Genetic Testing For Retinal Disease: Part 1

Five tests are currently available to identify patient risk for AMD.

Genetic Testing For Retinal Disease:


Five tests are currently available to help identify patient risk for AMD.

DAVID NELSON, O.D., M.B.A., Madison, Wise.

JEROME SHERMAN, O.D., F.A.A.O., New York, N.Y.

Because determining patient risk for developing retinal diseases aids us in our patient management decisions, the more concrete the risk data, the better. Thanks to genetic tests for retinal diseases, such information is available.

Here, in part one of this two part series, we discuss age-related macular degeneration (AMD) and the currently available genetic tests for this condition.

AMD: A review

AMD is comprised of two forms: non-exudative, or “dry,” and exudative, or “wet.” Dry AMD is made up of three stages: early AMD, intermediate AMD and advanced dry AMD.1

During the early stage, tiny drusen accumulate in and around the macula. Also, related pigment mottling is seen in the retinal pigment epithelium.1 Research shows that the macular layers, which contain the eye-protecting macula pigments lutein, zeaxanthin and mesozeaxanthin, lose pigment, causing one’s Macula Pigment Op-Optical Density (MPOD) to decrease.2

During the dry AMD intermediate stage, several medium-sized drusen or one or more large drusen are present. Although some intermediate dry AMD patients may not yet report symptoms, others will present with complaints of a blurred spot in their central vision.1 This may result from the macula’s layers allowing greater transmission of blue light, which, in turn, increasingly exposes the photoreceptor cells to harmful wavelengths of light. This light then produces metabolic by-products. Many of these patients often need more light to participate in daily activities.

In the condition’s advanced stage, large drusen are present, and the retinal pigment epithelium breaks down. This can result in geographic atrophy.1

We have found that many patients mistake “dry” AMD symptoms as simply a need for a change in their spectacle or contact lens prescription. Therefore, by the time many of these patients present for a comprehensive eye exam, they may have already converted from “dry” to “wet” AMD. This is the development of blood vessels under and around the macula due to choroidal neovascularization. Once this process begins, the new blood vessels often grow at about 20u a day or 600u in a month. All new vessels are fragile and bleed easily. In addition to bleeding, clear fluid and hard exudates often result. If this occurs under the fovea, vision can be lost very rapidly.

Without treatment, such as with intravitreal anti-vascular endothelial growth factor (VEGF) injections, the end result of “wet” AMD is often a fibroglial macula scar, or so-called disciform macula degeneration, which results in irreversible central vision loss and a dense central scotoma.

The delay in treatment of the first eye is the reason functional vision loss typically occurs more than half the time, whereas, the second eye’s vision remains nearly 92% of the time.3 (See Figure 1, page 31.) In now knowing that the patient is at high risk of conversion to “wet” AMD in the fellow eye, the eye-care practitioner provides more in-depth and frequent care, thereby increasing the likelihood of catching the choroidal neovascular net (CNV) early. Providing more comprehensive care for the second eye is the likely reason for the difference in outcomes.

AMD and genetics

Patients who have a single relative who has AMD are twice as likely to develop the disease, and those who have two or more relatives who have AMD are almost four times as likely to develop AMD.4 This risk is greater if the patient’s affected family members received the AMD diagnosis prior to age 65.

Genetic variations that regulate AMD risk have been identified. Thus far, variations in the ARMS2, complement factor B (CFB)/complement component 2 (C2), complement component 3 (C3) and the complement factor H (CFH) genes have been implicated as risk factors.5-9 Further, certain polymorphisms in the complement factor I (CFI), cholesteryl ester transfer protein (CETP), hepatic lipase (LIPC) and TIMP3 genes are also associated with AMD risk.10

Currently, five AMD genetic tests are available:

ARUP Laboratories ( This test identifies the following mutations: A69S (c.205G>T) in the ARMS2 gene (also called LOC387715) (age-related maculopathy susceptibility 2) and Y402H (c.1277T>C) in the CFH gene, encoding CFH. These mutations are associated with approximately 70% of the risk of AMD, the company says.11 The patient’s blood sample is mailed to the company’s lab and results are sent to you, the doctor, between one to two weeks, via your specified delivery system (e.g. e-mail, fax, etc.).

deCODEme ( The deCODEme Genetic Scan for AMD identifies five variants of European ancestry and one variant of East Asian ancestry, decode genetics says. The patient swabs each cheek with a separate deCodeme DNA Buccal Collector stick. The DNA is then mailed to a lab, and results are uploaded to the patient’s personal deCODEme account between two to four weeks. (A caveat: New York, Maryland and Pennsylvania require that laboratories providing genetic risk measurements obtain a laboratory license issued by that state. To date, deCODEme does not have a New York license.)

23andme ( This AMD genetic test determines the presence of the CFH single-nucleotide polymorphism (SNP) (marker rs106 1147), which is a “major risk factor for AMD,” the company says. The patient deposits roughly one-half teaspoon of saliva into the company’s sample collection kit. The DNA is then mailed to a lab. Results are provided to the patient’s personal account within two to three weeks, the company says.


The delay in treatment of the first eye is the reason functional vision loss typically occurs.

Macula Risk ( The Macula Risk test identifies a patient’s risk level of AMD progression based on the presence of CFH – 5 (rs1048 663, rs3766405, rs412852, rs11582939, rs1066420), C3 (rs2230199), ND2 (rs28357980, and ARMS2) (no SNP- but an insertion-deletion called - NM_001099667. 1:C.⋆ 372_815de l443ins54). The test takes into account patient smoking history as well. A physician obtains a cheek sample. The sample is then mailed to a lab. You, the doctor, receive the patient report in three weeks via fax and then mail. The report breaks the risk level into five categories with MR1 level risk being the lowest risk and MR5 being the highest risk.

