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Systems biology-based analysis implicates a novel role for vitamin D metabolism in the pathogenesis of age-related macular degeneration

Margaux A Morrison12, Alexandra C Silveira1, Nancy Huynh1, Gyungah Jun3, Silvia E Smith2, Fani Zacharaki4, Hajime Sato1, Stephanie Loomis1, Michael T Andreoli1, Scott M Adams1, Monte J Radeke5, Austin S Jelcick6, Yang Yuan6, Aristoteles N Tsiloulis4, Dimitrios Z Chatzoulis4, Giuliana Silvestri7, Maria G Kotoula4, Evangelia E Tsironi4, Bruce W Hollis8, Rui Chen9, Neena B Haider6, Joan W Miller10, Lindsay A Farrer11, Gregory S Hageman2, Ivana K Kim10, Debra A Schaumberg12 and Margaret M DeAngelis12*

Author Affiliations

1 Ocular Molecular Genetics Institute, Harvard Medical School, Massachusetts Eye and Ear, Boston, MA, USA

2 Department of Ophthalmology and Visual Sciences, University of Utah, Salt Lake City, UT, USA

3 Departments of Medicine (Section of Biomedical Genetics), Ophthalmology and Biostatistics, Boston University Schools of Medicine and Public Health, Boston, MA, USA

4 Department of Ophthalmology, University of Thessaly School of Medicine, Larissa, Greece

5 Center for the Study of Macular Degeneration, Neuroscience Research Institute, University of California, Santa Barbara, CA, USA

6 Department of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, NE, USA

7 Centre for Vision and Vascular Science, Queen's University, Belfast, UK

8 Pediatric Nutritional Sciences, Medical University of South Carolina, Charleston, SC, USA

9 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA

10 Retina Service, Harvard Medical School, Massachusetts Eye and Ear, Boston, MA, USA

11 Departments of Medicine (Section of Biomedical Genetics), Ophthalmology and Biostatistics, Neurology, Epidemiology, Boston University Schools of Medicine and Public Health, Boston, MA, USA

12 Division of Preventive Medicine, Brigham and Women's Hospital and the Department of Ophthalmology, Harvard Medical School, Boston, MA, USA

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Human Genomics 2011, 5:538-568  doi:10.1186/1479-7364-5-6-538

Published: 1 October 2011


Vitamin D has been shown to have anti-angiogenic properties and to play a protective role in several types of cancer, including breast, prostate and cutaneous melanoma. Similarly, vitamin D levels have been shown to be protective for risk of a number of conditions, including cardiovascular disease and chronic kidney disease, as well as numerous autoimmune disorders such as multiple sclerosis, inflammatory bowel diseases and type 1 diabetes mellitus. A study performed by Parekh et al. was the first to suggest a role for vitamin D in age-related macular degeneration (AMD) and showed a correlation between reduced serum vitamin D levels and risk for early AMD. Based on this study and the protective role of vitamin D in diseases with similar pathophysiology to AMD, we examined the role of vitamin D in a family-based cohort of 481 sibling pairs. Using extremely phenotypically discordant sibling pairs, initially we evaluated the association of neovascular AMD and vitamin D/sunlight-related epidemiological factors. After controlling for established AMD risk factors, including polymorphisms of the genes encoding complement factor H (CFH) and age-related maculopathy susceptibility 2/HtrA serine peptidase (ARMS2/HTRA1), and smoking history, we found that ultraviolet irradiance was protective for the development of neovascular AMD (p = 0.001). Although evaluation of serum vitamin D levels (25-hydroxyvitamin D [25(OH)D]) was higher in unaffected individuals than in their affected siblings, this finding did not reach statistical significance.

Based on the relationship between ultraviolet irradiance and vitamin D production, we employed a candidate gene approach for evaluating common variation in key vitamin D pathway genes (the genes encoding the vitamin D receptor [VDR]; cytochrome P450, family 27, subfamily B, polypeptide 1 [CYP27B1]; cytochrome P450, family 24, subfamily A, polypeptide 1 [CYP24A1]; and CYP27A1) in this same family-based cohort. Initial findings were then validated and replicated in the extended family cohort, an unrelated case-control cohort from central Greece and a prospective nested case-control population from the Nurse's Health Study and Health Professionals Follow-Up Studies, which included patients with all subtypes of AMD for a total of 2,528 individuals. Single point variants in CYP24A1 (the gene encoding the catabolising enzyme of the vitamin D pathway) were demonstrated to influence AMD risk after controlling for smoking history, sex and age in all populations, both separately and, more importantly, in a meta-analysis. This is the first report demonstrating a genetic association between vitamin D metabolism and AMD risk. These findings were also supplemented with expression data from human donor eyes and human retinal cell lines. These data not only extend previous biological studies in the AMD field, but further emphasise common antecedents between several disorders with an inflammatory/immunogenic component such as cardiovascular disease, cancer and AMD.

vitamin D; age-related macular degeneration