• Genetic Variants Linked to Poor AMD Treatment Outcomes

    By Lynda Seminara
    Selected By: Neil M. Bressler, MD, and Deputy Editors

    Journal Highlights

    JAMA Ophthalmology, August 2018

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    Currently, the most effective treatment for neovascular age-related macular degeneration (AMD) is intravitreal injection of anti−vascular endothelial growth factor (VEGF) drugs. How­ever, visual results vary considerably. Lorés-Motta et al. conducted a mul­ticenter genome-wide study aimed at identifying genetic factors associated with this variability. They found that the poorest visual acuity (VA) out­comes correlated with protein-altering variants in the C10orf88 and UNC93B1 genes.

    Their study included 678 patients with wet AMD for whom genome-wide genotyping data were gathered in the discovery phase. In addition, genotyp­ing was performed in the replication phase for another 1,380 patients with the disease. All participants received a loading dose of bevacizumab or ranibi­zumab, consisting of 3 injections given monthly. The primary outcome was the change in VA from baseline to comple­tion of therapy.

    The mean age of the entire study population was 78 years. All patients in the discovery cohort and most of those in the replication cohort were of European descent.

    At baseline, the mean (standard deviation) VA score was 51.3 (20.3) letters according to the Early Treatment Diabetic Retinopathy Study (ETDRS) system. After the third injection, the mean gain in VA was 5.1 (13.9) ETDRS letters, denoting improvement of 1 full line.

    Genome-wide analyses of common single variants showed that 5 inde­pendent loci were associated with a p value below 10 × 10−5. After replication and meta-analysis of the lead variants, rs12138564 in the CCT3 gene was nominally associated with a better VA outcome (letter gain of 1.7). The gene-based optimal unified sequence kernel association test of rare variants showed genome-wide significant associations for the C10orf88 and UNC93B1, both of which led to poorer outcomes. Patients with a rare variant in C10orf88 or UNC93B1 lost a mean of 30.6 letters (6.09 lines) or 26.5 letters (5.29 lines), respectively.

    Although the findings suggest that rare protein-altering genetic variants may signal a poor visual response to anti-VEGF therapy in patients with neovascular AMD, further investi­gations are warranted. Information gleaned from this study and similar research may help to personalize man­agement.

    The original article can be found here.