Rare variants contribute to bronchodilator drug response in Latino children with asthma. D. G. Torgerson1, K. A. Drake1, C. R. Gignoux1, J. M. Galanter1, L. A. Roth1, S. Huntsman1, D. Hu1, C. Eng1, S. W. Yee2, L. Lin2, C. D. Campbell3, E. E. Eichler3,4, R. D. Hernandez2, K. M. Giacomini2, E. G. Burchard1,2, and the GALA II investigators 1) Department of Medicine, University of California San Francisco, San Francisco, CA; 2) Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA; 3) Department of Genome Sciences, University of Washington, Seattle, WA; 4) Howard Hughes Medical Institute, Seattle, WA.
There is substantial variation in how well an individual responds to albuterol, the primary rescue medication used to treat asthma symptoms. Although these differences may be due to environmental factors, there is mounting evidence for a genetic contribution to variability in bronchodilator drug response (BDR). We performed a genome-wide association study (GWAS) and admixture mapping for BDR in 1,782 Latino children with asthma genotyped on the Axiom LAT1 array (World Array 4, Affymetrix), followed by exon sequencing of 3 genes in 787 Puerto Ricans. We identified six variants associated with BDR at a genome-wide significant threshold in our GWAS (p<5x10-8), all of which had frequencies below 5%. Carriers of these variants were validated using Sanger sequencing. Furthermore, we observed an excess of small p-values driven by variants at frequencies below 5%, and by variants near solute carrier genes (SLC genes), which include membrane transport proteins involved in the transport of endogenous compounds and xenobiotics. Admixture mapping identified five significant peaks, one of which contained population-specific associations with rare variants in SLC22A15: two variants were locus-wide associated with higher BDR in Mexicans (rs1281743 and rs1281748, p = 8.8x10-5), and one variant identified through sequencing was gene-wide associated with lower BDR in Puerto Ricans (rs146673261, p=8.4x10-4). RtPCR and immunohistochemistry confirmed that SLC22A15 is highly expressed in lung epithelial cells. Exon sequencing of 3 SLC genes in 787 Puerto Ricans revealed significant associations with multiple rare variants and BDR in those identified through GWAS: SLC24A2 (SKAT test, p=0.037), and SLC24A4 (p=0.018). Overall our results suggest that rare variation contributes to individual differences in response to albuterol in Latinos, notably in solute carrier genes. Resequencing in larger, multi-ethnic population samples and additional functional studies are required to further understand the role of rare variation in BDR.
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