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

Murray H. Brilliant, Kamyar Vaziri, Thomas B. Connor, Stephen G. Schwartz, Joseph J. Carroll, Catherine A. McCarty, Steven J. Schrodi, Scott J. Hebbring, Krishna S. Kishor, Harry W. Flynn, Andrew A. Moshfeghi, Darius M. Moshfeghi, M. Elizabeth Fini, Brian S. McKay

Research output: Contribution to journalArticlepeer-review

33 Scopus citations

Abstract

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

Original languageEnglish (US)
Pages (from-to)292-298
Number of pages7
JournalAmerican Journal of Medicine
Volume129
Issue number3
DOIs
StatePublished - Mar 1 2016
Externally publishedYes

Bibliographical note

Funding Information:
Funding: This project was partially supported by National Institutes of Health (NIH) grants UL1TR000427 and 1U01HG006389-01 , The Wisconsin Genome Initiative and the Marshfield Clinic (Marshfield Clinic); P30EY001931 , UL1TR000055 , The Edward N. & Della L. Thome Memorial Foundation , (Medical College of Wisconsin); NIH Center Core Grant P30EY014801 (Bascom Palmer Eye Institute); BrightFocus Foundation and unrestricted grants from Research to Prevent Blindness to the University of Arizona and Bascom Palmer Eye Institute .

Funding Information:
This project was partially supported by National Institutes of Health (NIH) grants UL1TR000427 and 1U01HG006389-01, The Wisconsin Genome Initiative and the Marshfield Clinic (Marshfield Clinic); P30EY001931, UL1TR000055, The Edward N. &amp; Della L. Thome Memorial Foundation, (Medical College of Wisconsin); NIH Center Core Grant P30EY014801 (Bascom Palmer Eye Institute); BrightFocus Foundation and unrestricted grants from Research to Prevent Blindness to the University of Arizona and Bascom Palmer Eye Institute.

Publisher Copyright:
© 2016 The Authors. Published by Elsevier Inc.

Keywords

  • Age-related macular degeneration (AMD)
  • GPR143
  • L-DOPA
  • Movement disorder
  • Parkinson's disease
  • Retinal pigment epithelium (RPE)
  • Retrospective study

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