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High-Dose Zinc, Antioxidant Supplement Effect Dependent on AMD Genotype

The effectiveness of this nutritional prophylactic supplement is determined by genetic variation, making genotype group identification an important factor.

Demetrios G. Vavvas, MD, PhD

The effectiveness of the nutritional supplement AREDS (Age-Related Eye Disease Study) formulation, designed to decrease progression of age-related macular degeneration (AMD), is seemingly dictated by individual patient genotype.

Although data from the study, led by Demetrios G. Vavvas, MD, PhD, the co-director of the Ocular Regenerative Medical Institute at Harvard Medical School, suggests that the formulation is effective in preventing disease progress in patients with certain genotypes, while other patients could see an increased risk of neovascular AMD development and geographic atrophy (GA) associated with AMD as a result of supplement use.

Vavvas and colleagues stated that their study identifies a “strong interaction of genetics with the AREDS formulation” and advises that, rather than recommending the supplements to all AMD patients, that AREDS formulation use "should be based on patient-specific genotype.”

The AREDS formulation consists of 80 mg of zinc (as zinc oxide), 2 mg of copper (as cupric oxide), 500 mg of vitamin C, 400 IU of vitamin E, and 15 mg of beta-carotene. Vavvas and colleagues wrote that the formulation is typically recommended by clinicians to patients with AMD “with the assumption of homogeneously distributed benefit and risk,” but the study data suggests that that assumption is false, and that response to this prophylactic treatment varies based on genomic factors.

In the past several years, data from the AREDS study, a placebo-controlled, long-term study of nutritional therapy on AMD progression, have been used to not only evaluate “the influence of genetic risk on the response to the AREDS formulation [but also to] address the phenomenon of interaction” between individual patient genetics and the AREDS formulation's ability to slow AMD progression, according to Vavvas.

The data utilized involved AREDS population subjects (n = 802) with category 3 or 4 AMD at baseline—which Vavvas described as “the subgroup of subjects for whom the AREDS formulation was reported beneficial in the original AREDS analysis.”

The researchers linked the AREDS study data on AMD disease progression with the AREDS formulation or placebo control group to genetic data on the presence/absence/variants of compliment factor H (CFH) and age-related maculopathy susceptibility 2 (ARMS2). The study participants were then separated into 4 genotype groups (GTGs) based on the number of risk alleles at CFH and ARMS2 for each subject.

Vavvas and colleagues found that among patients in the original AREDS formulation study, those participants carrying genotypes with low risk for CFH and high risk of ARMS2—designated as GTG 3 (n = 305)—saw decreased progression risk for AMD development into neovascular AMD (hazard ratio [HR], 0.05; P = .008) or GA (HR, 0.60; P = .09) when treated with AREDS formulation versus placebo.

Conversely, subjects in GTG 2 (n = 107) who carried a high risk for CFH and low risk for ARMS2, saw an increased rate and likelihood of AMD progression and development into neovascular AMD (HR, 2.92; P = .018) and GA (HR, 1.04; P = .93) when treated with AREDS formulation versus placebo.

Subjects in GTG1, which were low risk CFH, low risk ARMS2, and GTG 4, which were high risk CFH, high risk ARMS2, exhibited variations in response to AREDS formulation treatment, but to a lesser extent than GTG2 and GTG3. For the GTG1, the neovascularization HR was 1.41 (P = .43) and the GA HR was 0.70 (P = .40), while for GTG4 the neovascularization HR was 1.03 (P = .91) and the GA HR was 0.88 (P = .74)

“A strong interaction was seen between CFH andARMS2 risk alleles and AREDS formulation treatment,” Vavvas wrote. He noted that the group's findings suggested that “the AREDS formulation modifies the risk of progression to [neovascularization] based on individual genetics.”

Since the effectiveness of this nutritional prophylactic supplement is determined by genetic variation, and since the treatment can increase risk of disease progression in certain GTGs, identifying genotype groups “may be an effective method of identifying individuals who are likely to benefit, or not, from treatment,” Vavvas concluded.

The study, "CFH and ARMS2 genetic risk determines progression to neovascular age-related macular degeneration after antioxidant and zinc supplementation" was published in Proceedings of the National Academy of Sciences of the United States of America.