Age-related macular degeneration (AMD) is a complex, multifactorial disease impacted largely by age, smoking, diet, and genetics. AMD is the leading cause of blindness in people over 65 years old in the US, and mainly affects Caucasians. The disease can cause progressive loss of central vision and comes in dry or wet forms.
Wet AMD vs. dry AMD
Wet AMD, categorized as advanced disease, specifically features abnormal blood vessel growth, called neovascularization, which causes bleeding and/or fluid in the macula, resulting in vision loss. Wet or neovascular AMD, although aggressive and vision-threatening, can be treated successfully with serial eye injections to inhibit the blood vessel growth and improve vision.
Dry AMD features a retinal waste deposit called drusen and is categorized as early, intermediate (See Figure 1A, below), or advanced disease, which exhibits diffuse retinal loss known as geographic atrophy (See Figure 1B). Dry AMD, however, has few treatment options and can be just as visually devastating in the advanced stage.
Figures 1A and 1B: Fundus photo of intermediate dry AMD with large drusen (arrow) and fundus photo of advanced dry AMD with a large area of geographic atrophy (arrow) involving the macula, respectively.
Figures 1A and 1B: Courtesy of Kevin Cornwell, OD.
The Age-Related Eye Disease Study (AREDS)
In 2001, with the goal of decreasing the risk of dry AMD progressing to wet AMD, the National Institutes of Health (NIH) published the seminal Age-Related Eye Disease Study (AREDS), which showed that taking high doses of vitamin E, C, zinc, and anti-oxidants versus placebo lowered the risk of progression of dry intermediate level AMD to wet AMD by 25% over 5 years.1
This data armed eye doctors with the first treatment for dry AMD that could potentially modify the course of their disease—so-called AREDS supplements. Since that time, the updated over-the-counter “AREDS2” supplement formula has been universally recommended to patients with intermediate dry AMD.
However, the potential problem with following this universal protocol is that studies show that there are interactions between the genetic makeup of an individual and the treatment effect of these supplements, and for some, this can potentially worsen their disease.2
The importance of genetic testing for AMD patients
Many studies have shown that the genes complement factor H (CFH) and age-related maculopathy susceptibility 2 (ARMS2) impact a person’s susceptibility to AMD. CFH and ARMS2 genes impact inflammation and oxidative stress, which are known factors in the progression of AMD.
Certain versions of these genes, called risk alleles, are associated with a higher risk of developing AMD. An individual can be genotyped to determine their genetic risk, which may reveal either high, low, or no increased genetic risk for AMD-related genes.2-4
Importantly, studies have shown that an individual’s CFH and ARMS2 alleles significantly impact their response to standard AREDS2 supplements. Depending on an individual’s risk alleles, the AREDS2 supplements may be protective as intended, associated with a significant prophylactic effect, or could actually worsen AMD.2,5,6
In a carefully designed study, Vavvas et al. confirmed that subjects respond in opposite ways to AREDS supplements depending on their CFH and ARMS2 genetic risk alleles. As seen in the chart below, in those with high-risk CFH alleles and no ARMS2 risk alleles, the AREDS supplements increased the rate of conversion to wet AMD compared to a placebo.
However, for individuals with no or low CFH risk alleles but high-risk ARMS2 alleles, the AREDS supplements did slow progression to wet AMD versus placebo, as intended.
Figure 2: Chart A illustrates how AREDS supplements increased the risk of progression to wet AMD compared to placebo for subjects with high-risk CFH alleles and no ARMS2 risk alleles (hazard ratio of 2.9). Chart B illustrates how AREDS decreases the risk of progression to wet AMD compared to placebo for subjects with no or low CFH risk alleles and high-risk ARMS2 alleles (hazard ratio of 0.5).2
Figure 2: Adapted from Vavvas et al. with permission.
What causes this difference in treatment response to AREDS2?
Zinc, an element found in very high doses in the AREDS2 formula, plays a role in the inactivation of complement cascade proteins, but its interaction with complement proteins is likely impacted by an individual’s genetic variants.
