Characterization of Statin Low-Density Lipoprotein Cholesterol Dose-Response Using Electronic Health Records in a Large Population-Based Cohort.
Characterization of Statin Low-Density Lipoprotein Cholesterol Dose-Response Using Electronic Health Records in a Large Population-Based Cohort.
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DOI：
10.1161/circgen.117.002043
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发表时间：
2018-09
期刊：
影响因子：
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通讯作者：
Risch N
中科院分区：
文献类型：
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作者：
Oni-Orisan A;Hoffmann TJ;Ranatunga D;Medina MW;Jorgenson E;Schaefer C;Krauss RM;Iribarren C;Risch N
在真实人群中，他汀类药物对低密度脂蛋白胆固醇(LDL-C)的反应尚未完全阐明。这项研究的主要目的是研究他汀类药物低密度脂蛋白胆固醇的剂量反应特性及其在使用他汀类药物的多种族人群中的遗传性。我们利用来自Kaiser Permanente遗传学成人健康与老龄化研究(GERA)队列的33,139名他汀类药物使用者的电子健康记录(EHR)，确定了他汀类药物剂量对血脂测量的影响。确定他汀类药物限定日剂量(DDD)与血脂参数反应(变化百分比)的关系。DDD和低密度脂蛋白反应呈对数线性关系(β=−6.17，标准差[SE]=0.09，P<；10−300)，在调整了预先指定的协变量(调整后的β=−5.59，SE=0.12，P<；10−300)后，这种关系仍然显著。他汀类药物类型、性别、年龄、吸烟状况、糖尿病和东亚人种/民族是他汀类药物诱导的低密度脂蛋白胆固醇变化的显著独立预测因素。根据他汀类药物使用者中至少有一个一级亲属也是他汀类药物使用者(N=1,036)的子集内的方差分量方法，他汀类药物低密度脂蛋白反应的遗传度估计为11.7%(SE=8.6%，P=0.087)。使用EHR数据，我们观察到他汀类低密度脂蛋白-C的剂量反应与先前临床试验数据中的“6%规则”一致。他汀类低密度脂蛋白-C反应的临床和人口学预测指标显示出非常显著的影响，但影响不大。最后，没有发现他汀类药物引起的低密度脂蛋白-C的改变具有很强的遗传性。最终，这些发现证明了(1)EHR作为一个可靠的来源来为药物基因组研究产生强大的表型的有效性，以及(2)他汀类精确药物在脂质管理中的潜在作用。
Low-density lipoprotein cholesterol (LDL-C) response to statin therapy has not been fully elucidated in real-world populations. The primary objective of this study was to characterize statin LDL-C dose-response and its heritability in a large, multi-ethnic population of statin users. We determined the effect of statin dosing on lipid measures utilizing electronic health records (EHRs) in 33,139 statin users from the Kaiser Permanente Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort. The relationship between statin defined daily dose (DDD) and lipid parameter response (percent change) was determined. DDD and LDL-C response were associated in a log-linear relationship (β = −6.17, standard error [SE] = 0.09, P < 10−300) which remained significant after adjusting for pre-specified covariates (adjusted β = −5.59, SE = 0.12, P < 10−300). Statin type, sex, age, smoking status, diabetes, and East Asian race/ethnicity were significant independent predictors of statin-induced changes in LDL-C. Based on a variance-component method within the subset of statin users who had at least one first-degree relative who was also a statin user (N = 1,036), heritability of statin LDL-C response was estimated at 11.7% (SE = 8.6%, P = 0.087). Using EHR data, we observed a statin LDL-C dose response consistent with the “rule of 6%” from prior clinical trial data. Clinical and demographic predictors of statin LDL-C response exhibited highly significant, but modest effects. Finally, statin-induced changes in LDL-C were not found to be strongly inherited. Ultimately, these findings demonstrate (1) the utility of EHRs as a reliable source to generate robust phenotypes for pharmacogenomic research and (2) the potential role of statin precision medicine in lipid management.