摘要
全基因组关联(GWA)研究通过对成千上万人的无数的的共同序列变体进行大量的DNA扫描,从而达到构建性状或疾病相关的基因位点的目的。我们提供配体样本以及与老年性黄斑变性(AMD)领域的靶向性研究,以证明在验证性和试探性药物基因组学研究中GWA方法的价值。为配合这一基因组分析,我们用了一个简单的生化视网膜色素上皮细胞(RPE)的氧化物,细胞凋亡高通量筛选(HTS)检测,以确定化合物。这种配位体-靶向的DNA序列的变体对抗疾病的方法,为临床前研究合理设计上提供了指导。并能鉴别以下两种联系: 1)丙戊酸和高级AMD关联基因有能力改变GABA-琥珀信号(ALDH5A1、CACNA1C、SUCLA2 和GABBR2)和染色质重塑(HDAC9); 2)罗匹尼罗和地理萎缩相关基因(DRD3)能够改变涉及cAMP-PKA信号的系统。 在我们的方法中的这两个应用中,GWA研究发现的广度让结果得到了有效扩张,来确定富集途径和额外的配体能够针对通路成分。 一个疾病相关的SNP为基因-靶向-配体方法提供了指导,通过提示预防和治疗的临床前研究调查的靶点的作用:1)PPAR-RXR转录复合体成分的新生血管性AMD;高级AMD的应激活化蛋白激酶信号级联成分。我们的结论是,从GWA研究中公开获得的数据可以被成功使用,通过开放获取基因组学、蛋白质组学、结构化学、药物基因组学数据库,以高效、合理的方法来简化规划和实施的过程,对预防性或治疗性药物治疗的复杂疾病进行验证性和探索性临床前研究。
关键词: 老年性黄斑变性,全基因组关联,配体,遗传药理学,药物基因学,系统,靶点。
Current Molecular Medicine
Title:Application and Interpretation of Genome-Wide Association (GWA) Studies for Informing Pharmacogenomic Research - Examples from the Field of Age-Related Macular Degeneration
Volume: 14 Issue: 7
Author(s): J.P. SanGiovanni, R. Rosen and S. Kaushal
Affiliation:
关键词: 老年性黄斑变性,全基因组关联,配体,遗传药理学,药物基因学,系统,靶点。
摘要: Genome-wide association (GWA) studies apply broad DNA scans on hundreds-of-thousands of common sequence variants in thousands of people for the purpose of mapping trait- or disease-related loci. We provide examples of ligand- and target-based studies from the field of age-related macular degeneration (AMD) to demonstrate the value of the GWA approach in confirmatory and exploratory pharmacogenomics research. Complementing this genomic analysis, we used a simple biochemical retinal pigment epithelium (RPE) oxidative, apoptotic high throughput screening (HTS) assay to identify compounds. This ligand-to-targetto DNA sequence variant-to disease approach provided guidance on rational design of preclinical studies and identified associations between: 1) valproic acid and advanced AMD-associated genes with the capacity to alter GABA-succinate signaling (ALDH5A1, CACNA1C, SUCLA2, and GABBR2) and chromatin remodeling (HDAC9); and 2) Ropinirole and a geographic atrophy-associated gene (DRD3) with the capacity to alter systems involved in cAMP-PKA signaling. In both applications of our method, the breadth of GWA findings allowed efficient expansion of results to identify enriched pathways and additional ligands capable of targeting pathway constituents. A disease associated SNP-to gene-to target-to ligand approach provided guidance to inform preventive and therapeutic preclinical studies investigating roles of targets in: 1) PPAR-RXR transcription complex constituents for neovascular AMD; and 2) the stress activated MAPK signaling cascade constituents for advanced AMD. Our conclusion is that publically available data from GWA studies can be used successfully with open-access genomics, proteomics, structural chemistry, and pharmacogenomics databases in an efficient, rational approach to streamline the processes of planning and implementation for confirmatory and exploratory pre-clinical studies of preventive or therapeutic pharmacologic treatments for complex diseases.
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SanGiovanni J.P., Rosen R. and Kaushal S., Application and Interpretation of Genome-Wide Association (GWA) Studies for Informing Pharmacogenomic Research - Examples from the Field of Age-Related Macular Degeneration, Current Molecular Medicine 2014; 14 (7) . https://dx.doi.org/10.2174/1566524014666140811113606
DOI https://dx.doi.org/10.2174/1566524014666140811113606 |
Print ISSN 1566-5240 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5666 |
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