Incorporating Concomitant Medications into Genome-Wide Analyses for the Study of Complex Disease and Drug Response.
Incorporating Concomitant Medications into Genome-Wide Analyses for the Study of Complex Disease and Drug Response.
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DOI：
10.3389/fgene.2016.00138
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发表时间：
2016
影响因子：
3.7
通讯作者：
ACCORD/ACCORDion Investigators
中科院分区：
文献类型：
--
作者：
Graham HT;Rotroff DM;Marvel SW;Buse JB;Havener TM;Wilson AG;Wagner MJ;Motsinger-Reif AA;ACCORD/ACCORDion Investigators
鉴于进行药物反应试验的高成本，研究人员现在的目标是使用回溯性分析来进行全基因组关联研究(Gwas)，以确定潜在的遗传因素对药物反应变异的影响。为了防止GWAS调查药物反应的混淆结果，有必要考虑伴随药物，其定义为与被调查的主要药物同时服用的任何药物。我们使用来自心血管疾病控制行动(ACCORD)试验的数据，以便实施一种新的评分程序，将伴随的药物信息合并到线性回归模型中，为GWA做准备。为了实现这一点，选择了两种主要药物：噻唑烷二酮类和二甲双胍，因为这些药物的广泛使用和ACCORD试验中可获得的大样本数量。第三种药物非诺贝特和已知的混淆药物他汀类药物被选为评分程序的原则证明。先前的研究已经确定SNP rs7412与他汀类药物的反应有关。在这里，我们假设，将他汀类药物的得分作为协变量包括在GWAS模型中，将纠正他汀类药物的混淆，并在rs7412产生相关性变化。混杂信号的响应被成功地从p=3.19×10−7减小到p=1.76×10−5，通过使用这里提供的评分程序来考虑他汀类药物。这种方法为研究人员提供了在单一治疗方案不可用的复杂试验设计中解释伴随药物的能力。
Given the high costs of conducting a drug-response trial, researchers are now aiming to use retrospective analyses to conduct genome-wide association studies (GWAS) to identify underlying genetic contributions to drug-response variation. To prevent confounding results from a GWAS to investigate drug response, it is necessary to account for concomitant medications, defined as any medication taken concurrently with the primary medication being investigated. We use data from the Action to Control Cardiovascular Disease (ACCORD) trial in order to implement a novel scoring procedure for incorporating concomitant medication information into a linear regression model in preparation for GWAS. In order to accomplish this, two primary medications were selected: thiazolidinediones and metformin because of the wide-spread use of these medications and large sample sizes available within the ACCORD trial. A third medication, fenofibrate, along with a known confounding medication, statin, were chosen as a proof-of-principle for the scoring procedure. Previous studies have identified SNP rs7412 as being associated with statin response. Here we hypothesize that including the score for statin as a covariate in the GWAS model will correct for confounding of statin and yield a change in association at rs7412. The response of the confounded signal was successfully diminished from p = 3.19 × 10−7 to p = 1.76 × 10−5, by accounting for statin using the scoring procedure presented here. This approach provides the ability for researchers to account for concomitant medications in complex trial designs where monotherapy treatment regimens are not available.
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DOI：
10.1056/nejmoa1001282
发表时间：
2010-04-29
期刊：
The New England journal of medicine
影响因子：
--
作者：
ACCORD Study Group;Ginsberg HN;Elam MB;Lovato LC;Crouse JR 3rd;Leiter LA;Linz P;Friedewald WT;Buse JB;Gerstein HC;Probstfield J;Grimm RH;Ismail-Beigi F;Bigger JT;Goff DC Jr;Cushman WC;Simons-Morton DG;Byington RP
通讯作者：
Byington RP
影响因子：
2.6
作者：
Irvin, Marguerite R.;Rotroff, Daniel M.;Arnett, Donna K.
通讯作者：
Arnett, Donna K.
影响因子：
2.8
作者：
Buse, John B.
通讯作者：
Buse, John B.
影响因子：
3.7
作者：
Barber MJ;Mangravite LM;Hyde CL;Chasman DI;Smith JD;McCarty CA;Li X;Wilke RA;Rieder MJ;Williams PT;Ridker PM;Chatterjee A;Rotter JI;Nickerson DA;Stephens M;Krauss RM
通讯作者：
Krauss RM
影响因子：
5.8
作者：
Manichaikul, Ani;Mychaleckyj, Josyf C.;Chen, Wei-Min
通讯作者：
Chen, Wei-Min