Mining Retrospective Data for Virtual Prospective Drug Repurposing: L-DOPA and Age-related Macular Degeneration

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• 作者：Murray H. Brilliant ; PhD^a ; Kamyar Vaziri ; MD^b ; Thomas B. Connor Jr. ; MD^c ; Stephen G. Schwartz ; MD ; MBA^b ; Joseph J. Carroll ; PhD^c ; ^d ; Catherine A. McCarty ; PhD ; MPH^e ; Steven J. Schrodi ; PhD^a ; Scott J. Hebbring ; PhD^a ; Krishna S. Kishor ; MD^b ; Harry W. Flynn Jr. ; MD^b ; Andrew A. Moshfeghi ; MD^f ; Darius M. Moshfeghi ; MD^g ; M. Elizabeth Fini ; PhD^h ; ⁱ ; ^j ; Brian S. McKay ; PhD^k ; ^l ; ^{bsmckay@eyes.arizona.edu" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Age-related macular degeneration (AMD) ; GPR143 ; L-DOPA ; Movement disorder ; Parkinson's disease ; Retrospective study ; Retinal pigment epithelium (RPE)
• 刊名：The American Journal of Medicine
• 出版年：2016
• 出版时间：March 2016
• 年：2016
• 卷：129
• 期：3
• 页码：292-298
• 全文大小：403 K

文摘

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 protein–coupled receptor that, in response to its ligand, L-DOPA, up-regulates pigment epithelia–derived factor, while down-regulating vascular endothelial growth factor. In this study we investigated the potential relationship between L-DOPA and AMD.

absSec_2">Methods

abspara0015">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.

absSec_3">Results

abspara0020">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).

absSec_4">Conclusions

abspara0025">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-DOPA receptor; it is therefore plausible that GPR143 may be a fruitful target to combat this devastating disease.