Update on Clinical Genetic Testing for AMD

Several genetic screenings are now available to determine patients' risks

Update on Clinical Genetic Testing for AMD

Several genetic screenings are now available to determine patients' risks.

Jaclyn L. Kovach, MD • Ingrid U. Scott, MD, MPH

The pathogenesis of age-related macular degeneration is complex and multifactorial. The International Haplotype Map Project and the resultant genome-wide association studies have identified genetic variations that modulate AMD risk and have confirmed the pivotal role of genetics in the development of AMD.

To date, the most powerful genetic risk factors for the development and advancement of AMD are variations in the complement factor H (CFH),1-2 complement factor B (CFB)/complement component 2 (C2),3 complement component 3 (C3),4 and the ARMS25 genes. Specific polymorphisms in the complement factor I (CFI),6 hepatic lipase (LIPC), cholesteryl ester transfer protein (CETP), and TIMP37 genes also play a roles.

The discovery and identification of genetic polymorphisms associated with AMD are the first step toward not only predicting AMD development and severity but also in determining response to treatment. Use of this knowledge for gene therapy could foster a possible cure for AMD. Recently, the ability to test patients for high-risk genetic polymorphisms in a clinic setting has become a reality.

Since 2005, several commercially available genetic tests have entered the market, including Macula Risk (ArticDx, Inc., Toronto) and the RetnaGene AMD test (Sequenom, San Diego). Both tests analyze DNA from buccal cells, which are an easily accessible and stable source of genomic DNA for clinical diagnosis.8 Samples are mailed to the respective testing facilities, with results sent to the ordering physician in several weeks.

The Macula Risk test analyzes eight genetic polymorphisms in the CFH (rs1048663, rs412852, rs3766405, rs11582939, rs1066420), C3 (rs2230199), ARMS2, and mitochondrial DNA ND2 mtA4917G (rs28357980) genes and uses these data, along with smoking history, to stratify patients into one of five risk categories (MR 1 through 5).

Risk levels 3, 4 and 5 represent 20% of individuals. The company asserts that those in the MR5 group have more than a 60% chance of progressing to advanced AMD with significant vision loss (Figure 1).

The second generation of the Macula Risk test will also include polymorphisms in the CFB/C2, CFI, LIPC and TIMP3 genes. The Macula Risk test is intended for patients who have early or intermediate AMD. Information regarding risk level may provide guidance regarding examination frequency and may encourage compliance with life style modifications (eg, smoking cessation, dietary modifications).

Macula Risk is covered my most insurance providers, including Medicare, as long as the test is ordered by a physician or optometrist and the patient has one of the following diagnosis codes:
• 362.50, nonspecific AMD
• 362.51, nonexudative senile macular degeneration
• 362.52, exudative senile macular degeneration
• 362.57, drusen

The RetnaGene AMD test assesses 13 single nucleotide polymorphisms in the CFH (rs1061170, rs2274700, rs403846, rs12144939), CFHR4 (rs1409153), CFHR5 (rs1750311, rs10922153), F13B (rs698859, s2990510), C2 (rs9332739), CFB (rs641153), ARMS2 (rs10490924), and C3 (rs2230199). To date, the Retna Gene test is the only peer-reviewed and published validation of an AMD laboratory developed test where all markers have been tested in the same group of subjects. The validation study of this genetic model required a sample size of 1,132 CNV cases and 822 controls and yielded a sensitivity of 82% and a specificity of 63%.9

Individuals are stratified into one of three risk categories: low, moderate or high risk for CNV development (Figure 2). Those in the low-risk group have less than a 25% chance of CNV development, with the risk being 25% to 75% in the moderate-risk group and greater than 75% in the high-risk group. In patients with a diagnosis of AMD, individuals with a private insurer are currently guaranteed by Sequenom to have a maximum out-of-pocket expense of $150.

ARUP Laboratories (Salt Lake City) have developed a genetic test for AMD that assesses the risk alleles for the Y402H polymorphism in CFH and the ARMS2 rs10490924 single nucleotide polymorphism. A blood sample is sent to their lab with results available in one to two weeks.

23andMe, Inc. (New York), has developed a genetic test performed on DNA extracted from an individual's saliva sample that analyzes three polymorphisms: CFH (rs1061147), C2 (rs547154), and ARMS2 (rs3750847).

Currently, commercially available genetic tests for AMD demonstrate analytic and clinical validity. The ordering physician is responsible for interpreting the genetic profile results sent from the testing facility, with educational and genetic counseling support available upon request. Patients with dry AMD who fall in the higher-risk categories could theoretically benefit from closer follow-up and might be inclined to be more compliant with vitamin supplementation and elect to quit smoking and lead a healthier, active lifestyle.

It remains to be shown whether higher-risk wet AMD patients can benefit from more aggressive anti-VEGF therapy. The currently available genetic tests are designed for patients already diagnosed with AMD. Family members without AMD who want information regarding their genetic risk profiles and elect to pay for the test may choose to make lifestyle modifications if they are in the higher-risk categories.

Considering the novelty of these tests and the current lack of clinical evidence to guide practitioners, prudence is required when offering these tests to patients, especially those without a clinical diagnosis of AMD. As additional high-risk genetic AMD polymorphisms are identified, the clinical utility of genetic testing will improve and could provide guidance regarding lifestyle modification and personalization of treatment regimens. RP


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Jaclyn L. Kovach, MD, is assistant professor of clinical ophthalmology at the Bascom Palmer Eye Institute of the University of Miami Medical Center. Ingrid U. Scott, MD, MPH, is professor of ophthalmology and public health sciences at the Penn State Hershey Eye Center. Neither author reports any financial interest in any products mentioned in this article. Dr. Scott can be reached via e-mail at