Review of Cornea

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Genetic Testing for AMD

Genetic testing can help to identify which patients are at risk for the development of AMD.
Edited by Diana L. Shechtman, O.D., and Paul M. Karpecki, O.D.


A 75-year-old white male recently presented to the office with bilateral drusen and mild retinal pigment epithelium (RPE) changes, but no obvious hemorrhage or fluid. His vision still measured 20/25 O.U., and optical coherence tomography revealed just small modulation within the RPE that was associated with the drusen.

The patient was very concerned about losing his vision. Like many patients, he had a good friend who recently lost vision secondary to advanced AMD. We discussed his AMD at length, the role of nutrition and vitamins, and the need for close monitoring. Although he seemed comforted after our discussion, he was still troubled. One question remained: “What are the chances that I will end up like my friend?”

Until recently, the answer to such a question would be speculative at best. But, with the advent of new genetic diagnostic testing in the area of AMD, we now may be able to provide a reasonably accurate prognosis regarding disease progression.

Genetic Testing for AMD

Age-related macular degeneration is the leading cause of blindness in Americans older than 65 years of age. While the exact pathogenesis remains elusive, various risk factors, such as advanced age, smoking, UV exposure, obesity, diet and family history, have been identified.

Recent research in genetics is rapidly changing the way we view risk factors for AMD. In fact, many researchers believe that AMD may be the most inheritable mutagenic disease to date, providing a rare opportunity to identify individuals who are at risk while they are still asymptomatic.1

In 2005, Ronald Klein, M.D., M.P.H., and associates discovered a strong genetic link between AMD and variants of the complement factor H (CFH) gene on chromosome 1q31.2 One study revealed that having a homozygous form of the CFH gene variant may increase an individual’s chance of developing AMD by 18 times.3 Numerous other genes have been implicated in AMD, including LOC, Y402H, C2, C3, ARMS2, TIMP3 and mitochondrial DNA mutation (a4917G), and we are now just beginning to understand their roles.4-9

Nonetheless, these genetic markers may increase the risk of AMD by as much as 70%.2

So, can genetic testing potentially identify AMD suspects and/or established AMD patients who are at risk for progression?

Macula Risk
Several genetic tests are currently available and/or under development. Macula Risk (ArcticDX) is one commercially available genetic test that measures inheritable risk factors for AMD. When its results are combined with other risk factors (such as smoking), Macula Risk can help predict an individual’s prognosis for progression towards the more advanced stages of macular degeneration. A large, independent, prospective clinical trial demonstrated a 0.831 predictive value risk for progression associated with specific genetic variants in conjunction with others factors.10

The Macula Risk genetic test classifies individuals into one of five macula risk (MR) categories, with MR3 through MR5 representing an increased risk of AMD development––this range accounts for approximately 20% of the general population (see “Macula Risk Category,” above). Furthermore, an individual’s particular MR can help determine the risk for progression towards the more advanced stage of the disease. For example, MR1 indicates less than a 5% risk of the advanced stage of the disease, while MR5 reveals a 55% to 96.5% risk (see “Macula Risk Percentages”).11

The test only requires a simple in-office cheek swab (no CLIA certificate is necessary), which is sent directly to the genetic lab. A report is faxed back to the ordering doctor, which is followed by a written report in the mail a few weeks later. The report includes the test results as well as recommended genetic support for the patients. Further, there are full-time certified genetic counselors available for the doctor or patient, as needed.

Macula Risk’s results can help you devise a specific management and follow-up protocol for the patient in an attempt to identify an early CNV lesion. This may entail early intervention, increased frequency of follow-up visits and/or additional testing to help further investigate the progression of the disease.

Accounting for the current American Academy of Ophthalmology preferred practice guidelines for AMD, Arctic Dx and its Retina Medial Advisory Board have devised their own clinical recommendations, which may serve as a useful guideline (see “Practice Recommendations”).

