69116, R01 HL69167, HL69170, HL69174 and U10 HL098103. This project has been funded part with federal funds from the National Cancer Institute, National Institutes of Health, under contract HHSN26120080001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products or organizations imply endorsement by the U.S. Government. This research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. MLS was supported in part by a National Science Foundation Graduate Research Fellowship under grant no. 1144247. MP-Y was funded by the Ramón y Cajal Program (RYC-2015–17205) by the Spanish Ministry of Economy and Competitiveness. MP-Y was also supported by award number AC15/00015 by Instituto de Salud Carlos III thorough AES and EC within AAL framework, and the SysPharmPedia grant awarded from the ERACoSysMed 1st Joint Transnational Call from the European Union under the Horizon 2020; DGT was supported in part by the California Institute for Quantitative Biosciences (QB3). JG was supported in part by NIH Training Grant T32 (5T32GM007546) and career development awards from the NHLBI K23 (5K23HL111636) and NCATS KL2 (5KL2TR000143), as well as the Hewett Fellowship; NT was supported in part by a institutional training grant from the NIGMS (T32GM007546) and career development awards from the NHLBI (5K12HL119997 and K23-HL125551-01A1), Parker B. Francis Fellowship Program, and the American Thoracic Society; RK was supported with a career development award from the NHLBI (5K23HL093023); HJF was supported in part by the GCRC (RR00188); PCA was supported in part by the Ernest S. Bazley Grant. LKW received grant support from the Fund for Henry Ford Hospital, the American Asthma Foundation and the following NIH institutes: NHLBI (R01HL118267, R01HL079055), NIAID (R01AI079139) and NIDDK (R01DK064695). Study accession numbers in dbGaP are phs000921.v2.p1 and phs001180.v1.p1. The authors acknowledge the patients, families, recruiters, health-care providers and community clinics for their participation in SAGE and GALA II. In particular, we thank study coordinator Sandra Salazar and the recruiters who obtained the data: Duanny Alva, MD; Gaby Ayala-Rodriguez; Lisa Caine; Elizabeth Castellanos; Jaime Colon; Denise DeJesus; Blanca Lopez; Brenda Lopez, MD; Louis Martos; Vivian Medina; Juana Olivo; Mario Peralta; Esther Pomares, MD; Jihan Quraishi; Johanna Rodriguez; Shahdad Saeedi; Dean Soto; and Ana Taveras. The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of the NIH.

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Correspondence to Esteban G. Burchard.

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