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

Autor: Aristoteles N. Tsiloulis, Rui Chen, Lindsay A. Farrer, Ivana K. Kim, Bruce W. Hollis, Monte J. Radeke, Maria G Kotoula, Michael T. Andreoli, Margaux A. Morrison, Joan W. Miller, Margaret M. DeAngelis, Evangelia E. Tsironi, Giuliana Silvestri, Silvia E Smith, Dimitrios Z Chatzoulis, Debra A. Schaumberg, Alexandra C. Silveira, Austin S. Jelcick, Nancy Huynh, Hajime Sato, Stephanie J. Loomis, S. M. Adams, Gregory S. Hageman, Neena B. Haider, Fani Zacharaki, Yang Yuan, Gyungah Jun
Jazyk: angličtina
Rok vydání: 2011
Předmět:
Male
Candidate gene
lcsh:Medicine
vitamin D
Calcitriol receptor
Macular Degeneration
0302 clinical medicine
Risk Factors
Drug Discovery
Prospective Studies
Prospective cohort study
2. Zero hunger
Aged
80 and over
0303 health sciences
education.field_of_study
Greece
Systems Biology
Middle Aged
Prognosis
3. Good health
Complement Factor H
Molecular Medicine
Female
Primary Research
Adult
lcsh:QH426-470
Genotype
Population
Biology
vitamin D deficiency
03 medical and health sciences
CYP24A1
Genetics
medicine
Vitamin D and neurology
Humans
Genetic Predisposition to Disease
education
Molecular Biology
age-related macular degeneration
030304 developmental biology
Aged
Polymorphism
Genetic
Siblings
lcsh:R
Case-control study
medicine.disease
Vitamin D Deficiency
eye diseases
lcsh:Genetics
Epidemiologic Studies
Case-Control Studies
Immunology
030221 ophthalmology & optometry
Receptors
Calcitriol
Follow-Up Studies
Zdroj: Human Genomics
Human Genomics, Vol 5, Iss 6, Pp 538-568 (2011)
ISSN: 1479-7364
1473-9542
Popis: 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.
Databáze: OpenAIRE
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