Editor: I read with interest the article, “Pharmacogenetics and AMD: What we Know (and Don’t Know) So Far” by Parth Shah and Stephen G. Schwartz, MD, MBA (Retina Specialist, page 26, March 2017). They reviewed genetic tests for age-related macular degeneration for their prognostic value and for potential pharmacogenetic interaction with the Age-Related Eye Disease Study (AREDS).
They reviewed numerous reports related to the safety and efficacy of AREDS in the treatment of patients with intermediate AMD. Contrary to the authors’ note, Michael Klein, MD, and coauthors did not find that patients with two high-risk complement factor H (CFH) alleles had a statistically significant benefit from AREDS.
The authors pointed to the AREDS 38 publication, suggesting that all evaluated patients benefited from AREDS.1 However, for patients with the C2A0 genetic profile the hazard ratio (HR) for progression on AREDS vs. placebo was 1.78. These patients did not benefit from AREDS and they trended toward harm.
The authors also referenced a letter to the editor by Emily Chew, MD, detailing a report on 526 patients.2 There is no statistical analysis in this letter demonstrating the authors’ conclusions or that AREDS was beneficial to anyone. A proper scientific discussion on these data is long overdue.
The authors said that Johanna Seddon, MD, MSc, and colleagues reported that “antioxidants and zinc conferred no treatment benefits in patients with two risk alleles at CFH or no risk alleles at ARMS2” (C2A0 genotype).3 Dr. Seddon and colleagues did not analyze the C2A0 genotype alone; they combined it with the C1A0 genotype and showed that 33 percent of patients do not benefit and, in fact, trend toward harm from choroidal neovascularization (CNV) (HR=1.54). They said more study was needed to understand the biology behind this interaction, not to see if an interaction exists.
Is AREDS helpful or possibly harmful? All of the published studies, including AREDS 38, show that patients with the C2A0 genotype (13 to 19 percent of patients) either do not benefit or they may be harmed.
The authors suggested prognostic genetic testing confers no benefit because it is no better than the clinical eye examination. Many authors have demonstrated a statistically significant increased accuracy of adding genetics to the clinical eye exam with phenotype groups. In the model Dr. Seddon and colleagues developed, a typical five-year range of risk for patients with AREDS category 3 AMD would be 7 to 70 percent.4 According to the American Academy of Ophthalmology Preferred Practice Patterns, one would not manage these AREDS category 3 patients with higher or lower risk the same way.
Some prognostic studies that did not show statistical significance when genetics were added to the clinical eye examination included large groups of patients with AREDS category 1 disease.5 The eye examination is just as accurate in these cases because they do not progress in five to 10 years.
The MARINA study showed that patients with CNV referred early, when their visual acuity was 20/80 or better, had better outcomes from anti-VEGF treatment.6 Because the primary eye-care professional plays a key role in early treatment, the accuracy of AMD risk assessment is important.
Personalized medicine is a valuable tool in AMD. While the subject is controversial, the data are not. All the published data and the recent Centers for Medicare and Medicaid Services approval for reimbursement of pharmacogenetic testing show that AMD is predominately a genetic disease, and that personalized medicine is a useful prognostic and pharmacogenetic tool. RS
— Gregory Hines president and CEO Arctic Medical Laboratories Grand Rapids, Mich.
Editor’s note: The authors chose not to respond to Mr. Hines’ letter.
1. Chew EY, Klein ML, Clemons TE et al. No Clinically Significant Association between CFH and ARMS2 Genotypes and Response to Nutritional Supplements: AREDS Report Number 38. Ophthalmology 2014; 121.
2. Chew EY, Klein ML, Clemons TE et al. Genetic testing in persons with age-related macular degeneration and the use of the AREDS supplements: to test or not to test? Ophthalmology 2015; 122:212-215.
3. Seddon JM, Silver RE and Rosner B. Response to AREDS supplements according to genetic factors: survival analysis approach using the eye as the unit of analysis. Br J Ophthalmol. 2016; 100:1731-1737.
4. Seddon JM, Reynolds R, Yu Y et al. Validation of a prediction algorithm for progression to advanced macular degeneration subtypes. JAMA Ophthalmol 2013; 131:448-455.
5. Klein R, Myers CE, Meuer SM et al. Risk alleles in CFH and ARMS2 and the long-term natural history of age-related macular degeneration: the Beaver Dam Eye Study. JAMA Ophthalmol 2013; 131:383-392.
6. Boyer DS, Antoszyk AN, Awh CC, et al. Subgroup analysis of the MARINA study of ranibizumab in neovascular age-related macular degeneration. Ophthalmology 2007; 114:246-252.