title: Mining Retrospective Data for Virtual Prospective Drug Repurposing: L-DOPA and Age-related Macular Degeneration.
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.
authors.affiliation: Center for Human Genetics, Marshfield Clinic Research Foundation, Marshfield, Wis.
authors.forename: Murray H
authors.initials: MH
authors.lastname: Brilliant
authors.affiliation: Department of Ophthalmology, Bascom Palmer Eye Institute, Miller School of Medicine, University of Miami, Palm Beach Gardens, Fla.
authors.forename: Kamyar
authors.initials: K
authors.lastname: Vaziri
authors.affiliation: Department of Ophthalmology, Medical College of Wisconsin, Milwaukee.
authors.forename: Thomas B
authors.initials: TB
authors.lastname: Connor
authors.affiliation: Department of Ophthalmology, Bascom Palmer Eye Institute, Miller School of Medicine, University of Miami, Palm Beach Gardens, Fla.
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Schwartz
authors.affiliation: Department of Ophthalmology, Medical College of Wisconsin, Milwaukee; Department of Cell Biology, Neurobiology & Anatomy, Medical College of Wisconsin, Milwaukee.
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: Carroll
authors.affiliation: Essentia Institute of Rural Health, Duluth, Minn.
authors.forename: Catherine A
authors.initials: CA
authors.lastname: McCarty
authors.affiliation: Center for Human Genetics, Marshfield Clinic Research Foundation, Marshfield, Wis.
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Schrodi
authors.affiliation: Center for Human Genetics, Marshfield Clinic Research Foundation, Marshfield, Wis.
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Hebbring
authors.affiliation: Department of Ophthalmology, Bascom Palmer Eye Institute, Miller School of Medicine, University of Miami, Palm Beach Gardens, Fla.
authors.forename: Krishna S
authors.initials: KS
authors.lastname: Kishor
authors.affiliation: Department of Ophthalmology, Bascom Palmer Eye Institute, Miller School of Medicine, University of Miami, Palm Beach Gardens, Fla.
authors.forename: Harry W
authors.initials: HW
authors.lastname: Flynn
authors.affiliation: Department of Ophthalmology, USC Eye Institute, Keck School of Medicine of USC, University of Southern California, Los Angeles.
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Moshfeghi
authors.affiliation: Department of Ophthalmology, Byers Eye Institute, Stanford University School of Medicine, Palo Alto, Calif.
authors.forename: Darius M
authors.initials: DM
authors.lastname: Moshfeghi
authors.affiliation: USC Institute for Genetic Medicine, Keck School of Medicine of USC, University of Southern California, Los Angeles; Department of Cell & Neurobiology, Keck School of Medicine of USC, University of Southern California, Los Angeles; Department of Ophthalmology, Keck School of Medicine of USC, University of Southern California, Los Angeles.
authors.forename: M Elizabeth
authors.initials: ME
authors.lastname: Fini
authors.affiliation: Department of Ophthalmology and Vision Science, University of Arizona, Tucson; Department of Cellular and Molecular Medicine, University of Arizona, Tucson. Electronic address: bsmckay@eyes.arizona.edu.
authors.forename: Brian S
authors.initials: BS
authors.lastname: McKay
mesh_terms: D017677:Age Distribution; D017668:Age of Onset; D000368:Aged; D000978:Antiparkinson Agents / Q000494:pharmacology / Q000627:therapeutic use*; D015331:Cohort Studies; D057225:Data Mining; D005136:Eye Proteins / Q000502:physiology; D006801:Humans; D007980:Levodopa / Q000494:pharmacology / Q000627:therapeutic use*; D008268:Macular Degeneration / Q000453:epidemiology*; D008562:Membrane Glycoproteins / Q000502:physiology; D012189:Retrospective Studies; D014481:United States / Q000453:epidemiology
chemical_list: D000978:Antiparkinson Agents; D005136:Eye Proteins; C095276:GPR143 protein, human; D008562:Membrane Glycoproteins; D007980:Levodopa
keywords: Age-related macular degeneration (AMD); GPR143; L-DOPA; Movement disorder; Parkinson's disease; Retinal pigment epithelium (RPE); Retrospective study