التفاصيل البيبلوغرافية
| العنوان: |
Pharmacodynamic genome-wide association study identifies new responsive loci for glucocorticoid intervention in asthma. |
| المؤلفون: |
Wang, Y, Tong, C, Wang, Z, Mauger, D, Tantisira, K G, Israel, E, Szefler, S J, Chinchilli, V M, Boushey, H A, Lazarus, S C, Lemanske, R F, Wu, R |
| المصدر: |
Pharmacogenomics Journal; Oct2015, Vol. 15 Issue 5, p422-429, 8p |
| مصطلحات موضوعية: |
ASTHMA treatment, GENETICS of asthma, THERAPEUTIC use of glucocorticoids, PHARMACODYNAMICS, GENOMES, DISEASE prevalence |
| مستخلص: |
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. [ABSTRACT FROM AUTHOR] |
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| قاعدة البيانات: |
Complementary Index |
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