Review article| Volume 88, P101-112, June 2016

Circulating vitamin D concentration and age-related macular degeneration: Systematic review and meta-analysis

  • Cedric Annweiler
    Corresponding author at: Department of Neuroscience, Division of Geriatric Medicine, Angers University Hospital, 49933 Angers Cedex 9, France.
    Department of Neuroscience, Division of Geriatric Medicine and Memory Clinic, Angers University Hospital, UPRES EA 4638, University of Angers, LUNAM, Angers, France

    Robarts Research Institute, Department of Medical Biophysics, Schulich School of Medicine and Dentistry, The University of Western Ontario, London, Ontario, Canada
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  • Morgane Drouet
    Department of Neuroscience, Division of Ophthalmology, Angers University Hospital, Angers, France
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  • Guillaume T Duval
    Department of Neuroscience, Division of Geriatric Medicine and Memory Clinic, Angers University Hospital, UPRES EA 4638, University of Angers, LUNAM, Angers, France
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  • Pierre-Yves Paré
    Department of Neuroscience, Division of Geriatric Medicine and Memory Clinic, Angers University Hospital, UPRES EA 4638, University of Angers, LUNAM, Angers, France
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  • Stephanie Leruez
    Department of Neuroscience, Division of Ophthalmology, Angers University Hospital, Angers, France
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  • Mickael Dinomais
    Université d’Angers, Laboratoire Angevin de Recherche en Ingénierie des Systèmes (LARIS)—EA7315, LUNAM, Université d’Angers, Angers F-49000, France

    Département de Médecine Physique et de Réadaptation, CHU, Angers F-49933, France
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  • Dan Milea
    Department of Neuroscience, Division of Ophthalmology, Angers University Hospital, Angers, France

    Singapore Eye Research Institute, Singapore, Singapore

    Singapore National Eye Centre, Singapore, Singapore

    Duke-NUS, Neuroscience and Behavioural Disorders, Singapore, Singapore
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      • Vitamin D may be involved in ocular health and function.
      • High concentrations 25-hydroxyvitamin D are associated with less age-related macular degeneration.
      • Concentrations of 25-hydroxyvitamin D under 50 nmol/L are associated with late-stage age-related macular degeneration.
      • These findings provide a scientific basis for vitamin D replacement trials.


      Vitamin D may be involved in ocular function in older adults, but there is no current consensus on a possible association between circulating concentrations of 25-hydroxyvitamin D (25OHD) and the occurrence of age-related macular degeneration (AMD). Our objective was to systematically review and quantitatively assess the association of circulating 25OHD concentration with AMD. A Medline search was conducted in November 2015, with no date limit, using the MeSH terms “Vitamin D” OR “Vitamin D deficiency” OR “Ergocalciferols” OR ‘Cholecalciferol’ combined with “Age-related macular degeneration” OR “Macular degeneration” OR “Retinal degeneration” OR “Macula lutea” OR “Retina”. Fixed and random-effects meta-analyses were performed to compute (i) standard mean difference in 25OHD concentration between AMD and non-AMD patients; (ii) AMD risk according to circulating 25OHD concentration. Of the 243 retrieved studies, 11 observational studies—10 cross-sectional studies and 1 cohort study—met the selection criteria. The number of participants ranged from 65 to 17,045 (52–100% women), and the number with AMD ranged from 31 to 1440. Circulating 25OHD concentration was 15% lower in AMD compared with non-AMD on average. AMD was inversely associated with the highest 25OHD quintile compared with the lowest (summary odds ratio (OR) = 0.83 [95%CI:0.71–0.97]), notably late AMD (summary OR = 0.47 [95%CI:0.28–0.79]). Circulating 25OHD < 50 nmol/L was also associated with late-stage AMD (summary OR = 2.18 [95%CI:1.34–3.56]), an association that did not persist when all categories of AMD were considered (summary OR = 1.26 [95%CI:0.90–1.76]). In conclusion, this meta-analysis provides evidence that high 25OHD concentrations may be protective against AMD, and that 25OHD concentrations below 50 nmol/L are associated with late AMD.


