SanGiovanni J P, Rosen R, Kaushal S
National Eye Institute, Bethesda, MD 20892-1863, USA.
Curr Mol Med. 2014;14(7):814-32. doi: 10.2174/1566524014666140811113606.
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.
全基因组关联（GWA）研究对数千人的数十万种常见序列变异进行广泛的DNA扫描，以绘制与性状或疾病相关的基因座。我们提供了年龄相关性黄斑变性（AMD）领域基于配体和靶点的研究示例，以证明GWA方法在验证性和探索性药物基因组学研究中的价值。作为这种基因组分析的补充，我们使用了一种简单的生化视网膜色素上皮（RPE）氧化、凋亡高通量筛选（HTS）试验来鉴定化合物。这种从配体到靶点再到DNA序列变异再到疾病的方法为临床前研究的合理设计提供了指导，并确定了以下之间的关联：1）丙戊酸与具有改变GABA-琥珀酸信号传导（ALDH5A1、CACNA1C、SUCLA2和GABBR2）和染色质重塑（HDAC9）能力的晚期AMD相关基因；2）罗匹尼罗与具有改变参与cAMP-PKA信号传导系统能力的地理萎缩相关基因（DRD3）。在我们方法的这两种应用中，GWA研究结果的广度使得能够有效地扩展结果，以识别富集的途径和能够靶向途径成分的其他配体。一种从疾病相关单核苷酸多态性到基因再到靶点再到配体的方法为预防和治疗性临床前研究提供了指导，这些研究调查靶点在以下方面的作用：1）新生血管性AMD的PPAR-RXR转录复合物成分；2）晚期AMD的应激激活MAPK信号级联成分。我们的结论是，GWA研究的公开数据可以与开放获取的基因组学、蛋白质组学、结构化学和药物基因组学数据库成功结合，以一种高效、合理的方法简化复杂疾病预防或治疗性药物治疗的验证性和探索性临床前研究的规划和实施过程。