RetnaGene ( This test determines “wet” AMD risk. Specifically, it combines a patient’s disease stage with genetic predisposition, age and smoking history to provide the probability of converting to “wet” AMD. The risk prediction algorithm relies on a clinical exam of the fundus to assign each patient an AREDS Simplified Severity Scale grade. Patient disease grade is combined with genetic predisposition captured through the survey of 12 disease-associated variants detecting polymorphisms in AMRS2 (rs10490924), C2 (rs9332739), C3 (rs9932739), C3 (rs2230199), CFB (rs641 153), CFH (rs1061170, rs2274 700, rs12144939), CFHR4 (rs1409153), CFHR5 (rs17503 11, rs10922153) and F13B (rs69 8859, s2990510). Smoking status and age are also evaluated to provide an accurate estimation of risk in Caucasians age 55 and older. The patient’s probability of converting to “wet” AMD is reported at two, five and 10 years. RetnaGene requires either a cheek swab (company-supplied buccal swab collection kit) or blood sample, which is mailed to a lab. You, the doctor, receive the results within 10 business days via fax and or through a privacy-protected physician web portal.

One can argue that patients who are in high-risk categories deserve more in-depth and frequent care.

The benefit

Given that early intervention, such as the Age-Related Eye Disease Study (AREDS) 1 oral formula, is key to maintaining these patients’ vision and early intervention is contingent on AMD risk, employing AMD genetic testing makes sense. (It is worth noting, however, that recent research refutes that genetic risk factors predict the incidence and progression of AMD.12)

Consider this: The AREDS formula of 500mg/d vitamin C, 400IU/d vitamin E, 15mg/d beta carotene, 80mg/d zinc oxide and 2mg/d cupric oxide (copper) has been shown to decrease the risk of advanced AMD by 25% in patients who had at least one large druse, extensive intermediate drusen, noncentral geographic atrophy in one eye or bilaterally or advanced AMD of vision loss (<20/32) resulting from AMD in one eye.13 In addition, the typical central peak of macular pigment (MP) can be achieved in subjects who have atypical MP spatial profiles, post supplementation, when containing all three macular carotenoids, a study recently reveals.3

With the availability of the aforementioned AMD genetic tests, we now have concrete data regarding risk level, and, thus, how often we should schedule follow-up visits, employ devices for disease monitoring (e.g. digital fundus photography, OCT, etc.) and when to prescribe the lifestyle changes and treatments proven to preserve vision. OM

Part 2 will discuss genetic tests for retinal degenerations, such as retinitis pigmentosa.

Special thanks to Roshelle Rozenblum and Jinyoung Choe for help in crafting this article.

1. National Eye Institute. Facts About Age-Related Macular Degeneration. Dry AMD. (Accessed 4/17/12’)

2. Nolan JM, Akkali MC, Loughman J. Macular carotenoid supplementation in subjects with atypical spatial profiles of macula pigment. Exp Eye Res. 2012 Aug;101:9-15.

3. Boyer DS, Antoszyk AN, Awh CC, et al. Subgroup analysis of the MARINA study of ranibizumab in neovascular age-related macular degeneration. Ophthalmology. 2007 Feb;114(2):246-52.

4. deCODEme. Age-related Macular Degeneration. (Accessed 11/16/12’)

5. Rivera A, Fisher SA, Fritsche LG, et al. Hypothetical LOC387715 is a second major susceptibility gene for age-related macular degeneration, contributing independently to complement factor H to risk. Hum Mol Genet. 2005 Nov 1; 14(21):3227-3236.

6. Gold B, Merriam JE, Zernant J, et al. Variation in factor B (BF) and complement component 2 (C2) genes is associated with age-related macular degeneration. Nat Genet. 2006 Apr;38(4):458-62.

7. Gehrs KM, Jackson JR, Brown EN et al. Complement, age-related macular degeneration and a vision of the future. Arch Ophthalmol. 2010 Mar;128(3): 349-58.

8. Clark SJ, Bishop PN, Day AJ. Complement factor H and age-related macular degeneration: the role of glycosaminoglycan recognition in disease pathology. Biochem Soc Trans. 2010 Oct;38(5):1342-48.

9. Donoso LA, Vrabec T, Kuivaniemi H. The role of complement factor H in age-related macular degeneration: a review. Surv Ophthalmol. 2010 May-Jun;55(3):227-46.

10. Zipfel PH, Lauer N, Skerka C. The role of complement in AMD. Adv Exp Med Biol. 2010;703:9-24. Review

11. ARUP Laboratories. National Reference Laboratory. ARUP’s Laboratory Test Directory. Macular Degeneration, Age-Related, 2 DNA Markers: 0051674. (Accessed 11/16/12’)

12. Klein R, Myers C, Meuer S, et al. Risk Alleles in CFH and ARMS2 and the Long-term Natural History of Age-Related Macular Degeneration. Arch Ophthalmol. Published online November 9, 2012.

13. Age-Related Eye Disease Study Research Group. A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E, beta-carotene, and zinc for age-related macular degeneration and vision loss: AREDS report no. 8. Arch Ophthalmol. 2001 Oct;119(10):1417-36.


Dr. Nelson practices privately with three other optometrists in Madison, Wisc. He regularly writes articles on ocular health, provides educational lectures and offers consulting services to other O.D.s on how to implement new technology and dietary supplements/patient lifestyle changes. In addition, he is vice president Optometry Professional Relations for ArcticDx, maker of Macula Risk, and he consults for Optos and Optovue. E-mail him at


Dr. Sherman is a distinguished teaching professor of clinical sciences at SUNY State College of Optometry. He serves as president of the Optometric Retina Society. E-mail him at j.sher, or send comments to