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        • Holick M.F.
        Vitamin D deficiency.
        N. Engl. J. Med. 2007; 357: 266-281
        • Annweiler C.
        • Souberbielle J.C.
        • Schott A.M.
        • et al.
        Vitamin D in the ederly: 5 points to remember.
        Geriatr. Psychol. Neuropsychiatr. Vieil. 2011; 9: 259-267
        • Reins R.Y.
        • McDermott A.M.
        Vitamin D: implications for ocular disease and therapeutic potential.
        Exp. Eye Res. 2015; 134: 101-110
        • Broadhead G.K.
        • Grigg J.R.
        • Chang A.A.
        • McCluskey P.
        Dietary modification and supplementation for the treatment of age-related macular degeneration.
        Nutr. Rev. 2015; 73: 448-462
        • Graffe A.
        • Beauchet O.
        • Fantino B.
        • Milea D.
        • Annweiler C.
        Vitamin D and macular thickness in the elderly: an optical coherence tomography study.
        Invest. Ophthalmol. Vis. Sci. 2014; 55: 5298-5303
        • Uro M.
        • Beauchet O.
        • Cherif M.
        • Graffe A.
        • Milea D.
        • Annweiler C.
        Age-related vitamin D deficiency is associated with reduced macular ganglion cell complex: a cross-sectional high-definition optical coherence tomography study.
        PLoS One. 2015; 10: e0130879
        • Goncalves A.
        • Milea D.
        • Gohier P.
        • et al.
        Serum vitamin D status is associated with the presence but not the severity of primary open angle glaucoma.
        Maturitas. 2015; 81: 470-474
        • Beauchet O.
        • Milea D.
        • Graffe A.
        • Fantino B.
        • Annweiler C.
        Association between serum 25-hydroxyvitamin D concentrations and vision: a cross-sectional population-based study of older adults.
        J. Am. Geriatr. Soc. 2011; 59: 568-570
        • Seddon J.M.
        • Reynolds R.
        • Shah H.R.
        • Rosner B.
        Smoking, dietary betaine, methionine, and vitamin d in monozygotic twins with discordant macular degeneration: epigenetic implications.
        Ophthalmology. 2011; 118: 1386-1394
        • Resnikoff S.
        • Pascolini D.
        • Etya'ale D.
        • et al.
        Global data on visual impairment in the year 2002.
        Bull. World. Health. Organ. 2004; 82: 844-851
        • Delcourt C.
        • Carriere I.
        • Delage M.
        • et al.
        Plasma lutein and zeaxanthin and other carotenoids as modifiable risk factors for age-related maculopathy and cataract: the POLA Study.
        Invest. Ophthalmol. Vis. Sci. 2006; 47: 2329-2335
        • Penfold P.
        • Killingsworth M.
        • Sarks S.
        An ultrastructural study of the role of leucocytes and fibroblasts in the breakdown of Bruch's membrane.
        Aust. J. Ophthalmol. 1984; 12: 23-31
        • Coscas G.
        Age related macular degeneration and subretinal neovessels. Primary cause of acquired blindness in adults in France.
        Rev. Prat. 1991; 41: 2320-2322
        • Jager R.D.
        • Mieler W.F.
        • Miller J.W.
        Age-related macular degeneration.
        N. Engl. J. Med. 2008; 358: 2606-2617
        • von Elm E.
        • Altman D.G.
        • Egger M.
        • Pocock S.J.
        • Gotzsche P.C.
        • Vandenbroucke J.P.
        The strengthening the reporting of observational studies in epidemiology (STROBE) statement: guidelines for reporting observational studies.
        J. Clin. Epidemiol. 2008; 61: 344-349
        • Parekh N.
        • Chappell R.J.
        • Millen A.E.
        • Albert D.M.
        • Mares J.A.
        Association between vitamin d and age-related macular degeneration in the third national health and nutrition examination survey, 1988 through 1994.
        Arch. Ophthalmol. 2007; 125: 661-669
        • Millen A.E.
        • Voland R.
        • Sondel S.A.
        • et al.
        Vitamin D status and early age-related macular degeneration in postmenopausal women.
        Arch. Ophthalmol. 2011; 129: 481-489
        • Golan S.
        • Shalev V.
        • Treister G.
        • Chodick G.
        • Loewenstein A.
        Reconsidering the connection between vitamin D levels and age-related macular degeneration.
        Eye (London). 2011; 25: 1122-1129
        • Morrison M.A.
        • Silveira A.C.
        • Huynh N.
        • et al.
        Systems biology-based analysis implicates a novel role for vitamin D metabolism in the pathogenesis of age-related macular degeneration.
        Hum. Genomics. 2011; 5: 538-568
        • Graffe A.
        • Annweiler C.
