Pharmacodynamic genome-wide association study identifies new responsive loci for glucocorticoid intervention in asthma

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Abstract

Asthma is a chronic lung disease that has a high prevalence. The therapeutic intervention of this disease can be made more effective if genetic variability in patients’ response to medications is implemented. However, a clear picture of the genetic architecture of asthma intervention response remains elusive. We conducted a genome-wide association study (GWAS) to identify drug response-associated genes for asthma, in which 909 622 SNPs were genotyped for 120 randomized participants who inhaled multiple doses of glucocorticoids. By integrating pharmacodynamic properties of drug reactions, we implemented a mechanistic model to analyze the GWAS data, enhancing the scope of inference about the genetic architecture of asthma intervention. Our pharmacodynamic model observed associations of genome-wide significance between dose-dependent response to inhaled glucocorticoids (measured as %FEV1) and five loci (P=5.315 × 10−7 to 3.924 × 10−9), many of which map to metabolic genes related to lung function and asthma risk. All significant SNPs detected indicate a recessive effect, at which the homozygotes for the mutant alleles drive variability in %FEV1. Significant associations were well replicated in three additional independent GWAS studies. Pooled together over these three trials, two SNPs, chr6 rs6924808 and chr11 rs1353649, display an increased significance level (P=6.661 × 10−16 and 5.670 × 10−11). Our study reveals a general picture of pharmacogenomic control for asthma intervention. The results obtained help to tailor an optimal dose for individual patients to treat asthma based on their genetic makeup.

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Acknowledgements

We thank Kwangmi Ahn for her assistance in data management. This research was funded by grants NIH/NHLBI-1U10HL098115, UL1 TR000127, U10 HL-51810, U10 HL-51834, U10 HL-51831, U10 HL-51823, U10 HL-51845, U10 HL-51843, and U10 HL-56443. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH.

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Correspondence to D Mauger or R Wu.

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Wang, Y., Tong, C., Wang, Z. et al. Pharmacodynamic genome-wide association study identifies new responsive loci for glucocorticoid intervention in asthma. Pharmacogenomics J 15, 422–429 (2015) doi:10.1038/tpj.2014.83

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