Elsevier

Ophthalmology

Volume 120, Issue 11, November 2013, Pages 2317-2323
Ophthalmology

Original article
CFH and ARMS2 Genetic Polymorphisms Predict Response to Antioxidants and Zinc in Patients with Age-related Macular Degeneration

https://doi.org/10.1016/j.ophtha.2013.07.039Get rights and content

Objective

The Age-Related Eye Disease Study (AREDS) demonstrated that antioxidant and zinc supplementation decreases progression to advanced age-related macular degeneration (AMD) in patients with moderate to severe disease. We evaluated the interaction of genetics and type of nutritional supplement on progression from moderate to advanced AMD.

Design

Genetic analysis of a randomized, prospective clinical trial.

Participants

White patients with AREDS category 3 AMD in 1 eye and AREDS categories 1 through 4 AMD in the fellow eye enrolled in the AREDS with available peripheral blood-derived DNA (995).

Methods

Subjects were evaluated for known AMD genetic risk markers and treatment category. The progression rate to advanced AMD was analyzed by genotypes and AREDS treatment group using Cox regression.

Main Outcome Measures

The effect of inherited gene polymorphisms on treatment group–specific rate of progression to advanced AMD.

Results

Over an average of 10.1 years, individuals with 1 or 2 complement factor H (CFH) risk alleles derived maximum benefit from antioxidants alone. In these patients, the addition of zinc negated the benefits of antioxidants. Treatment with zinc and antioxidants was associated with a risk ratio (RR) of 1.83 with 2 CFH risk alleles (P = 1.03E-02), compared with outcomes for patients without CFH risk alleles. Patients with age-related maculopathy sensitivity 2 (ARMS2) risk alleles derived maximum benefit from zinc-containing regimens, with a deleterious response to antioxidants in the presence of ARMS2 risk alleles. Treatment with antioxidants was associated with an RR of 2.58 for those with 1 ARMS2 risk allele and 3.96 for those with 2 ARMS2 risk alleles (P = 1.04E-6), compared with patients with no ARMS2 risk alleles. Individuals homozygous for CFH and ARMS2 risk alleles derived no benefit from any category of AREDS treatment.

Conclusions

Individuals with moderate AMD could benefit from pharmacogenomic selection of nutritional supplements. In this analysis, patients with no CFH risk alleles and with 1 or 2 ARMS2 risk alleles derived maximum benefit from zinc-only supplementation. Patients with one or two CFH risk alleles and no ARMS2 risk alleles derived maximum benefit from antioxidant-only supplementation; treatment with zinc was associated with increased progression to advanced AMD. These recommendations could lead to improved outcomes through genotype-directed therapy.

Financial Disclosure(s)

Proprietary or commercial disclosure may be found after the references.

Section snippets

Methods

Study procedures of the AREDS have been reported.1 The AREDS dataset was provided by the database of genotypes and phenotypes under an investigator agreement. Patients had been characterized at AREDS enrollment, with retinal images classified by a central reading center.1

The AREDS participants varied at enrollment, ranging from those with normal eyes to those with advanced AMD. Disease was classified by the AREDS investigators based on the category of AMD in the patient's worse eye: AREDS

Patients

Of patients enrolled in the AREDS (n = 4757), white persons with AREDS category 3 disease in at least 1 eye at the time of enrollment (n = 2258) were selected for study. DNA was available from a subset of these (n = 995) from the Coriell Institute repository, collected under general research use or eye diseases only consent conditions. These samples constituted the sample set for our analysis.

To ensure that this sample set (n = 995) was representative of all white patients in AREDS with

Discussion

The AREDS demonstrated a beneficial effect of the AREDS formulation on progression to advanced AMD (adjusted odds ratio, 0.68; 99% confidence interval, 0.49–0.93).1 Although the average duration of treatment was 6.3 years, the beneficial effect of nutritional supplementation was sustained for at least a decade, suggesting value in life-long therapy.16

We present evidence, based on a large genetic dataset of patients with AREDS category 3 disease in 1 eye and AREDS category 1 through 4 disease in

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    Financial Disclosure(s): The author(s) have made the following disclosure(s):

    Carl C. Awh - Consultant, Scientific Advisory Board, Equity owner, Patents - ArcticDx

    Steven Hawken - Consultant - ArcticDx

    Brent Zanke - Employee, Equity owner, Patents - ArcticDx

    Ivana K. Kim - Consultant, Scientific Advisory Board - ArcticDx

    Supported by funding from ArcticDx, Inc., Toronto, Canada.

    View full text