Dan Roden
Faculty Member
Last active: 2/8/2016

Characterization of statin dose response in electronic medical records.

Wei WQ, Feng Q, Jiang L, Waitara MS, Iwuchukwu OF, Roden DM, Jiang M, Xu H, Krauss RM, Rotter JI, Nickerson DA, Davis RL, Berg RL, Peissig PL, McCarty CA, Wilke RA, Denny JC
Clin Pharmacol Ther. 2014 95 (3): 331-8

PMID: 24096969 · PMCID: PMC3944214 · DOI:10.1038/clpt.2013.202

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.

MeSH Terms (20)

Algorithms Alleles Atorvastatin Cholesterol, LDL Cohort Studies Databases, Factual Dose-Response Relationship, Drug Electronic Health Records Genotype Heptanoic Acids Humans Hydroxymethylglutaryl-CoA Reductase Inhibitors Hyperlipidemias Lipid Metabolism Lipids Phenotype Polymorphism, Single Nucleotide Pyrroles Randomized Controlled Trials as Topic Simvastatin

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