Frequently Asked Questions

1. What is Macula Risk^®?
2. Why should an eye-care professional use Macula Risk^®?
3. What is the recommended patient profile for Macula Risk^® testing in your practice?
4. What are AREDS Categories for diagnosing AMD progression?
5. Which ICD-9 diagnostic codes apply to Macula Risk^®?
6. Is Macula Risk^® Reimbursed?
7. Does the sample require special storage?
8. Is Macula Risk^® approved by Regulatory Authorities?
9. What is the turnaround time for the running of this test?
10. How often does a patient need to take this test?
11. What does Macula Risk^® measure?
12. How accurate is Macula Risk^®?
13. Can a patient order Macula Risk^® testing?
14. How are the patient samples delivered to the laboratory?
15. Where is the Macula Risk test performed on my sample?
16. What can the eye-care professional do for his/her patient?
17. Is there any precedent for increased monitoring of high-risk AMD patients?
18. What AMD genes have been identified in the literature?

References

1. What is Macula Risk^®?

Macula Risk^® is a prognostic DNA test intended for patients who have a diagnosis of early or intermediate AMD. Using the complete combination of AMD genes, and smoking history, Macula Risk^® identifies those most likely to progress from early or intermediate Dry AMD to advanced AMD with vision loss. The patient sample is a cheek swab taken in the doctor's office. Macula Risk^® scores the patient's inherited risk for progression to vision loss on a scale from 1 (lowest risk) to 5 (highest risk).

2. Why should an eye-care professional use Macula Risk^®?

Macula Risk^® identifies the risk potential for Dry AMD patients to progress to vision loss. Macula Risk^® allows the doctor to stratify patients for appropriate monitoring as recommended by the AOA and the AAO Preferred Practice Patterns - "in an effort to detect asymptomatic CNV at a treatable stage." ¹ Once AMD patients are stratified for risk, eye-care professionals should tailor an appropriate surveillance plan leading to more timely interventions and the preservation of sight.

3. What is the recommended patient profile for Macula Risk^® testing in your practice?

The selection of patients for genetic testing should be based on their clinical signs of AMD (AREDS Category), their Family History of Advanced AMD and their Age. The table below is a guide for eye care professionals:

4. What are AREDS Categories for diagnosing AMD progression?

The AREDS 1 study that was designed by the National Eye Institute generated a classification system for the progression of Age related Macular Degeneration (AMD). There are 4 main categories that allow an eye-care professional to measure disease progression during eye examinations. The AREDS Categories are as follows:

Category 1:

Few small or no drusen

Category 2:

Early AMD, having small drusen (< 63 micrometers [µm]) and few intermediate drusen (≥ 63 µm and <125 µm)

Category 3:

Intermediate AMD, having extensive intermediate drusen or large drusen (≥125 µm)

Category 4:

Advanced AMD in 1 eye, either Geographic Atrophy (GA) in the center or neovascular AMD

5. Which ICD-9 diagnostic codes apply to Macula Risk^®?

Macula Risk^® is reimbursed for diagnosed AMD patients. An ICD-9 code is required to confirm to the payor the patient has in fact AMD. This is also required for the CLIA laboratory to begin the testing process. The four standard codes are listed on the test requisition form. They are:

• 362.50 – Non-specific AMD
• 362.51 – Non-exudative senile macular degeneration
• 362.52 – Exudative senile macular degeneration
• 362.57 – Drusen

6. Is Macula Risk^® Reimbursed?

Macula Risk^® is reimbursed for all patients who have a diagnosis of AMD and a valid insurance plan. Reimbursement is provided by most private and public insurers including Medicare. There are no co-pays or deductibles required for laboratory tests like Macula Risk^® by Medicare. 

Patient Payments: Patients who are required to pre-pay for the test are those who have no diagnosis of AMD (no ICD-9 code) or no insurance coverage. The pre-pay fee is $1018, payable to the laboratory by check or credit card.

