Retinal Physician

JAN-FEB 2017

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18 R E T I N A L P H Y S I C I A N . C O M | M A Y 2 0 1 3 18 R E T I N A L P H Y S I C I A N | J A N U A R Y / F E B R U A R Y 2 0 1 7 created a task force on genetic testing and published recommendations in 2012, 26 which were updated in 2014. These recommendations support offering genetic testing to patients suspected of having a monogenic (Mendelian) disease and providing such patients with genetic counseling (or referring to a genetic counselor). The task force recommended avoiding direct-to-con- sumer genetic testing and avoiding routine testing of complex genetic diseases such as AMD. A M D PHAR M ACOGENETICS AMD is most commonly managed with pharmacother- apies. Patients with neovascular AMD are generally treated with anti-VEGF agents, including ranibi- zumab (Lucentis, Genentech, South San Francisco, CA), aflibercept (Eylea, Regeneron, Tarrytown, NY ), and bevacizumab (Avastin, Genentech). 27 Additionally, patients with at least intermediate AMD are typi- cally offered nutritional supplementation based on the results of the Age-Related Eye Disease study (AREDS) 28 and AREDS 2 29 trials. Small series have reported statistically significant associations between treatment responses to various anti-VEGF agents and variants in CFH, ARMS2, and other genes. 30 To date, these findings have not been validated, and major randomized clinical trials have not reported any statistically significant associations. The Comparison of AMD Treatments trials (CATT) compared patients with neovascular AMD treated with bevacizumab or ranibizumab and reported no significant association between various anatomic and visual outcomes and variants in CFH, ARMS2, HTRA1, and complement factor 3 (C3); 31 endothe- lial PAS domain-containing protein 1 (EPAS1); 32 and VEGF-A and VEGF receptor 2. 33 Additionally, the Inhibit VEGF in Patients with Age-Related Choroidal Neovascularization (IVAN) study compared patients with neovascular AMD treated with bevacizumab or ranibizumab; it reported no significant association between central retinal thickness on optical coherence tomography and variants in CFH, HTRA1/ARMS2, EPAS1, and frizzled class receptor 4 (FZD4). 34 Using pooled data from CATT and IVAN, the researchers found no significant association between mean change in visual acuity and VEGF receptor 2. 35 Hong et al performed a systematic review and meta-analysis for investigation of the association of the polymorphism Y402H in the CFH gene with response to anti-VEGF treatment in AMD and concluded that Y402H might be a genetic predictor of treatment response to anti- VEGF therapy in AMD patients. 36 Greater controversy exists regarding the poten- tial pharmacogenetic relationship between AREDS nutritional supplementation and the risk of progres- sion to advanced AMD (including neovascular AMD and central GA). 37 AREDS categorized patients using a one to four scale in which categories one and two had mild disease; category three had at least one large (≥125 µm) druse, extensive intermediate (63-124 µm) drusen, and/or noncentral GA; and category four had central GA, neovascular AMD, and/or best corrected visual acuity less than 20/32 resulting from AMD in one eye. AREDS randomized patients to receive one of four treatments: antioxidants alone (beta-carotene, vitamin C, and vitamin E), zinc alone (zinc plus cop- per), antioxidants plus zinc, and neither (placebo). In patients with category three or four AMD, treat- ment with antioxidants plus zinc — which eventually became the AREDS formulation — was associated with an approximate 25% decrease in disease progres- sion rates at 5 years. The AREDS Investigative Group collected genetic information from some participants, but did not incorporate this information into their reported findings. 28 A retrospective subgroup analysis of 876 patients with category three or four disease from the AREDS trial compared outcomes of patients stratified by gen- otype at CFH and ARMS2. The investigators reported that all patients in this subgroup benefited from AREDS supplementation, but patients with no risk alleles at CFH experienced significantly more favor- able outcomes than did patients with two risk alleles at CFH. There was no association with ARMS2. Despite the statistically significant association with CFH, the investigators did not recommend a change in treat- ment (because all patients experienced some benefit) and called for additional studies to corroborate the Figure 3. Fundus photo of the right macula demonstrates a choroidal neovascular membrane secondary to wet AMD. P E E R R E V I E W E D

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