Retinal Physician

JAN-FEB 2017

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R E T I N A L P H Y S I C I A N | J U N E 2 0 1 3 19 genetic findings. 38 Another retrospective subgroup analysis on the same AREDS trial, this time involving 995 patients, was performed. These patients had AREDS category 3 disease in at least one eye. 39 Researchers looked for asso- ciations between genotypes at CFH and ARMS2 and outcomes stratified by the four treatment categories (antioxidants, zinc, both, and neither). They reported the benefit of zinc-only supplementation in reducing progression to advanced AMD in subjects with no risk alleles for CFH and one or two ARMS2 risk alleles. 39 The authors found that 49% of subjects analyzed derived more benefit from a supplementation regimen other than the AREDS formulation. The investigators concluded that a pharmacogenetic approach in which patients were assigned to nutritional supplementation based on genotypes at CFH and ARMS2 might lead to more favorable outcomes. 39 Next, a subgroup of 1237 patients with category three or four disease from the same AREDS trial was investigated. Here, investigators reported no signifi- cant associations between progression rates stratified by nutritional supplementation and genotypes at CFH and ARMS2. 40 Another study looking at CFH, ARMS2, and cat- egory three or four disease was initiated, this retrospec- tive subgroup analysis involving 989 patients from the original AREDS trial. 41 A complex relationship between CFH, ARMS2 was found, with outcomes stratified by nutritional supplementation. These authors concluded that "most " patients would benefit from either no sup- plementation or a supplementation other than AREDS formulation (antioxidants plus zinc). The recommen- dation was that patients be offered genotype-directed nutritional supplementation. 41 An attempt to replicate the study that analyzed only a subset of the patients in the original AREDS trial could not be replicated. This study involved 525 patients. The investigators reported that, among the 526 patients analyzed, the AREDS formulation (anti- oxidants plus zinc) was the most beneficial nutritional supplement for all genetic subtypes studied. 42 More recently, another group 44 evaluated the role of genetic variants in modifying the relationship between supple- mentation and progression to advanced AMD using the eye as the unit of analysis. The authors considered 4,124 eyes in 2,317 AREDS subjects in their survival analysis and reported that among the antioxidant and zinc supplement users compared with placebo, subjects with the nonrisk genotype for CFH had a lower risk of progression to advanced AMD. No significant treat- ment effect was noted among subjects who were homo- zygous for the CFH risk allele. A protective effect of the combined supplementation was observed among high-risk ARMS2 carriers. The authors concluded that the effectiveness of antioxidant and zinc supplementa- tion appears to differ by genotype, and they called for additional studies. 44 CONCLUSION To date, there has not yet been a prospective clinical trial that specifically has studied genotype-phenotype relationships with respect to nutritional supplemen- tation or anti-VEGF therapy in AMD patients. Dr. Edwin Stone, an expert in ophthalmic genetics, pub- lished a special communication in JAMA Ophthalmolog y in May 2015 in which he wrote that improved out- comes for genotyped AMD patients have not yet been demonstrated in a prospective clinical trial and that the costs and risks of routine genetic testing currently out- weigh the benefits in AMD patients. 45 As noted above, the American Academy of Ophthalmology also recom- mends avoiding routine genetic testing for genetically complex disorders like AMD. 26 AMD is a multifactorial disease with many genetic and environmental risk factors. Over the past decade, much insight has been gained regarding AMD risk variants, but at this time there is no convincing evi- dence that genetic testing is beneficial in the routine management of AMD patients. Data from future large, prospective trials may provide validation for the phar- macogenetics of AMD. At the present time, genetic testing is more useful as a research tool than in clinical management. RP REFERENCES 1. Fritsche LG, Igl W, Bailey JN, et al. A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants. Nat Genet. 2016;48:134-143. 2. Hampton BM, Kovach JL, Schwartz SG. Pharmacogenetics and nutritional supplementation in age-related macular degeneration. Clin Ophthalmol. 2015;9:873-876. 3. Schwartz SG, Hampton BM, Kovach JL, Brantley MA Jr. Genetics and 19 R E T I N A L P H Y S I C I A N . C O M | J A N U A R Y / F E B R U A R Y 2 0 1 7 AMD is a multifactorial disease with many genetic and environmental risk factors. P E E R R E V I E W E D

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