Web-based Phenotyping for Genome Wide Association Studies of Drug Response

描述(由申请人提供)：更多关于药物疗效或毒性的个性化遗传信息的可获得性可导致改善患者护理，并每年为消费者、保险公司和医疗机构节省数十亿美元。虽然药物基因组学领域在发现遗传变异与药物反应之间的关系方面取得了一些成功，但药物反应中的大量遗传变异仍未得到解释。我们广泛的、长期的研究目标是利用基于网络的几种主要药物类别的有效性和毒性的表型来确定新的药物遗传学关联。考虑到这一目标，我们的短期目标是确定基于网络的表型数据收集以及数千名23andMe客户的全基因组数据是否导致对质子泵抑制剂(PPI)的反应和基因CYP2C19之间的已知关联的复制，以及对几种常用药物的反应和基因CYP2C9之间的复制。这项研究的具体目标是(1)开发和管理基于网络的调查，以收集至少3,000人对几种常用药物(包括抗组胺药、止痛药、血液稀释剂和质子泵抑制剂)的反应信息；以及(2)确定这种基于网络的研究模型是否复制了几种常用药物与CYP2C19和CYP2C9基因之间的已知关联。为了进行这项创新研究，23andMe研究小组将利用多种资源，包括23andMe定制基因分型阵列上一系列与药物代谢相关的单核苷酸多态(SNPs)。该项目还将利用迅速扩大的、积极参与的、分型的23andMe客户队列的参与，这些客户可以选择通过回答基于网络的问卷来参与研究。这一研究模式的并行和连续性质允许同时有效地招募许多研究的参与者，并减少重新联系以进行额外分析的成本。作为我们快速组建队列能力的证据，一项关于常用药物的初步调查在一个月内征集了大约2500名在580,000个SNPs上进行基因分型的人的回复。这项研究的可能结果包括复制已知的药物基因组关联和发现新的关联。如果这项研究在复制方面取得成功，它将为快速、强大和成本效益高的对大量药物反应的变异进行研究奠定基础，从而显著促进个性化药物的发展。 公共卫生相关性：获得有关药物疗效或毒性的个性化遗传信息可改善患者护理，并每年为消费者、保险公司和医疗机构节省数十亿美元。考虑到这一目标，我们在这笔赠款中的近期目标是确定基于网络的表型数据收集以及数千名23andMe客户的全基因组数据是否导致两个基因(CYP2C9和CY2C19)和几种常用药物的主要药物类别的已知关联的复制。

DESCRIPTION (provided by applicant): Greater availability of personalized genetic information regarding the efficacy or toxicity of medications could lead to improved patient care and save consumers, insurers and medical institutions billions of dollars per year. Although the field of pharmacogenomics has had some success in discovering relationships between genetic variants and drug response, a great deal of genetic variation in drug response remains unexplained. Our broad, long term research aim is to identify novel pharmacogenetic associations using web-based phenotyping of efficacy and toxicity for several major drug classes. With that goal in mind, our short term aim is to determine whether web-based collection of phenotype data along with genome-wide data for thousands of 23andMe customers leads to replication of known associations between responses to proton pump inhibitors (PPIs) and the gene CYP2C19, and between responses to several commonly used medications and the gene CYP2C9. The specific aims of this study are (1) to develop and administer web-based surveys to collect information regarding response to several commonly used classes of medications (including antihistamines, analgesics, blood thinners, and proton-pump inhibitors) from at least 3,000 individuals; and (2) to determine whether this web-based research model yields replications of known associations between several commonly used medications and the genes CYP2C19 and CYP2C9. To conduct this innovative study the 23andMe research group will leverage several resources, including a broad set of drug metabolism-related single nucleotide polymorphisms (SNPs) on the 23andMe custom genotyping array. This project will also leverage involvement of a rapidly expanding, engaged, genotyped cohort of 23andMe customers who have the option to participate in research by responding to web-based questionnaires. The parallel and continuous nature of this research model allows for the efficient recruitment of participants to many studies at once and reduces the cost of re-contacting for additional analyses. As evidence of our rapid capability to assemble a cohort, an initial survey regarding commonly used medications solicited, within a month, responses from about 2500 individuals genotyped at 580,000 SNPs. Possible outcomes of this study include the replication of known pharmacogenomic associations and the discovery of novel associations. If the study is successful in yielding replications, it will set the stage for rapid, well-powered and cost-effective research on variation in response to a large number of medications, thereby significantly advancing personalized medicine. PUBLIC HEALTH RELEVANCE: The availability of personalized genetic information regarding the efficacy or toxicity of medications could lead to improved patient care, and save consumers, insurers and medical institutions billions of dollars per year. With that goal in mind, our near term aim in this grant is to determine whether web-based collection of phenotype data along with genome-wide data for thousands of 23andMe customers leads to replication of known associations two genes (CYP2C9 and CY2C19) and several major drug classes of commonly used medications.