All patient billing for Macula Risk^® is managed by the laboratory. The doctor's office does not collect any money from the patient for the test. 

7. Does the sample require special storage?

No. A patient's DNA sample is stable at room temperature for at least 2 years. The instructions for packaging the sample collection device are included in the package provided.

8. Is Macula Risk^® approved by Regulatory Authorities?

Yes, Macula Risk^® is being provided to healthcare professionals as a laboratory-developed and validated genetic test. This is in keeping with regulatory guidelines for the medical introduction of laboratory-developed tests under CAP and CLIA accreditation standards.

9. What is the turnaround time for the running of this test?

It takes approximately 3 weeks for the test to be processed and the results to be sent back to the eye-care professional.

10. How often does a patient need to take this test?

A patient should only need to take this test once in their lifetime.

11. What does Macula Risk^® measure?

Macula Risk^® measures genetic variants related to complement protein metabolism, oxidative stress and smoking history.

Complement: Genetic variations (Haplotypes) in the Complement Factor H (CFH) gene and one Single Nucleotide Polymorphism (SNP) in the Complement Component 3 (C3) gene are measured.

Oxidative Stress: Genetic variants related to oxidative stress include an insertion /deletion in the ARMS2/HTRA1 gene and a SNP in the mitochondrial ND2 gene.

Smoking has been extensively studied in AMD patients. Individuals who smoke are over three times more likely to progress to advanced AMD with vision loss than those who have never smoked. Smoking history is included in the Macula Risk^® prognosis.

The table below identifies the genes currently tested and the specific alleles or haplotypes. The odds ratios presented describe the risk for progression to advanced AMD with vision loss for individuals carrying the homozygous risk genotype.

12. How accurate is Macula Risk^®?

DNA laboratory testing is very accurate. The laboratory service has validated the Macula Risk^® assay to a target of at least 99.9% accuracy. 

13. Can a patient order Macula Risk^® testing?

No. Macula Risk^® is a medical test. It must be ordered by a doctor; the patient results will only be provided to the doctor. Testing is usually ordered by an ophthalmologist or an optometrist.

14. How are the patient samples delivered to the laboratory?

Once a patient's cheek swab has been collected in your office. It is packaged with a Test Request Form/Informed Consent and Insurance billing information in a padded envelope provided. Samples will be collected by a courier and transported to the laboratory for processing.

15. Where is the Macula Risk test performed on my sample?

Macula Risk^® testing is performed at a CAP/CLIA approved independent genetic testing laboratory. National Jewish Health, Denver CO. is an established national hospital and academic institution. Your patient samples, reports and other confidential information are maintained within their system.

16. What can the eye-care professional do for his/her patient?

Patients may be stratified using their AMD clinical status (AREDS), Macula Risk^® score and their age for follow up examinations by primary eye care professionals and retina specialists as recommended below:

17. Is there any precedent for increased monitoring of high-risk AMD patients?

Yes. There are numerous precedents for monitoring patients with early or intermediate AMD. The AOA and the AAO both recommend increased monitoring of AMD patients with early or intermediate disease.

AAO Preferred Practice Patterns:

The American Academy of Ophthalmology publishes "Preferred Practice Patterns" for AMD. It is recommended that patients with early or intermediate AMD be monitored every 6 – 24 months and more frequently than this in very high-risk situations "in an effort to detect asymptomatic CNV at a treatable stage."

Peer Reviewed Publications:

There have been numerous publications that support monitoring high-risk AMD patients. In a 5-year study published in the American Journal of Ophthalmology (33), Dr. M. Maguire et al (The CAPT Research Group): made the following conclusion:

"When patients are monitored closely, many CNV lesions can be detected outside of the fovea, when they are relatively small. Early detection may lead to improved long-term visual acuity."

