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Study: Genetics largely determines treatment response to AREDS
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Researchers validated the existence of an interaction between genetics and response to treatment with the Age-Related Eye Disease Study formulation.
Using bootstrap validation, which the researchers said accurately identifies true determinants of clinical outcomes better than analysis of a single data set, Vavvas and colleagues concluded that the AREDS formulation modifies the risk of progression to neovascularization and that its use should be based on patient-specific genotype.
A total of 802 subjects were included from the Age-Related Eye Disease Study with category 3 or 4 age-related macular degeneration at baseline who had been treated with placebo or the AREDS formulation. Subjects were evaluated for differences in the risk of progression to neovascular AMD as a function of complement factor H (CFH) and age-related maculopathy susceptibility 2 (ARMS2) genotype groups.
The AREDS investigation randomized subjects to receive placebo, zinc (80 mg daily), antioxidants (-carotene, 15 mg; vitamin C, 500 mg; and vitamin E, 400 IU), or both zinc plus antioxidants.
A strong interaction was seen between CFH and ARMS2 risk alleles and AREDS formulation treatment with neovascular AMD as a progression end point, researchers wrote.
No significant interaction was observed between AREDS formulation treatment and CFH or ARMS2 risk alleles on progression to central geography atrophy (GA).
In subjects with high CFH risk alleles and without ARMS2 risk alleles, a significant increase in the rate of progression to neovascular AMD was observed among those treated with the AREDS formulation compared to placebo. For those with low CFH and high ARMS2, a marked decrease in the rate of progression to neovascular AMD was observed among those treated with the AREDS formulation.
Researchers “confirm that the effectiveness of AREDS formulation treatment is dependent upon CFH and ARMS2 genetic risk status.”
Additionally, one genotype group (GTG2) is likely harmed by treatment with AREDS2 formulation, while GTG3 substantially benefits, they concluded. – by Abigail Sutton
Disclosure: Vavvas reports no relevant financial disclosures. Please see the full study for all remaining authors’ financial disclosures.
Perspective
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Jerome Sherman, OD, FAAO
Perhaps the most hotly contested and clinically important controversy in eye care over the past several years has centered on the role of genetics to determine which nutraceutical should be prescribed for which patients with intermediate AMD. The prestigious National Eye Institute contends that all patients with intermediate AMD, regardless of their genetics, should take the AREDS2 formulation, which contains 80 mg of zinc in addition to select vitamins and copper. The often-quoted result of AREDS is that the risk of progression can be reduced by about 25% with the recommended nutraceutical combination regardless of the patients’ genetic profile.
This has been challenged, primarily by Carl Awh, et al, in several publications dating back to 2013. This group obtained genetic profiles of patients in the original AREDS database and discovered that patients with two high-risk CFH alleles and no high-risk ARMS2 alleles have an increased rate of progression if taking the AREDS formulation when compared to those taking a placebo.
The present study by Vavvas and colleagues revisited this controversy by using a novel, rigorous and very powerful statistical tool termed “bootstrapping” on a group of subjects never tested before. An analysis of this study (just published in one of the most respected scientific journals worldwide) and others concludes that, based upon their specific genetic profile, the AREDS formula may reduce an individual’s risk of progression to choroidal neovascularization by as much as 85%, but also increases the risk to nearly 300% in those with the genetic profile previously identified by Awh and colleagues. (Interestingly, there is no identified link between nutraceuticals and genetics in geographic atrophy.)
The bottom line question is: “Will the AREDS formulation help or harm your patient with intermediate AMD?” The answer is in their genetics, a test that is readily available to all clinicians.
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