Zinc supplementation inhibits complement activation in age-related macular degeneration.
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.


BACKGROUND
The Netherlands National Trial Register NTR2605.
Department of Ophthalmology, Radboud university medical center, Nijmegen, the Netherlands.
Dzenita
D
Smailhodzic
Department of Ophthalmology, Radboud university medical center, Nijmegen, the Netherlands.
Freekje
F
van Asten
Section of Medical Protein Chemistry, Department of Laboratory Medicine Malmo, Lund University, Malmo, Sweden.
Anna M
AM
Blom
Section of Medical Protein Chemistry, Department of Laboratory Medicine Malmo, Lund University, Malmo, Sweden.
Frida C
FC
Mohlin
Department of Ophthalmology, Radboud university medical center, Nijmegen, the Netherlands; Department of Human Genetics, Radboud university medical center, Nijmegen, the Netherlands.
Anneke I
AI
den Hollander
Department of Ophthalmology, Radboud university medical center, Nijmegen, the Netherlands.
Johannes P H
JP
van de Ven
Department of Ophthalmology, Radboud university medical center, Nijmegen, the Netherlands.
Ramon A C
RA
van Huet
Department for Health Evidence, Radboud university medical center, Nijmegen, the Netherlands.
Joannes M M
JM
Groenewoud
University Eye Clinic Maastricht, Maastricht, the Netherlands.
Yuan
Y
Tian
University Eye Clinic Maastricht, Maastricht, the Netherlands.
Tos T J M
TT
Berendschot
Department of Ophthalmology, Radboud university medical center, Nijmegen, the Netherlands.
Yara T E
YT
Lechanteur
Department of Ophthalmology, University of Cologne, Cologne, Germany.
Sascha
S
Fauser
Innomedics, Düsseldorf, Germany.
Chris
C
de Bruijn
Department of Nephrology, Leiden University Medical Center, Leiden, the Netherlands.
Mohamed R
MR
Daha
Department for Health Evidence, Radboud university medical center, Nijmegen, the Netherlands.
Gert Jan
GJ
van der Wilt
Department of Ophthalmology, Radboud university medical center, Nijmegen, the Netherlands.
Carel B
CB
Hoyng
Department of Ophthalmology, Radboud university medical center, Nijmegen, the Netherlands.
B Jeroen
BJ
Klevering
D000368:Aged; D000369:Aged, 80 and over; D002478:Cells, Cultured; D003167:Complement Activation / Q000187:drug effects*; D003176:Complement C3 / Q000276:immunology / Q000378:metabolism*; D015933:Complement C3d / Q000276:immunology / Q000378:metabolism*; D015936:Complement C5a / Q000276:immunology / Q000378:metabolism; D011415:Complement Factor B / Q000276:immunology / Q000378:metabolism; D017242:Complement Factor H / Q000276:immunology / Q000378:metabolism; D019327:Copper Sulfate / Q000008:administration & dosage; D019587:Dietary Supplements; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D005260:Female; D015870:Gene Expression; D006801:Humans; D008268:Macular Degeneration / Q000097:blood / Q000178:diet therapy* / Q000276:immunology / Q000473:pathology; D008297:Male; D009154:Mutation; D011506:Proteins / Q000235:genetics / Q000276:immunology; D012160:Retina / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D055213:Retinal Pigment Epithelium / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D019287:Zinc Sulfate / Q000008:administration & dosage*
C514392:ARMS2 protein, human; D003176:Complement C3; D011506:Proteins; D019287:Zinc Sulfate; D015933:Complement C3d; D015936:Complement C5a; D017242:Complement Factor H; D011415:Complement Factor B; D019327:Copper Sulfate