Current Medical Practice:

Monitoring of 'high-risk' dry AMD patients. CNV patients with involvement in one bad eye are at increased risk of CNV in their companion eye. The current standard of care is to monitor these 'high-risk' companion eyes with an increased frequency. Eye examinations every 3 to 6 months, including advanced imaging and possibly fluorescein angiograms, represent today's standard of care for these patients. A similar approach is advocated for the high-risk AMD patient's 'first eye'.

18. What AMD genes have been identified in the literature?

The first reports of specific genetic markers associated with AMD risk appeared in the medical literature in 2005 and the pace of discovery doesn't appear to be slowing (1). First identified were complement gene polymorphisms, CFH is an important inhibitor of this inflammatory cascade and a disease-associated polymorphism in the complement factor H (CFH) gene strongly associates with AMD (1, 3-7). Thus an AMD pathophysiological model of chronic low-grade complement activation and inflammation in the macula has been advanced (8, 9). Lending credibility to this has been the discovery of disease-associated genetic polymorphisms in other elements of the complement cascade, including complement component 3 (C3), complement component 2 (C2), complement factor B (CFB) and complement Factor I (CFI)(10-14).

The role of retinal oxidative stress in the etiology of AMD, by causing further inflammation of the macula, is suggested by the enhanced rate of disease in smokers and those exposed to UV irradiation (15-17). The mitochondria are a major source of oxygen free radicals that occur as a byproduct of energy metabolism. Mitochondrial gene polymorphisms, such as that in the ND2 molecule predicts wet AMD (18, 19). A powerful predictor of AMD is found on chromosome 10q26 at LOC 387715. An insertion/deletion polymorphism at this site reduces expression of the ARMS2 gene though destabilization of its mRNA through deletion of the polyadenylation signal (20, 21). ARMS2 protein may localize to the mitochondrion and participate in energy metabolism, though much remains to be discovered about its function (22).

The spectrum of AMD-associated genes has been rounded out by two genome-wide association studies (14, 23). This technique evaluates the entire genome in an unbiased fashion for phenotype-associated genetic variables. These large studies confirmed previously identified disease markers and supplemented these with markers in the tissue inhibitor of metalloproteinase 3 gene (TIMP3) and a family of molecules important for cholesterol metabolism (14). These include the hepatic lipase gene (LIPC), the lipoprotein lipase gene (LPL), cholesterol ester transferase gene (CETP) and the ABC-binding cassette A1 (ABCA1) gene (14, 23). How these polymorphisms fit into a practical pathophysiological framework awaits further research, though the relationship between cholesterol, retinal pigment, carotenoids, UV protection and AMD has been noted (13).

One practical application of these disease-associated markers is in the prediction of progression of AMD from early stages of the disease to neovascularization. Such a clinical tool will allow the identification of individuals at greatest risk that will benefit from monitoring, early detection and timely treatment that is associated with a superior visual outcome. A recent report suggests that a combination of these markers and clinical parameters can predict progression to wet AMD with an accuracy of over 90% (24, 25).

A second application of these genetic variations is in the prediction of treatment response or pharmacogenetics. Early studies demonstrate positive findings (28, 29, 30, 31, 32).

Development of algorithms using the full range of disease-associated markers may aid treatment selection and will form an important component of the development of novel agents for this important disease.

Confirmed polymorphic genes associated with age-related macular degeneration and their functional classification.

 

Please contact us with any further questions

 

References

1. Klein RJ, Zeiss C, Chew EY, Tsai JY, Sackler RS, Haynes C, et al. Complement factor H polymorphism in age-related macular degeneration. Science. 2005;308(5720):385-9.

2. Mullins RF, Russell SR, Anderson DH, Hageman GS. Drusen associated with aging and age-related macular degeneration contain proteins common to extracellular deposits associated with atherosclerosis, elastosis, amyloidosis, and dense deposit disease. FASEB J. 2000 May;14(7):835-46.

