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    Genotype-directed therapy may help patients with moderate AMD

    Patients respond differently to nutritional supplement, based on measurable genetic risk markers

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    Genotyping reveals that certain patients with moderate age-related macular degeneration may benefit more from the AREDS formulation than others.  

     

    Nashville, TN—Genotype-directed nutritional therapy may benefit patients with moderate age-related macular degeneration (AMD), said Carl C. Awh, MD, of Tennessee Retina PC, Nashville.

    Dr. Awh presented his research, conducted along with Brent Zanke, MD, PhD, of Arctic DX in Toronto. The research presented built on a genetic analysis led by Dr. Awh and published last year, which found that patients with moderate AMD could benefit from pharmacogenomic selection of nutritional supplements.1

    That research used all DNA available from participants in the Age Related Eye Disease Study (AREDS)—989 white patients—who had moderate AMD in one or both eyes. Researchers measured major AMD genetic risk markers and evaluated their effect on assigned treatment category, determined by rate of progression to advanced AMD over 10 years. They focused on the two major genes that are associated with AMD risk, complement factor H (CFH) and Age-related Maculopathy Susceptibility 2 (ARMS2), Dr. Awh said.

    “Patients with no CFH [complement factor H] risk alleles and with one or two ARMS2 risk alleles derived maximum benefit from zinc-only supplementation,” the researchers wrote in their previously published study. “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 findings were based on statistical modeling of the 989 patients. Dr. Awh presented an analysis based on the actual outcomes of the same 989 patients, divided into four distinct genotype groups, as followed in AREDS.

    Researchers placed patients in one of four genotype groups:

    1. CFH risk but no ARMS2 risk.
    2. ARMS2 risk but no CFH risk.
    3. Both CFH and ARMS2 risk.
    4. Those with neither CFH nor ARMS2 risk.

    They defined AMD progression as the development of advanced AMD in one eye during the course of the study.

    Response to components

    Like the previous study, the research presented at ARVO found that genetic risk can predict a different response to components of the AREDS formulation, Dr. Awh said.

    “Even though the overall average patient with moderate AMD did well, by looking at outcomes based on genetic risk, we find that this average benefit is driven by some who do tremendously well with AREDS formulation combined with the outcomes of smaller groups of patients who do not benefit, and some who we think fared worse by taking the AREDS formulation, due to an adverse response to high-dose zinc,” Dr. Awh said. “That resulted in a worst outcome than taking placebo.”

    Still, the AREDS formula is the appropriate choice for patients with moderate AMD in the absence of genetic information—which was the case when the AREDS formula was first introduced, Dr. Awh said.

    Although AMD progression decreased overall in those who had received the AREDS formula, patients with CFH risk (n = 352) had increased AMD progression with zinc-only treatment. Those randomized to treatment with antioxidants alone had decreased AMD progression, and the AREDS formula itself was not shown to alter AMD progression to a significant degree.

    Patients with only the ARMS2 risk (n = 62) trended toward a decreased progression if they received only zinc, but they had no demonstrated change in progression with either antioxidant-containing formulation.

    There was reduced AMD progression in patients with both CFH and ARMS2 risk (n = 516) treated with antioxidants or the AREDS formulation.

    The researchers observed no difference in progression with any treatment in patients without the CFH or ARMS2 risk (n = 58).

    “Now that we can look at their genetics, we can see if you start to give each subgroup what’s best for them, the overall benefit to the population is much greater. We believe with genotype-directed therapy, we can have a substantial decrease in the number of patients with advanced AMD. This can have a huge public health impact,” he said.

    Looking forward

    Although the research is retrospective, Dr. Awh noted that it is still based upon high-quality data collected by the original AREDS investigators. He also said that the results show highly significant differences based on measureable genetic risk.

    Future studies that can further validate and replicate these results would be valuable, Dr. Awh said, but there is still a take-away message from the research.

    “We think the numbers are large enough and compelling enough that it’s reasonable to consider making some changes in how we treat patients with moderate AMD with nutritional supplements,” he said.

    The results that show patients with high CFH risk and no ARMS2 risk seem to have done worse with zinc also makes sense biologically, he said.

    Study co-author Brent Zanke, MD, PhD, works with ArcticDX, a Toronto-based company that offers a prognostic test for AMD progression risk based upon the clinical stage of AMD together with non-genetic and genetic risk factors. The genetic risk markers can also be used to determine genotype-directed nutritional therapy.

     


    Reference

    1. Awh CC, Lane AM, Hawken S, Zanke B, Kim IK. CFH and ARMS2 genetic polymorphisms predict response to antioxidants and zinc in patients with age-related macular degeneration. Ophthalmology. 2013;120:2317-2323.

     

    Carl C. Awh, MD

    E: carlawh@gmail.com

    This article is adapted from Dr. Awh’s presentation at the 2014 meeting of the Association for Research in Vision and Ophthalmology. Dr. Awh is a consultant for Arctic DX.

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