Mining Retrospective Data for Virtual Prospective Drug Repurposing: L-DOPA and Age-related Macular Degeneration
Mining Retrospective Data for Virtual Prospective Drug Repurposing: L-DOPA and Age-related Macular Degeneration
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DOI：
10.1016/j.amjmed.2015.10.015
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发表时间：
2016-03-01
影响因子：
5.9
通讯作者：
McKay, Brian S.
中科院分区：
文献类型：
--
作者：
Brilliant, Murray H.;Vaziri, Kamyar;McKay, Brian S.
背景：年龄相关性黄斑变性（AMD）是老年人视力丧失的主要原因。视网膜色素上皮是AMD的关键细胞类型，它表达一种G蛋白偶联受体，该受体响应其配体L-DOPA，上调色素上皮衍生因子，同时下调血管内皮生长因子。在这项研究中，我们探讨了左旋多巴与AMD之间的潜在关系。方法：采用回顾性分析的方法，比较左旋多巴服用组与未服用组AMD的发生率。我们分析了来自Marshfield诊所（大约17000和20000）和Truven MarketScan门诊和数据库（大约8700万）患者的大量医疗记录的两个独立的患者队列。我们使用国际疾病分类，第9修订版代码来确定AMD诊断和左旋多巴处方，以确定有或没有左旋多巴处方的AMD的相对风险和发病年龄。结果：在没有左旋多巴处方的患者中，3个独立回顾性队列的AMD发病年龄分别为71.2、71.3和71.3岁。年龄相关性黄斑变性在服用左旋多巴的患者中发生的时间明显较晚，在所有队列中为79.4。左旋多巴与AMD发生的比值比也呈显著负相关（比值比0.78，置信区间0.76 ~ 0.80,P < 0.001）。在新生血管性AMD中观察到类似的结果（P < 0.001）。结论：外源性左旋多巴对AMD有保护作用。左旋多巴通常在色素组织中产生，如视网膜色素上皮，作为酪氨酸酶合成黑色素的副产物。GPR143是唯一已知的L-DOP受体；因此，GPR143可能是抗击这一毁灭性疾病的有效目标，这是合理的。(C) 2016年作者。Elsevier Inc.出版。
BACKGROUND: Age-related macular degeneration (AMD) is a leading cause of visual loss among the elderly. A key cell type involved in AMD, the retinal pigment epithelium, expresses a G proteine-coupled receptor that, in response to its ligand, L-DOPA, up-regulates pigment epitheliae-derived factor, while down-regulating vascular endothelial growth factor. In this study we investigated the potential relationship between L-DOPA and AMD.METHODS: We used retrospective analysis to compare the incidence of AMD between patients taking vs not taking L-DOPA. We analyzed 2 separate cohorts of patients with extensive medical records from the Marshfield Clinic (approximately 17,000 and approximately 20,000) and the Truven MarketScan outpatient and databases (approximately 87 million) patients. We used International Classification of Diseases, 9th Revision codes to identify AMD diagnoses and L-DOPA prescriptions to determine the relative risk of developing AMD and age of onset with or without an L-DOPA prescription.RESULTS: In the retrospective analysis of patients without an L-DOPA prescription, AMD age of onset was 71.2, 71.3, and 71.3 in 3 independent retrospective cohorts. Age-related macular degeneration occurred significantly later in patients with an L-DOPA prescription, 79.4 in all cohorts. The odds ratio of developing AMD was also significantly negatively correlated by L-DOPA (odds ratio 0.78; confidence interval, 0.76-0.80; P < .001). Similar results were observed for neovascular AMD (P < .001).CONCLUSIONS: Exogenous L-DOPA was protective against AMD. L-DOPA is normally produced in pigmented tissues, such as the retinal pigment epithelium, as a byproduct of melanin synthesis by tyrosinase. GPR143 is the only known L-DOP Areceptor; it is therefore plausible that GPR143 may be a fruitful target to combat this devastating disease. (C) 2016 The Authors. Published by Elsevier Inc.