Department of Biomedical Informatics, Vanderbilt University, Nashville, Tennessee, USA.
Department of Medicine, Vanderbilt University, Nashville, Tennessee, USA.
Clin Pharmacol Ther. 2014 Mar;95(3):331-8. doi: 10.1038/clpt.2013.202. Epub 2013 Oct 4.
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.
尽管人们努力定义他汀类药物反应变异性的遗传结构，但取得的成果有限，这可能是因为之前的研究仅限于单一剂量的效果。我们利用电子病历（EMR）提取他汀类药物剂量反应曲线的效价（ED50）和效能（Emax），并测试它们与 144 个预先选择的变体之间的关联。两个大型生物库分别用于构建 2026 名和 2252 名接受辛伐他汀和阿托伐他汀治疗的受试者的剂量反应曲线。阿托伐他汀比辛伐他汀更有效、更强效，且个体间变异性更小。一项来自随机试验的药效学变异体（PRDM16）与两者的 Emax 相关。对于阿托伐他汀，在纯合子携带次要等位基因的受试者中，Emax 为 51.7mg/dl，而在纯合子携带主要等位基因的受试者中，Emax 为 75.0mg/dl。我们还鉴定了与 ED50 相关的几个位点。从电子病历中严格定义的特征提取用于药物遗传学研究的方法代表了进一步了解导致药物反应的遗传因素的一种很有前途的方法。
