by Rod Nowakowski, OD, PhD Genetic & Advanced Diagnostic Testing Disclosures 1. I have no financial or other interest in any company or product referenced in this article. 2. This is a follow-up to the case Dr. Batson presented in a previous email involving a 54-year-old woman who developed prominent macular drusen observed to increase in number and size over 1 year. (Click here to read Dr. Batson's piece.) 3. Thank you to those of you who posed questions about his case and the related genetic testing. Some are answered below and others may be addressed later. 4. This is a summary of a complex topic and is missing a lot of detail that you can find in various references. Why you should read this! "The AREDS formulation modifies the risk of progression to NV [neovascular AMD] based on individual genetics. Its use should be based on patient-specific genotype." (Click here to read more!) In other words, there is good evidence that for some people with ARMD, using the AREDS formula actually increases their risk for developing neovascular ARMD and recommending the AREDS formula may make their vision worse. That risk is based on the presence of specific risk alleles in their genetic profile. Similarly, others had a greater than expected decrease in risk. Hence the recommendation at the start of this section that "its use should be based on patient-specific genotype." You can test for that.
What are risk alleles? We have 2 copies of each gene that are not necessarily identical in structure and these are referred to as alleles. If one of those alleles are found more often than expected in persons with a certain condition (say 2%) it is referred to as a "risk allele" meaning that if you have it, your risk of having or developing that condition is higher than the risk for someone who does not have that allele. If a specific allele is invariably present in people who have a certain disorder (say 99%), we refer to it as pathogenic; i.e., disease-causing. Increasing risk is different from causing disease. The illustration below shows two hypothetical genes except for a difference in one base pair so we have two alleles that are slightly different. That difference could increase your risk for a disorder and hence be a "risk allele" or "risk variant" as opposed to being a pathogenic gene variant. The AREDS connection The AREDS studies made a blanket recommendation for the use of the AREDS formula based on clinical findings, not genetic makeup. Studies over the past several years looked at the genetic profiles of actual AREDS participants trying to ascertain if that blanket formula recommendation, and some of the components of the formula like zinc, might be helpful for some but not for all, or might even make the ARMD worse based on an individual's genetic profile for (guess what?) certain "risk alleles." Who should we test? The Macula Risk test is "...designed to aid in the selection of appropriate eye supplement formulations for a patient diagnosed with Intermediate** Dry Age-related Macular Degeneration" (http://www.macularisk.com/) but there is a little more to the story. The genetic studies leading to the recommendation for doing genetic testing for ARMD were done on DNA from actual participants in AREDS so the subsequent recommendations are applicable for equivalent people. The subjects in AREDS were 55-80 years old at the time of enrollment. Therefore, if you applied the risk-allele test results to a 40-year-old with macular drusen, that may be a logical extension, somewhat like off-label drug use, but it is not directly supported by the existing science and the patient should be informed of that fact with documentation in the chart. Notice that the case example Dr. Batson presented was age 54 which is close but outside the age range for AREDS. What are the stages of AMD? (Source: https://www.aao.org/preferred-practice-pattern/age-related-macular-degeneration-ppp-2015) Stage Definition Treatment Recommendation:
If you have heard me talk on issues in biomedical science in various CE programs you can guess where this is going. The studies and counter-studies surrounding genetic testing related to supplement use in ARMD are shrouded in controversy, conflict-of-interest issues, questionable statistics, data subset selection and more even though published in peer-reviewed journals (imagine that). Opinions by third-party insurance providers and the American Academy of Ophthalmology have also been influential. I have followed this issue carefully for several years, read the paper's pro and con, and have had an ongoing discussion with a representative of Macula Risk (re-read disclosure number one above). Based on that, I think the data supports the value of genetic testing of currently established risk alleles for patients with Intermediate ARMD as described above. Am I doing it? I'm getting ready to start using the Macula Risk test kits. I would definitely recommend genetic testing for the patient presented by Dr. Batson with the goal of recommending the most appropriate use of supplements based on the test results and the best science as I understand it today. Speaking of science, remember that you need to decide for yourself what is best for your patients based on your own evaluation of the existing data. Dr. Nowakowski will be giving a one-hour lecture on this topic at the upcoming VisionAmerica December CE.
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August 2019
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