Zinc supplementation inhibits complement activation in age-related macular degeneration

PLoS One. 2014 Nov 13;9(11):e112682. doi: 10.1371/journal.pone.0112682. eCollection 2014.


Age-related macular degeneration (AMD) is the leading cause of blindness in the Western world. AMD is a multifactorial disorder but complement-mediated inflammation at the level of the retina plays a pivotal role. Oral zinc supplementation can reduce the progression of AMD but the precise mechanism of this protective effect is as yet unclear. We investigated whether zinc supplementation directly affects the degree of complement activation in AMD and whether there is a relation between serum complement catabolism during zinc administration and the complement factor H (CFH) gene or the Age-Related Maculopathy susceptibility 2 (ARMS2) genotype. In this open-label clinical study, 72 randomly selected AMD patients in various stages of AMD received a daily supplement of 50 mg zinc sulphate and 1 mg cupric sulphate for three months. Serum complement catabolism-defined as the C3d/C3 ratio-was measured at baseline, throughout the three months of supplementation and after discontinuation of zinc administration. Additionally, downstream inhibition of complement catabolism was evaluated by measurement of anaphylatoxin C5a. Furthermore, we investigated the effect of zinc on complement activation in vitro. AMD patients with high levels of complement catabolism at baseline exhibited a steeper decline in serum complement activation (p<0.001) during the three month zinc supplementation period compared to patients with low complement levels. There was no significant association of change in complement catabolism and CFH and ARMS2 genotype. In vitro zinc sulphate directly inhibits complement catabolism in hemolytic assays and membrane attack complex (MAC) deposition on RPE cells. This study provides evidence that daily administration of 50 mg zinc sulphate can inhibit complement catabolism in AMD patients with increased complement activation. This could explain part of the mechanism by which zinc slows AMD progression.

Trial registration: The Netherlands National Trial Register NTR2605.

Publication types

  • Clinical Trial
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Cells, Cultured
  • Complement Activation / drug effects*
  • Complement C3 / immunology
  • Complement C3 / metabolism*
  • Complement C3d / immunology
  • Complement C3d / metabolism*
  • Complement C5a / immunology
  • Complement C5a / metabolism
  • Complement Factor B / immunology
  • Complement Factor B / metabolism
  • Complement Factor H / immunology
  • Complement Factor H / metabolism
  • Copper Sulfate / administration & dosage
  • Dietary Supplements*
  • Epithelial Cells / cytology
  • Epithelial Cells / drug effects
  • Epithelial Cells / immunology
  • Female
  • Gene Expression
  • Humans
  • Macular Degeneration / blood
  • Macular Degeneration / diet therapy*
  • Macular Degeneration / immunology
  • Macular Degeneration / pathology
  • Male
  • Mutation
  • Proteins / genetics
  • Proteins / immunology
  • Retina / drug effects
  • Retina / immunology
  • Retina / pathology
  • Retinal Pigment Epithelium / cytology
  • Retinal Pigment Epithelium / drug effects
  • Retinal Pigment Epithelium / immunology
  • Zinc Sulfate / administration & dosage*


  • ARMS2 protein, human
  • Complement C3
  • Proteins
  • Zinc Sulfate
  • Complement C3d
  • Complement C5a
  • Complement Factor H
  • Complement Factor B
  • Copper Sulfate

Associated data

  • NTR/NTR2605

Grant support

This work was supported by the Netherlands Organisation for Scientific Research (grant 016.096.309), the MD Fonds, the Oogfonds, the Landelijke Stichting voor Blinden en Slechtzienden, the Algemene Nederlandse Vereniging ter Voorkoming van Blindheid, the Stichting Researchfonds Oogheelkunde, the Stichting Nederlands Oogheelkundig Onderzoek, the Stichting Blindenhulp, the Gelderse Blindenstichting, the Swedish Research Council (K2012-66X-14928-09-5) and the grant for clinical research (ALF). Zinc sulphate and cupric sulphate capsules were a generous gift from Sanmed, Almere, the Netherlands. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.