Development of a Pharmacogenetic Predictive Test i... [Pharmacogenet Genomics. 2009] - PubMed result

Pharmacogenet Genomics. 2009 Dec 22. [Epub ahead of print]

Development of a Pharmacogenetic Predictive Test in asthma: proof of concept.
Wu AC, Himes BE, Lasky-Su J, Litonjua A, Li L, Lange C, Lima J, Irvin CG, Weiss ST.

aDepartment of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute bDepartment of General Pediatrics, Children's Hospital cChanning Laboratory, Brigham and Women's Hospital dCenter for Genomic Medicine, Department of Medicine, Brigham and Women's Hospital eChildren's Hospital Informatics Program fHarvard School of Public Health, Boston gHarvard-MIT Division of Health Sciences and Technology, Cambridge, Massachusetts hNemours Children's Clinic, Centers for Clinical Pediatric Pharmacology & Pharmacogenetics, Jacksonville, Florida iVermont Lung Center, University of Vermont, College of Medicine, Burlington, Vermont, USA.

OBJECTIVE: To assess the feasibility of developing a Combined Clinical and Pharmacogenetic Predictive Test, comprised of multiple single nucleotide polymorphisms (SNPs) that is associated with poor bronchodilator response (BDR). METHODS: We genotyped SNPs that tagged the whole genome of the parents and children in the Childhood Asthma Management Program (CAMP) and implemented an algorithm using a family-based association test that ranked SNPs by statistical power. The top eight SNPs that were associated with BDR comprised the Pharmacogenetic Predictive Test. The Clinical Predictive Test was comprised of baseline forced expiratory volume in 1 s (FEV1). We evaluated these predictive tests and a Combined Clinical and Pharmacogenetic Predictive Test in three distinct populations: the children of the CAMP trial and two additional clinical trial populations of asthma. Our outcome measure was poor BDR, defined as BDR of less than 20th percentile in each population. BDR was calculated as the percent difference between the prebronchodilator and postbronchodilator (two puffs of albuterol at 180 mug/puff) FEV1 value. To assess the predictive ability of the test, the corresponding area under the receiver operating characteristic curves (AUROCs) were calculated for each population. RESULTS: The AUROC values for the Clinical Predictive Test alone were not significantly different from 0.50, the AUROC of a random classifier. Our Combined Clinical and Pharmacogenetic Predictive Test comprised of genetic polymorphisms in addition to FEV1 predicted poor BDR with an AUROC of 0.65 in the CAMP children (n=422) and 0.60 (n=475) and 0.63 (n=235) in the two independent populations. Both the Combined Clinical and Pharmacogenetic Predictive Test and the Pharmacogenetic Predictive Test were significantly more accurate than the Clinical Predictive Test (AUROC between 0.44 and 0.55) in each of the populations. CONCLUSION: Our finding that genetic polymorphisms with a clinical trait are associated with BDR suggests that there is promise in using multiple genetic polymorphisms simultaneously to predict which asthmatics are likely to respond poorly to bronchodilators.

PMID: 20032818 [PubMed - as supplied by publisher]

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Development of a Pharmacogenetic Predictive Test i... [Pharmacogenet Genomics. 2009] - PubMed result