3. Hageman GS, Anderson DH, Johnson LV, Hancox LS, Taiber AJ, Hardisty LI, et al. A common haplotype in the complement regulatory gene factor H (HF1/CFH) predisposes individuals to age-related macular degeneration. ProcNatlAcadSciUSA. 2005;102(20):7227-32.

4. Chen LJ, Liu DT, Tam PO, Chan WM, Liu K, Chong KK, et al. Association of complement factor H polymorphisms with exudative age-related macular degeneration. Mol Vis. 2006;12:1536-42.

5. Despriet DD, Klaver CC, Witteman JC, Bergen AA, Kardys I, de Maat MP, et al. Complement factor H polymorphism, complement activators, and risk of age-related macular degeneration. JAMA. 2006;%19;296(3):301-9.

6. Li M, tmaca-Sonmez P, Othman M, Branham KE, Khanna R, Wade MS, et al. CFH haplotypes without the Y402H coding variant show strong association with susceptibility to age-related macular degeneration. NatGenet. 2006;38(9):1049-54.

7. Haines JL, Hauser MA, Schmidt S, Scott WK, Olson LM, Gallins P, et al. Complement factor H variant increases the risk of age-related macular degeneration. Science. 2005;308(5720):419-21.

8. Rohrer B, Long Q, Coughlin B, Renner B, Huang Y, Kunchithapautham K, et al. A targeted inhibitor of the complement alternative pathway reduces RPE injury and angiogenesis in models of age-related macular degeneration. Adv Exp Med Biol.703:137-49.

9. Kunchithapautham K, Rohrer B. Sublytic membrane-attack-complex (MAC) activation alters regulated rather than constitutive VEGF secretion in retinal pigment epithelium monolayers. J Biol Chem. May 12.

10. Yates JR, Sepp T, Matharu BK, Khan JC, Thurlby DA, Shahid H, et al. Complement C3 variant and the risk of age-related macular degeneration. NEnglJMed. 2007;357(6):553-61.

11. Gold B, Merriam JE, Zernant J, Hancox LS, Taiber AJ, Gehrs K, et al. Variation in factor B (BF) and complement component 2 (C2) genes is associated with age-related macular degeneration. NatGenet. 2006;38(4):458-62.

12. Spencer KL, Hauser MA, Olson LM, Schmidt S, Scott WK, Gallins P, et al. Protective effect of complement factor B and complement component 2 variants in age-related macular degeneration. Human Molecular Genetics. 2007;16(16):1986-92.

13. Reynolds R, Rosner B, Seddon JM. Serum lipid biomarkers and hepatic lipase gene associations with age-related macular degeneration. Ophthalmology. 2010 Oct;117(10):1989-95.

14. Chen W, Stambolian D, Edwards AO, Branham KE, Othman M, Jakobsdottir J, et al. Genetic variants near TIMP3 and high-density lipoprotein-associated loci influence susceptibility to age-related macular degeneration. Proc Natl Acad Sci U S A. 2010 Apr 20;107(16):7401-6.

15. Thornton J, Edwards R, Mitchell P, Harrison RA, Buchan I, Kelly SP. Smoking and age-related macular degeneration: a review of association. Eye. 2005;19(9):935-44

16. Tomany SC, Cruickshanks KJ, Klein R, Klein BE, Knudtson MD. Sunlight and the 10-year incidence of age-related maculopathy: the Beaver Dam Eye Study. Arch Ophthalmol. 2004 May;122(5):750-7.

17. Szaflik JP, Janik-Papis K, Synowiec E, Ksiazek D, Zaras M, Wozniak K, et al. DNA damage and repair in age-related macular degeneration. Mutat Res. 2009 Jun 25.

18. Udar N, Atilano SR, Memarzadeh M, Boyer D, Chwa M, Lu S, et al. Mitochondrial DNA Haplogroups Associated with Age-Related Macular Degeneration. Invest Ophthalmol Vis Sci. 2009 Jan 17.