        • Mauget-Faÿsse M.
        • Beauchet O.
        • Kodjikian L.
        • Milea D.
        Association between hypovitaminosis D and late stages of age-related macular degeneration: a case-control study.
        J. Am. Geriatr. Soc. 2012; 60: 1367-1369
        • Day S.
        • Acquah K.
        • Platt A.
        • Lee P.P.
        • Mruthyunjaya P.
        • Sloan F.A.
        Association of vitamin D deficiency and age-related macular degeneration in medicare beneficiaries.
        Arch. Ophthalmol. 2012; 130: 1070-1071
        • Singh A.
        • Falk M.K.
        • Subhi Y.
        • Sørensen T.L.
        The association between plasma 25-hydroxyvitamin D and subgroups in age-related macular degeneration: a cross-sectional study.
        PLoS One. 2013; 8: e70948
        • Kim E.C.
        • Han K.
        • Jee D.
        Inverse relationship between high blood 25-hydroxyvitamin D and late stage of age-related macular degeneration in a representative Korean population.
        Invest. Ophthalmol. Vis. Sci. 2014; 55: 4823-4831
        • Itty S.
        • Day S.
        • Lyles K.W.
        • Stinnett S.S.
        • Vajzovic L.M.
        • Mruthyunjaya P.
        Vitamin D deficiency in neovascular versus nonneovascular age-related macular degeneration.
        Retina. 2014; 34: 1779-1786
        • Cougnard-Grégoire A.
        • Merle B.M.
        • Korobelnik J.F.
        • et al.
        Deficiency in community-dwelling elderly is not associated with age-related macular degeneration.
        J. Nutr. 2015; 145 (1865–1772)
        • Millen A.E.
        • Meyers K.J.
        • Liu Z.
        • et al.
        Association between vitamin D status and age-related macular degeneration by genetic risk.
        JAMA Ophthalmol. 2015; 133: 1171-1179
        • Mackinnon A.
        A spreadsheet for the calculation of comprehensive statistics for the assessment of diagnostic tests and inter-rater agreement.
        Comput. Biol. Med. 2000; 30: 127-134
        • Higgins J.P.
        • Thompson T.S.
        Quantifying heterogeneity in a meta-analysis.
        Stat. Med. 2002; 21: 1539-1558
        • Lee V.
        • Rekhi E.
        • Kam J.H.
        • Jeffery G.
        Vitamin D rejuvenates aging eyes by reducing inflammation, clearing amyloid beta and improving visual function.
        Neurobiol. Aging. 2012; 33: 2382-2389
        • Nussenblatt R.B.
        • Liu B.
        • Li Z.
        Age-related macular degeneration: an immunologically driven disease.
        Curr. Opin. Investig. Drugs. 2009; 10: 434-442
        • Wang Y.
        • Wang V.M.
        • Chan C.C.
        The role of anti-inflammatory agents in agerelated macular degeneration (AMD) treatment.
        Eye (London). 2011; 25: 127-139
        • Tang J.
        • Zhou R.
        • Luger D.
        • et al.
        Calcitriol suppresses antiretinal autoimmunity through inhibitory effects on the Th17 effector response.
        J. Immunol. 2009; 182: 4624-4632
        • Chung I.
        • Yu W.D.
        • Karpf A.R.
        • et al.
        Anti-proliferative effects of calcitriol on endothelial cells derived from two different microenvironments.
        J. Steroid. Biochem. Mol. Biol. 2007; 103: 768-770
        • Albert D.M.
        • Scheef E.A.
        • Wang S.
        • et al.
        Calcitriol is a potent inhibitor of retina neovascularization.
        Invest. Ophthalmol. Vis. Sci. 2007; 48: 2327-2334
        • Annweiler C.
        • Schott A.M.
        • Berrut G.
        • et al.
        Vitamin D and ageing: neurological issues.
        Neuropsychobiology. 2010; 62: 139-150
        • Artaza J.N.
        • Norris K.C.
        Vitamin D reduces the expression of collagen and keyprofibrotic factors by inducing an antifibrotic phenotype in mesenchymalmultipotent cells.
        J. Endocrinol. 2009; 200: 207-221
        • Bouillon R.
        • Van Schoor N.M.
        • Gielen E.
        • et al.
        Optimal vitamin D status: a critical analysis on the basis of evidence-based medicine.
        J. Clin. Endocrinol. Metab. 2013; 98: E1283-304
        • Pahl L.
        • Schubert S.
        • Skawran B.
        • Sandbothe M.
        • Schmidtke J.
        • Stuhrmann M.
        25-Dihydroxyvitamin D decreases HTRA1 promoter activity in the rhesusmonkeyea plausible explanation for the influence of vitamin D on age-relatedmacular degeneration?.
        Exp. Eye. Res. 2013; 116: 234-239
        • Riley R.D.
        • Higgins J.P.
        • Deeks J.J.
        Interpretation of random effects meta-analyses.
        BMJ. 2011; 342: d549