Without question, an increased frequency of eye examinations is recommended for your high-risk patients (MR3 to MR5). As an example, a patient in MR4 or MR5 warrants quarterly exams with periodic optical coherence tomography scans as well as other emerging technologies, such as preferential hyeracuity perimetry (Foresee PHP, Reichert Technologies). In contrast, a patient categorized as MR2 could be seen yearly, with an annual dilated fundus exam and home Amsler grid testing.

Macula Risk genetic testing is covered by most insurance providers, including Medicare, as long as the specific diagnosis (ICD-9) codes for AMD are used. The four allowable codes are:
• 362.50––non-specific AMD
• 362.51––non-exudative senile macular degeneration
• 362.52––exudative senile macular degeneration
• 362.57––drusen

There are no CPT codes required. Keep in mind, however, that because this prognostic DNA test is intended for patients who have a diagnosis of early or intermediate AMD, the individual will be responsible for the entire fee (approximately $750) if there is no existing diagnosis of AMD (such as an “at risk patient”).11

Despite the increasing availability of current treatment options, many people are still losing vision from AMD. We need to take a proactive role, which includes tailoring examination protocols based on the risk of AMD development, an increased frequency of examinations, improved patient education regarding preventative measures, and making proper vitamin therapy recommendations. We play a significant role in the identification of people who are at high risk for the development of advanced AMD. Future research in the area of prophylactic treatment options as well as pharmacogenomics will soon become an integral part in the prevention of future visual deterioration.

As for our patient, genetic testing was not available at the time of his visit. At his next visit, however, we will reassess his level of AMD and discuss genetic testing, which may provide him with a better idea of his long-term prognosis.

Thanks to Steven Ferrucci, O.D., chief of optometry and residency director at the Sepulveda VA Ambulatory Care Center & Nursing Home in California for contributing this article.

1. Swaroop, Branham KE, Chen W, Abecasis G. Genetic susceptibility to age-related macular degeneration: a paradigm for dissecting complex disease traits. Hum Mol Genet. 2007 Oct 15;16 Spec No. 2:R174-82.

2. Klein RJ. Complement factor H polymorphism in age-related macular degeneration. Science. 2005 Apr 15;308(5720):385-9.
3. Seddon JM, Francis PJ, George S, et al. Association of CFH Y402H and LOC387715 A69S with progression of age-related macular degeneration. JAMA. 2007 Apr 25;297(16):1793-800.
4. Yates JR, Sepp T, Matharu BK, et al. Complement C3 variant ad the risk of age-related maculr degeneration. N Engl J Med. 2007 Aug 9;357(6):553-61.
5. Maller JB, Fagerness JA, Reynolds RC, et al. Variation in complement factor 3 is associated with risk of age-related macular degeneration. Nat Genet. 2007 Oct;39(10):1200-1.
6. Despriet DD, Duijn CM, Oostra BA, et al. Complement component C3 and risk of age-related macular degeneration. Ophthalmology. 2009 Mar;116(3):474-480.e2.
7. Fritsche LG, Loenhardt T, Janssen A, et al. Age-related macular degeneration is associated with an unstable ARMS2(LOC387715) mRNA. Nat Genet. 2008 Jul;40(7):892-6.
8. Rivera A, Fisher SA, Fritsche LG, et al. Hypothetical LOC387715 is a second major gene for age-related macular degeneration, contributing independently of complement factor H to disease risk. Hum Mol Genet. 2005 Nov 1;14(21):3227-36.
9. Canter JA, Olson LM, Spencer K, et al. Mitochondrial DNA polymorphism A4917G is independently associated with age-related macular degeneration. PloS One. 2008 May 7;3(5);e2091.
10. Seddon JM, Reynolds R, Maller J, et al. Prediction model for prevalence and incidence of advanced age-related n=macular degeneration based on genetic, demographic, and environmental variables. Invest Ophthalmol Vis Sci. 2009 May;50(5):2044-53.
11. Macula Risk. About the Test. Available at: (accessed December 13, 2010).

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