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Researcher says genetic testing will soon lead to personalized medicine for AMD
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More than 20 genetic variants that influence the risk of age-related macular degeneration have been identified, which, when combined with environmental considerations, will allow for personalized medicine, according to Johanna M. Seddon, MD, ScM.
Seddon, a professor of ophthalmology at Tufts University School of Medicine and founding director of the Ophthalmic Epidemiology and Genetics Service at New England Eye Center, spoke at the Ocular Nutrition Society meeting in March, held in conjunction with Vision Expo East.
“The function of the common variants, to date, is poorly understood, but the rare variants can have much larger biologic effects, confer large disease risk, have clear functional significance and can reveal disease mechanisms,” Seddon said in her presentation.
Johanna M.
Seddon
For example, patients with the rare complement factor H (CFH) have a high risk of developing AMD, she said.
“It causes early onset of disease and a more severe disease phenotype … through amplification of the alternative complement pathways,” Seddon said.
“We have also found rare variants in the genes CFI, C3 and C9 that are associated with a high risk of advanced macular degeneration,” she added.
Genes are important, and a patient’s environment can also modify genetic susceptibility, Seddon said. A favorable genotype in combination with a favorable diet, for example, results in lower risk.
Calculating AMD risk
In a 2009 study published in Investigational Ophthalmology & Visual Science, Seddon and colleagues evaluated the roles of genetics, demographics and environmental factors on AMD.
“These analyses and results indicate the potential for individual prediction of risk for AMD,” the researchers reported.
Several of Seddon’s studies suggested using a point system in calculating a patient’s risk, considering smoking status, body mass index, antioxidant and zinc status, and the various genetic variants. High-risk individuals could be examined more frequently, Seddon and colleagues said, educated about modifiable risk factors and urged to improve their diet and take antioxidant-mineral supplements.
Seddon also noted in her presentation that C-reactive proteins (CRP) and genes are independently associated with risk for AMD.
“The presence of both higher CRP and risk variants for CFH and ARMS2 confer the highest risk,” she said.
Possible association between genes, supplements
“A possible treatment interaction between CFHY402H genotype and the AREDS supplement has also been found,” Seddon said. “We found in 2007 that the response to the AREDS supplement may be related to the CFH genotype; the low-risk genotype had greater reduction in risk. And it may be related to zinc components.”
Seddon addressed more recent reports that have focused on associations between these high-risk genes and nutrition.
“Awh found that if you had no risk alleles for CFH and one or two ARMS2 risk alleles, zinc only was better in terms of progression; if you didn’t have any of the ARMS2 risk alleles and one or two CFH risk alleles, antioxidants only were better, and zinc appeared to increase progression,” she said in her presentation.
In a study published in Ophthalmology in 2013, Carl C. Awh, MD, and colleagues investigated whether the type of nutritional supplement in conjunction with genetics had an impact on the progression from moderate to advanced AMD.
The study, categorized as a genetic analysis of a randomized, prospective clinical trial, included 989 white participants who were enrolled in the Age-Related Eye Disease Study. The participants all had AREDS category 3 AMD in one eye and AREDS categories 1 through 4 AMD in their other eye. Participants were randomized to one of four treatment arms: placebo, antioxidants, zinc or antioxidants plus zinc.
“Individuals with moderate AMD could benefit from pharmacogenomic selection of nutritional supplements,” the researchers wrote in their conclusion. “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.
“Based on the distribution of genetic risk alleles and the observed outcomes for the different treatments, the average 10-year progression rate for this patient population if all were treated with placebo, AREDS formulation or genotype-directed therapy would have been 47.0%, 40.5%, and 31.7%, respectively,” they continued. “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.”
Differing opinions
Seddon said in her presentation that Emily Y. Chew, MD, PhD, deputy director of the Division of Epidemiology and Clinical Applications and the deputy clinical director at the National Eye Institute, discussed the counterpoint.
“She and our group suggested that simultaneous testing of all four treatment groups would be necessary,” Seddon said. “The number of the individuals in the subgroups in the Awh study was small, and the differences were not significant.
“There’s still some difference of opinion of this interpretation of that data,” Seddon added.
Chew shared her view in a perspective written for the Jan. 25, 2014, issue of Ocular Surgery News, Primary Care Optometry News’ sister publication.
“AREDS required thousands of participants to demonstrate that the combination of antioxidant vitamins and zinc is beneficial, and neither vitamins nor zinc by itself was superior,” she said. “This combination remains the treatment of choice.
“Such hypotheses-generating data from this report are considered to be observational or retrospective and cannot be translated into treatment recommendations,” Chew continued. “These are subgroup analyses with insufficient power to achieve both statistical and clinical significance. Further validations of the statistical methodology used and the genetic markers considered in this study are needed. The American Academy of Ophthalmology Task Force recommends confining genetic testing for AMD to research studies. The clinical use of pharmacogenetic information must be based upon strong evidence. In the case of genetic testing determining supplements for patients with AMD, the evidence falls far short of this goal.”
Emily Y. Chew,
In a response to a letter to the editor of Ophthalmology from Stephen Schwartz, MD, Awh and colleagues addressed some of Chew’s concerns online in May.
“Dr. Schwartz observes that a retrospective analysis is not the same as a prospective clinical trial,” they wrote. “Despite this obvious difference, the U.S. Food and Drug Administration has used retrospective genetic subset analyses of a drug registration trial as reason to revise therapeutic label indications for anti-endothelial growth factor receptor therapy in colorectal cancer owing to differing treatment responses. Our study uses prospectively collected AREDS data and modern analysis of genetic samples collected by AREDS investigators for the purpose of post hoc analysis.”
Awh and colleagues said their data expands on similar observations by Klein, Seddon and others.
“Given our corroborating findings and considering the potential public health benefit and cost savings associated with genotype-directed treatment, we think that appropriate (not routine) genetic testing is justified,” they said.
Chew restated her position on the subject in a presentation at the Association for Research in Vision and Ophthalmology meeting in May.
“There was no statistically significant influence of the genetic variants on response to AREDS supplements,” she said in her ARVO presentation. “The AREDS formulation was never demonstrated to be beneficial with each component alone. The combination of vitamins and zinc was best – proven in over 4,000 participants.”
In an email to PCON, a spokesperson said that Chew believes in genetic testing for disease progression risk assessment and for identifying disease mechanisms and developing treatments.
“Genetic testing remains important in research,” Chew concluded at ARVO. “Hopefully, genetic testing in the near future will help predict progression of disease and guide current and future treatments for AMD. We are not ready to change the recommendations of the American Academy of Ophthalmology Task Force on Genetic Testing: avoid genetic testing of AMD, at least for the management of AREDS supplements for now.”
At the end of her presentation, Seddon shared her opinion on the debate.
“These are all very plausible associations that require additional research and replication,” she said. “We have shown gene-nutrition interactions, and there are now additional reports of possible gene-supplement interactions and associations; they are definitely plausible. There’s not enough hard data yet to say it’s definite.
“We are in the era of personalized medicine whether we are ready or not,” she concluded. “We will be facing doing genetic testing and prediction modeling in the not-too-distant future.”