Genes May Shape Supplements' Effect on Macular Degeneration

Laird Harrison

August 10, 2016

SAN FRANCISCO — A person's genotypes may influence whether or not nutritional supplements help or hinder the progress of age-related macular degeneration, according to the results of two new studies.

The studies lend support to the controversial proposal that clinicians should administer genetic tests to see who could benefit — or potentially be harmed — by the nutritional supplement formula devised for the Age-Related Eye Disease Study (AREDS).

"Why would you tell people to take a nutritional supplement for decades at their own cost when it does them no benefit at all?" Carl Awh, MD, from Tennessee Retina in Nashville, said to Medscape Medical News.

Dr Awh presented one of the studies here at the American Society of Retina Specialists (ASRS) 2016 Annual Meeting.

For both studies, researchers reanalyzed data from the AREDS trial, which was funded by the National Eye Institute.

The initial trial showed that nutritional supplements slowed disease progression in patients with moderate age-related macular degeneration.

However, in subsequent analyses of the data, Dr Awh and colleagues found that how patients responded to the supplement depended on their complement factor H (CFH) and age-related maculopathy susceptibility 2 (ARMS2) risk alleles, with some patients' condition worsening.

In the new study Dr Awh presented at the ASRS, the researchers looked at 554 patients from the original AREDS trial who had no macular degeneration. These patients took antioxidants in the original AREDS formulation without zinc.

This time Dr Awh and his colleagues did not distinguish between CFH and ARMS2 but simply counted the total risk alleles. They found that patients were more likely to progress to intermediate macular degeneration in 7.5 years if they had fewer risk alleles.

Table 1. Risk for Macular Degeneration Based on Number of Alleles

Number of Alleles Hazard Ratio Antioxidant Treatment vs Placebo P Value
0 3.98 0.005
1 2.54 0.01
2 0.67 0.15
3 or 4 0.27 0.008


"The treatment implications are that individuals without macular degeneration and high genetic risk may benefit from the antioxidant formulation," said Dr Awh.

Often the children of people with macular degeneration ask if they can do anything to avoid getting the disease. They might be good candidates for a genetic test, he added.

In an independent study, Johanna Seddon, MD, from Tufts Medical Center in Boston, Massachusetts, and colleagues conducted a similar analysis of the AREDS data. They divided patients according to different groupings of CFH and ARMS2 risk alleles.

Table 2. Number of CFH and ARMS2 Alleles

0 0
0 1 - 2
0-2 0
1 - 2 1 - 2


The analysis included only patients in intermediate stages of macular degeneration, the population for which the original AREDS trials found a benefit.

Patients with no risk alleles, only ARMS2, or one or two of both kinds of risk alleles were less likely to experience disease progression if they took the supplements than if they took the placebo, but the results were only statistically significant for the group with no CFH risk alleles and 1 to 2 ARMS2 risk alleles (P = .03).

The researchers found that patients in the only-CFH group were 1.23 times more likely to experience progression, but this result was not statistically significant (P = .33).

The study was published in the British Journal of Ophthalmology.

I know from previous experience I can't trust their statisticians to do the right thing. Dr Emily Chew

However, Emily Chew, MD, principal investigator of both AREDS trials, remains skeptical of the merits of genetic testing. She and her colleagues tried to replicate Dr Awh's original results, without success.

"We did our analysis exactly the same way, but we had a larger number of patients, and we did not find the same results he did," she told Medscape Medical News.

She also questions whether the statistics in the new study are valid. In their previous work, Dr Awh and his colleagues chose genetic groupings most likely to show a correlation between taking supplements and genetic risks, creating biased results, she said.

"I know from previous experience I can't trust their statisticians to do the right thing," she added.

And Dr Chew doesn't think a genetic test would provide any benefit, because an eye examination can already tell who is most at risk.

"You see the drusen," she explained. "These are the risk factors for progression. If your parents have macular degeneration, or you smoke or don't eat well, have the eye test. No point taking a genetic test."

The American Academy of Ophthalmology has so far taken a conservative approach, stating in a 2015 guideline that randomized controlled trials were needed to settle the question. In the meantime, they say, "the routine use of genetic testing is not supported by the existing literature and is not recommended at this time."

The ASRS plans to release its own position paper this fall, according to President Elect Mark Humayun, MD, PhD.

Dr Awh holds shares in ArcticDX, which makes genetic tests. Dr Chew has disclosed that the National Eye Institute receives royalties for the sale of supplements on the basis of sales of the AREDS formula. Although Dr Chew does not personally have a financial interest, her supervisor, Frederick Ferris III, MD, chairman of the AREDS study, receives royalties on the formula. Dr Seddon has received a research grant from Novartis.

American Society of Retina Specialists (ASRS) 2016 Annual Meeting. Presented August 10, 2016.


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