AMD Genetic Findings May Guide Nutritional Therapy

Damian McNamara

September 03, 2013

Genotype-directed therapy could come to the aid of patients with age-related macular degeneration and usher in an era of targeted nutritional intervention, according to a study reported August 20 in Ophthalmology.

Reanalyzing data from a randomized controlled trial, researchers identified genetic polymorphisms that predict which patients with moderate-to-severe age-related macular degeneration (AMD) are most likely to respond to antioxidant or zinc supplementation.

"Our conclusion that genetic testing can be used to identify the optimal nutritional supplement for patients with moderate AMD is based upon a large subset from the study that has guided the nutritional treatment of AMD for over a decade," lead study author Carl Awh, MD, a private practice ophthalmologist at Tennessee Retina in Nashville, told Medscape Medical News.

Of the 2258 participants in the Age-Related Eye Disease Study (AREDS) with category 3 disease in at least one eye (Arch Ophthalmol. 2001;119:1417-1413), Dr. Awh and his colleagues assessed a subset of 995 patients for whom DNA was available.

Their pharmacogenetics analysis focused on 2 known risk alleles: complement factor H (CFH) and age-related maculopathy sensitivity 2 (ARMS2), noting the number of alleles each participant carried (0, 1, or 2).

As anticipated, progression among participants who received placebo correlated with CFH and ARMS2 risk alleles, according to forward stepwise Cox regression analysis (P = 2.29E-4 and P = 2.30E-2, respectively).

n the antioxidant-only group, 1 ARMS2 risk allele was associated with a 2.58-fold increased for progression of AMD, compared with 0 risk alleles (P = 5.75E-5), whereas 2 alleles were associated with a 3.96-fold increased risk (P = 2.22E-6).

Among those treated with zinc alone, 1 CFH risk allele was associated with a 2.18-fold increased risk for AMD progression (P = 4.16 E-2) and 2 alleles were associated with a 4.46-fold increased risk, compared with 0 alleles (P = 7.52E-05).

Moreover, the researchers found that individuals homozygous for either risk allele had approximately a 1.8-fold increased risk when taking the combination of zinc and antioxidants (ARMS2: relative risk, 1.89; P = 8.54E-04; CFH: relative risk, 1.83; P = 1.03E-02) compared with those who had no risk alleles.

"Consistent with the deleterious interactions of CFH and ARMS2 risk alleles with zinc and antioxidant treatment, respectively, individuals with 2 copies of each risk allele fared comparatively poorly and derived minimal benefit from any therapy," the authors write.

The authors note, however, that these are relative risks and do not suggest that individuals are being harmed by supplements. Rather, some individuals may just benefit more than others. "We emphasize that the AREDS was the basis of a treatment that has been beneficial for countless individuals with AMD. Our study allows us to identify subgroups of patients who benefit from AREDS supplements, but who would benefit even more with an alternative treatment," said Dr. Awh.

The authors point out subgroups of patients who would derive the greatest benefit from various 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."

In an interview with Medscape Medical News, Dr. Awh emphasized the applicability of the data. "Given the high quality of AREDS data and the compelling results of our statistical analysis, we think our findings are immediately applicable to clinical practice."

When asked by Medscape Medical News to comment, Leo A. Kim, MD, PhD, a retina surgeon and researcher at Massachusetts Eye and Ear Infirmary in Boston, said the study findings are "really very interesting and definitely very relevant for treatment of age-related macular degeneration. This is one of the first examples where you have … genetic findings actually guiding treatment."

Using the findings to enhance benefit and avoid potential harm from therapy is a great example of personalized medicine, Dr. Kim said. "This will definitely affect how I treat my patients. It's going to make a difference for the outcomes of patients with advanced age-related macular degeneration." However, he cautioned that the results are based only on associations between genetic polymorphisms and AMD progression.

Michael L. Klein, MD, professor of ophthalmology at Oregon Health & Science University in Portland, was a bit more tempered in his response to the data. "This study's methodology and interpretation warrant careful attention and analysis by independent statisticians and geneticists," Dr. Klein told Medscape Medical News.

"The results have just been released and there hasn't yet been time for this to occur," he continued. "At present, I would not recommend adopting these unconfirmed recommendations, which call for additional testing and changes in accepted management of a large proportion of individuals with age-related macular degeneration." 

Dr. Awh acknowledged that the field might need more data before his team's new findings are widely accepted. "We understand that the opinions of experts in the field are important to the widespread adoption of our recommendations and we await comments upon our findings."

However, Dr. Awh himself appears to have no reservations. The company that funded the study, and for which Dr. Awh consults and owns equity in, is already marketing a genetic test based on these results, he told Medscape Medical News.

Maximizing Benefit With Genetics

The researchers also calculated the maximal overall benefit to AREDS study participants had they initially been assigned to receive genotype-directed nutritional therapy. Taking the distribution of genetic risk alleles and treatment outcomes into account, they write: "We estimate that genotype-directed therapy of the study population would have more than doubled the reduction in AMD progression rate compared with treatment with the AREDS formulation."

At baseline in the AREDS study, participants were randomly assigned to placebo or dietary supplementation with antioxidants (β-carotene, 15 mg; vitamin C, 500 mg; and vitamin E, 400 IU), zinc (80 mg as zinc oxide and copper 2 mg), and antioxidants and zinc combined.

Generalizability of the current study's results beyond a white population is a potential limitation of the study. "Because the genetics of AMD have been studied most thoroughly in white persons, patients of other racial backgrounds were eliminated from our study," the authors write.

Further refinement may be forthcoming. Genetic analysis of AREDS2 data may reveal additional relationships between genetic risk markers, zinc dosage, and different antioxidant components, Dr. Awh said.

Dr. Awh is a consultant, member of the Scientific Advisory Board, and equity owner (patents) for Arctic Diagnostics Inc, which funded the study. Dr. Kim and Dr. Klein have disclosed no relevant financial relationships.

Ophthalmology. Published online August 20, 2013. Abstract


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