title: Systems biology-based analysis implicates a novel role for vitamin D metabolism in the pathogenesis of age-related macular degeneration.
abstract: 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.
authors.affiliation: Ocular Molecular Genetics Institute, Harvard Medical School, Massachusetts Eye and Ear, Boston, MA, USA.
authors.forename: Margaux A
authors.initials: MA
authors.lastname: Morrison
authors.forename: Alexandra C
authors.initials: AC
authors.lastname: Silveira
authors.forename: Nancy
authors.initials: N
authors.lastname: Huynh
authors.forename: Gyungah
authors.initials: G
authors.lastname: Jun
authors.forename: Silvia E
authors.initials: SE
authors.lastname: Smith
authors.forename: Fani
authors.initials: F
authors.lastname: Zacharaki
authors.forename: Hajime
authors.initials: H
authors.lastname: Sato
authors.forename: Stephanie
authors.initials: S
authors.lastname: Loomis
authors.forename: Michael T
authors.initials: MT
authors.lastname: Andreoli
authors.forename: Scott M
authors.initials: SM
authors.lastname: Adams
authors.forename: Monte J
authors.initials: MJ
authors.lastname: Radeke
authors.forename: Austin S
authors.initials: AS
authors.lastname: Jelcick
authors.forename: Yang
authors.initials: Y
authors.lastname: Yuan
authors.forename: Aristoteles N
authors.initials: AN
authors.lastname: Tsiloulis
authors.forename: Dimitrios Z
authors.initials: DZ
authors.lastname: Chatzoulis
authors.forename: Giuliana
authors.initials: G
authors.lastname: Silvestri
authors.forename: Maria G
authors.initials: MG
authors.lastname: Kotoula
authors.forename: Evangelia E
authors.initials: EE
authors.lastname: Tsironi
authors.forename: Bruce W
authors.initials: BW
authors.lastname: Hollis
authors.forename: Rui
authors.initials: R
authors.lastname: Chen
authors.forename: Neena B
authors.initials: NB
authors.lastname: Haider
authors.forename: Joan W
authors.initials: JW
authors.lastname: Miller
authors.forename: Lindsay A
authors.initials: LA
authors.lastname: Farrer
authors.forename: Gregory S
authors.initials: GS
authors.lastname: Hageman
authors.forename: Ivana K
authors.initials: IK
authors.lastname: Kim
authors.forename: Debra A
authors.initials: DA
authors.lastname: Schaumberg
authors.forename: Margaret M
authors.initials: MM
authors.lastname: DeAngelis
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016022:Case-Control Studies; D017242:Complement Factor H / Q000235:genetics; D016021:Epidemiologic Studies; D005260:Female; D005500:Follow-Up Studies; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006115:Greece / Q000453:epidemiology; D006801:Humans; D008268:Macular Degeneration / Q000453:epidemiology / Q000209:etiology* / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic / Q000235:genetics*; D011379:Prognosis; D011446:Prospective Studies; D018167:Receptors, Calcitriol / Q000235:genetics; D012307:Risk Factors; D035781:Siblings; D049490:Systems Biology; D014807:Vitamin D / Q000378:metabolism*; D014808:Vitamin D Deficiency / Q000150:complications* / Q000453:epidemiology / Q000235:genetics
chemical_list: D018167:Receptors, Calcitriol; D014807:Vitamin D; D017242:Complement Factor H