Studies suggest that the high dose of zinc in the standard AREDS2 formula is responsible for the differing pharmacogenetic responses to the AREDS supplement, and therefore, a patient’s genetics should be considered before recommending a certain supplement to treat their dry AMD.2,5,6
Note, the American Academy of Ophthalmology does not currently recommend genetic testing for AMD-associated risk, citing that gene-dependent therapy does not exist for AMD treatment, and therefore, the data is not yet useful.7
However, your interpretation of the current literature may lead you to pursue genetic testing for your intermediate dry AMD patients in order to ensure your supplement recommendation is helpful, not harmful, to your patient.
Protocol for AMD genetic testing
Considering the cost, twice daily burden, and potential negative impact to vision, it is imperative that the eye doctor’s recommendation only provides benefit to the patient and their disease course. Thankfully, AMD genetic testing is readily available to easily determine the best care plan for your patient.
For my patients with intermediate AMD, before suggesting they begin AREDS2 supplements, I educate them that there is genetic testing available to determine which specific supplement is best and safe for them. Once a patient understands that studies show there could be a harmful, not beneficial, effect of AREDS2 depending on their genetic makeup, they are very motivated to participate in the testing.
The ideal candidate has newly diagnosed intermediate AMD and therefore qualifies to begin AREDS2 supplements. Note that the test is only appropriate for Caucasian patients since the AREDS studies were conducted on this population.
Commercially available genetic testing to identify a patient’s AMD-associated risk alleles is available through a handful of clinical laboratories and include:
- Macula Risk from ArcticDx
- RetnaGene AMD from Sequenom (offered by Nicox)
- Mutation testing from ARUP Laboratories
A closer look at Macula Risk testing
Currently, the only test that assesses potential interactions of genetics with zinc is Macula Risk, which uses age, body mass index, smoking status, education, and 14 AMD-associated risk alleles, including CFH and ARMS2, to generate a pharmacogenetic-based supplement recommendation and a personalized visual prognosis report.
Using the results from Macula Risk, clinicians can make a personalized supplement recommendation to each AMD patient, either supporting the standard AREDS2 formula or a zinc-free AREDS2 formula. The report includes a 2-, 5-, and 10-year risk of progressing to advanced AMD from the time the testing is completed, helping to inform the patient on the visual prognosis of their disease. This invaluable information is gained from a simple buccal sample or cheek swab taken in-office.
At this time, Macula Risk testing is not covered by insurance and therefore does have out-of-pocket costs to the patient. Our office uses a modest markup from the clinical laboratory cost of $155 per test. The sample is mailed to the laboratory for genotyping and the results are available within 4 weeks.
At our practice, we schedule the patient for a medical follow-up visit to review their results and discuss their personalized supplement recommendation 6 weeks from the initial visit. During this follow-up visit, we are prepared to review their report and educate the patient on resources where they can purchase modified zinc-free AREDS2 supplements, if indicated.
Patient education on genetic risk
Reviewing the Macula Risk report with the patient, I first show them the 14 AMD-associated risk alleles that were analyzed and their resulting Genetic Risk Percentile compared to the normal population. This educates the patient on their genetic risk level which is, of course, not modifiable. Next, we review their 10-year Macula Risk Score for progression to advanced AMD.
This informs the patient on their personalized prognosis at 2-, 5-, and 10-years from the time of the testing. For example, a patient may have a 75% risk of progression to advanced AMD at 10 years. This can provide compelling information to motivate the patient to improve modifiable risk factors, such as smoking and diet.
Finally, using the resulting personalized pharmacogenetic supplement recommendation based on CFH and ARMS2 genotyping, you can confidently educate your patient on how to best reduce their risk of progressing to wet AMD, either by starting the standard AREDS2 formula or a zinc-free AREDS2 formula.
Conclusions
Although this area of research is still under investigation, there is a clear role for investigating AMD-associated risk alleles before recommending an AREDS2 supplement to your patients. Studies have shown that depending on a patient’s genotype, their response to AREDS2 supplements can be beneficial or harmful—actually increasing their risk of progression to advanced disease.2,5,6
AMD genetic testing identifies patients who should avoid the high doses of zinc in the standard AREDS2 formula and allows you to guide them to alternative supplements to best protect their vision.
For patients with intermediate AMD, genetic testing should be used to provide them with a safe supplement recommendation that will decrease their risk of progression to advanced AMD, as intended.
