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Clin Pharmacol Ther. 2014 Mar;95(3):331-8. doi: 10.1038/clpt.2013.202. Epub 2013 Oct 4.

Characterization of statin dose response in electronic medical records.

Author information

1
Department of Biomedical Informatics, Vanderbilt University, Nashville, Tennessee, USA.
2
Department of Medicine, Vanderbilt University, Nashville, Tennessee, USA.
3
Department of Molecular Physiology and Biophysics, Center for Human Genetics Research, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
4
1] Department of Medicine, Vanderbilt University, Nashville, Tennessee, USA [2] Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA [3] Oates Institute for Experimental Therapeutics, Vanderbilt University School of Medicine, Nashville, Tennessee, USA [4] Office of Personalized Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
5
Department of Biomedical Informatics, University of Texas, Houston, Texas, USA.
6
Children's Hospital Oakland Research Institute, Oakland, California, USA.
7
Institute for Translational Genomics and Population Sciences, Los Angeles BioMedical Research Institute and Department of Pediatrics, Harbor-UCLA Medical Center, Torrance, Califonia, USA.
8
Department of Genome Sciences, University of Washington, Seattle, Washington, USA.
9
Kaiser Permanente Georgia, Center for Health Research Southeast, Atlanta, Georgia, USA.
10
Biomedical Informatics Research Center, Marshfield Clinic Research Foundation, Marshfield, Wisconsin, USA.
11
Essentia Institute of Rural Health, Duluth, Minnesota, USA.
12
Department of Internal Medicine, Sanford Healthcare, Fargo, North Dakota, USA.

Abstract

Efforts to define the genetic architecture underlying variable statin response have met with limited success, possibly because previous studies were limited to effect based on a single dose. We leveraged electronic medical records (EMRs) to extract potency (ED50) and efficacy (Emax) of statin dose-response curves and tested them for association with 144 preselected variants. Two large biobanks were used to construct dose-response curves for 2,026 and 2,252 subjects on simvastatin and atorvastatin, respectively. Atorvastatin was more efficacious, was more potent, and demonstrated less interindividual variability than simvastatin. A pharmacodynamic variant emerging from randomized trials (PRDM16) was associated with Emax for both. For atorvastatin, Emax was 51.7 mg/dl in subjects homozygous for the minor allele vs. 75.0 mg/dl for those homozygous for the major allele. We also identified several loci associated with ED50. The extraction of rigorously defined traits from EMRs for pharmacogenetic studies represents a promising approach to further understand the genetic factors contributing to drug response.

PMID:
24096969
PMCID:
PMC3944214
DOI:
10.1038/clpt.2013.202
[Indexed for MEDLINE]
Free PMC Article

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