19. Canter JA, Olson LM, Spencer K, Schnetz-Boutaud N, Anderson B, Hauser MA, et al. Mitochondrial DNA polymorphism A4917G is independently associated with age-related macular degeneration. PLoSONE. 2008;3(5):e2091.

20. Fritsche LG, Loenhardt T, Janssen A, Fisher SA, Rivera A, Keilhauer CN, et al. Age-related macular degeneration is associated with an unstable ARMS2 (LOC387715) mRNA. NatGenet. 2008;40(7):892-6.

21. Kenealy SJ, Schmidt S, Agarwal A, Postel EA, De La Paz MA, Pericak-Vance MA, et al. Linkage analysis for age-related macular degeneration supports a gene on chromosome 10q26. Mol Vis. 2004 Jan 26;10:57-61.

22. Kanda A, Chen W, Othman M, Branham KE, Brooks M, Khanna R, et al. A variant of mitochondrial protein LOC387715/ARMS2, not HTRA1, is strongly associated with age-related macular degeneration. ProcNatlAcadSciUSA. 2007;104(41):16227-32.

23. Neale BM, Fagerness J, Reynolds R, Sobrin L, Parker M, Raychaudhuri S, et al. Genome-wide association study of advanced age-related macular degeneration identifies a role of the hepatic lipase gene (LIPC). Proc Natl Acad Sci U S A. 2010 Apr 20;107(16):7395-400.

24. Seddon JM, Reynolds R, Maller J, Fagerness JA, Daly MJ, Rosner B. Prediction Model for Prevalence and Incidence of Advanced Age-Related Macular Degeneration Based on Genetic, Demographic, and Environmental Variables. Invest Ophthalmol Vis Sci. 2008 Dec 30.

25. Seddon JMR, R.;Yu, Y.;Daly, M.J.;Rosner, B. Prediction risk Modeling for Progression to Advanced Age-Related Macular Degeneration Using Baseline Demographic, Environmental, Genetic and Ocular Variables.2011.

26. Ip MS, Scott IU, Brown GC, Brown MM, Ho AC, Huang SS, et al. Anti-vascular endothelial growth factor pharmacotherapy for age-related macular degeneration: a report by the American Academy of Ophthalmology. Ophthalmology. 2008 Oct;115(10):1837-46.

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

28. Lee AY, Raya AK, Kymes SM, Shiels A, Brantley MA, Jr. Pharmacogenetics of complement factor H (Y402H) and treatment of exudative age-related macular degeneration with ranibizumab. Br J Ophthalmol. 2009 May;93(5):610-3.

29. Teper SJ, Nowinska A, Pilat J, Palucha A, Wylegala E. Involvement of genetic factors in the response to a variable-dosing ranibizumab treatment regimen for age-related macular degeneration. Mol Vis. 2008 ;16:2598-604.

30. Lee AY, Raya AK, Kymes SM, Shiels A, Brantley MA, Jr. Pharmacogenetics of Complement Factor H (Y402H) and treatment of exudative age-related macular degeneration with ranibizumab. Br J Ophthalmol. 2008 Dec 17.

31. Golk JCA, M.D.; Orien, J.A.; Christopher, M.A.; Scheetz, T.E.; Mullins, R.F.;Eyestone, M.E.; East, J.S.; Schinddler, E.I., Stone, E.M. Age-related macular degeneration risk alleles and response to treatment with anti-VEGF agents. ARVO Abstracts. 2011;5238(D1122).

32. El Annan JS, S.; Tezel, T. H. Genetic risk factors for age-related macular degeneration (AMD) can also be predictive for the functional and anatomical outcome of intravitreal antiVEGF treatment. ARVO Abstracts. 2011;5255(D1139).

33. Maguire, Maureem G., Alexander J., Fine S. Characteristics of Choroidal Neovascularization in the Complications of Age-Related Mcular Degeneration Prevention Trial. doi.1016/j.ophtha. 2008.02.026