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In the news: Zinc May Be Protective in AMD by Blocking Complement Activation

The Complement System and AMD

The complement system has important protective functions in both the innate and the adaptive immune systems. It helps defend against invading microorganisms and clears away cellular debris. But the complement system can also, when inappropriately activated, cause inflammation and tissue damage.

Three lines of evidence support the involvement of complement in AMD. First, it’s been found that drusen contain proteins of the alternative complement pathway (one of three pathways of complement activation). This has led to the hypothesis that drusen could be involved in local complement-mediated inflammation.

Second, there is a strong association between AMD and genetic variants in complement factor H (CFH) gene, which is a major inhibitor of the alternative complement pathway. This also suggests that complement-mediated inflammation at the level of the retina plays a pivotal role in AMD. A third line of evidence comes from studies showing that AMD patients have higher levels of complement activation products in their blood.

Exploratory Study of Zinc & Complement

The findings of the AREDS trial established the importance of zinc in AMD: zinc alone significantly slowed disease progression, and its effectiveness was amplified when combined with antioxidants. However, the mechanism by which zinc exerts its beneficial effect has not yet been identified.

To better understand zinc’s protective mechanism, researchers examined the effect of zinc on the activity of the alternative complement pathway in AMD patients. They also asked whether the response to zinc supplements correlates with the CFH and Age-Related Maculopathy Susceptibility 2 (ARMS2) genotypes. Lastly, they evaluated whether zinc directly affects complement activation in vitro.

Study Details and Results

In this open-label study (1), 72 randomly selected AMD patients in various stages of AMD received 50 mg zinc/1 mg copper daily for 3 months. Serum complement catabolism – a measure of complement activation and defined as the C3d/C3 ratio – was assessed at baseline and over the 3 month period.

Results

AMD patients with high levels of complement catabolism at baseline exhibited a steeper decline in serum complement activation (p <0.001) during the 3 months of supplementation compared to those with low baseline complement catabolism levels.

In vitro, zinc showed direct and dose-dependent inhibition of complement activation in hemolytic assays. zinc was also shown to dose-dependently inhibit the deposit of membrane attack complex (MAC) on retinal pigment epithelial cells in response to oxidative stress (with activation of the alternative complement pathway, MAC disrupts membranes and destroys cells).

Lastly, no association between the change in complement activation and CFH and ARMS2 genotypes was observed. Genotype did not have an effect on either baseline or change of complement activation levels.

Comments

Though relatively small and exploratory, this study offers one possible explanation of how zinc slows AMD progression. The results suggest that zinc benefits AMD patients with high complement activation levels, independent of genotype.

In contrast, a recent subgroup analysis using AREDS data reports that the response to zinc and antioxidants may be influenced by CFH and ARMS2 genotypes (2). The authors recommend that those with CFH genotype avoid zinc, though the methods employed in that analysis raise concerns about the validity of the findings.

A new analysis from the NEI used a different subset of AREDS participants to test the validity of the purported detrimental effect of zinc on CFH genotype. In this analysis, the combination of antioxidants and zinc was found to be beneficial and the treatment of choice for both people with CFH and ARMS2 genotypes (3).

For more information on these and related studies, go to: www.sbh.com/genetic

References

1. Smailhodzic D, et al. Zinc supplementation inhibits complement activation in age-related macular degeneration. The Netherlands National Trial Register NTR2605. PLoS ONE 9(11): e112682, 2014.
2. Awh CC, et al. Treatment response to antioxidants and zinc based on CFH and ARMS2 genetic risk allele number in the age-related eye disease study. Ophthalmol [Epub ahead of print] Sept, 2014.
3. Chew EY, et al. Report: Genetic Testing in Persons with Age-Related Macular Degeneration and the Use of the AREDS Supplements: To Test or Not to Test? JAMA Ophthalmol [Epub ahead of print] November, 2014.