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      Association of Genetic Variants With Response to Anti–Vascular Endothelial Growth Factor Therapy in Age-Related Macular Degeneration

      1 , 2 , 3 , 4 , 1 , 5 , 6 , 7 , 1 , 5 , 1 , 2 , 8 , 9 , 9 , 10 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 12 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 21 , 22 , 23 , 8 , 24 , 2 , 1 , 1 , 9 , 25 , 1 , 5 , 2 , 4

      JAMA Ophthalmology

      American Medical Association (AMA)

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          <div class="section"> <a class="named-anchor" id="ab-eoi180040-1"> <!-- named anchor --> </a> <h5 class="section-title" id="d8640113e901">Question</h5> <p id="d8640113e903">Are genetic variants associated with response to anti–vascular endothelial growth factor treatment in neovascular age-related macular degeneration (nAMD)? </p> </div><div class="section"> <a class="named-anchor" id="ab-eoi180040-2"> <!-- named anchor --> </a> <h5 class="section-title" id="d8640113e906">Findings</h5> <p id="d8640113e908">In this multicenter genome-wide association study including 2058 patients with nAMD, rare protein-altering variants in the <i>C10ORF88</i> and <i>UNC93B1</i> genes were associated with worse visual acuity response to anti–vascular endothelial growth factor therapy. The effect of these rare variants was remarkably large, as patients carrying variants in the <i>C10orf88</i> and <i>UNC93B1</i> genes lost a mean 6 and 5 lines, respectively, on the Early Treatment of Diabetic Retinopathy Study letter chart after treatment. </p> </div><div class="section"> <a class="named-anchor" id="ab-eoi180040-3"> <!-- named anchor --> </a> <h5 class="section-title" id="d8640113e923">Meaning</h5> <p id="d8640113e925">The results of this study may be used to adapt treatment strategies to individual needs in nAMD. </p> </div><p class="first" id="d8640113e928">This multicenter genome-wide association study identifies genetic factors associated with variability in the response to anti–vascular endothelial growth factor therapy for patients with neovascular age-related macular degeneration. </p><div class="section"> <a class="named-anchor" id="ab-eoi180040-4"> <!-- named anchor --> </a> <h5 class="section-title" id="d8640113e932">Importance</h5> <p id="d8640113e934">Visual acuity (VA) outcomes differ considerably among patients with neovascular age-related macular degeneration (nAMD) treated with anti–vascular endothelial growth factor (VEGF) drugs. Identification of pharmacogenetic associations may help clinicians understand the mechanisms underlying this variability as well as pave the way for personalized treatment in nAMD. </p> </div><div class="section"> <a class="named-anchor" id="ab-eoi180040-5"> <!-- named anchor --> </a> <h5 class="section-title" id="d8640113e937">Objective</h5> <p id="d8640113e939">To identify genetic factors associated with variability in the response to anti-VEGF therapy for patients with nAMD. </p> </div><div class="section"> <a class="named-anchor" id="ab-eoi180040-6"> <!-- named anchor --> </a> <h5 class="section-title" id="d8640113e942">Design, Setting, and Participants</h5> <p id="d8640113e944">In this multicenter genome-wide association study, 678 patients with nAMD with genome-wide genotyping data were included in the discovery phase; 1380 additional patients with nAMD were genotyped for selected common variants in the replication phase. All participants received 3 monthly injections of bevacizumab or ranibizumab. Clinical data were evaluated for inclusion/exclusion criteria from October 2014 to October 2015, followed by data analysis from October 2015 to February 2016. For replication cohort genotyping, clinical data collection and analysis (including meta-analysis) was performed from March 2016 to April 2017. </p> </div><div class="section"> <a class="named-anchor" id="ab-eoi180040-7"> <!-- named anchor --> </a> <h5 class="section-title" id="d8640113e947">Main Outcomes and Measures</h5> <p id="d8640113e949">Change in VA after the loading dose of 3 monthly anti-VEGF injections compared with baseline. </p> </div><div class="section"> <a class="named-anchor" id="ab-eoi180040-8"> <!-- named anchor --> </a> <h5 class="section-title" id="d8640113e952">Results</h5> <p id="d8640113e954">Of the 2058 included patients, 1210 (58.8%) were women, and the mean (SD) age across all cohorts was 78 (7.4) years. Patients included in the discovery cohort and most of the patients in the replication cohorts were of European descent. The mean (SD) baseline VA was 51.3 (20.3) Early Treatment Diabetic Retinopathy Study (ETDRS) score letters, and the mean (SD) change in VA after the loading dose of 3 monthly injections was a gain of 5.1 (13.9) ETDRS score letters (ie, 1-line gain). Genome-wide single-variant analyses of common variants revealed 5 independent loci that reached a <i>P</i> value less than 10 × 10 <sup>−5</sup>. After replication and meta-analysis of the lead variants, <a data-untrusted="" href="http://www.ncbi.nlm.nih.gov/snp/12138564" id="d8640113e962" target="xrefwindow">rs12138564</a> located in the <i>CCT3</i> gene remained nominally associated with a better treatment outcome (ETDRS letter gain, 1.7; β, 0.034; SE, 0.008; <i>P</i> = 1.38 × 10 <sup>−5</sup>). Genome-wide gene-based optimal unified sequence kernel association test of rare variants showed genome-wide significant associations for the <i>C10orf88</i> ( <i>P</i> = 4.22 × 10 <sup>−7</sup>) and <i>UNC93B1</i> ( <i>P</i> = 6.09 × 10 <sup>−7</sup>) genes, in both cases leading to a worse treatment outcome. Patients carrying rare variants in the <i>C10orf88</i> and <i>UNC93B1</i> genes lost a mean (SD) VA of 30.6 (17.4) ETDRS score letters (ie, loss of 6.09 lines) and 26.5 (13.8) ETDRS score letters (ie, loss of 5.29 lines), respectively, after 3 months of anti-VEGF treatment. </p> </div><div class="section"> <a class="named-anchor" id="ab-eoi180040-9"> <!-- named anchor --> </a> <h5 class="section-title" id="d8640113e1001">Conclusions and Relevance</h5> <p id="d8640113e1003">We propose that there is a limited contribution of common genetic variants to variability in nAMD treatment response. Our results suggest that rare protein-altering variants in the <i>C10orf88</i> and <i>UNC93B1</i> genes are associated with a worse response to anti-VEGF therapy in patients with nAMD, but these results require further validation in other cohorts. </p> </div>

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          Most cited references 44

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          Ranibizumab and bevacizumab for neovascular age-related macular degeneration.

          Clinical trials have established the efficacy of ranibizumab for the treatment of neovascular age-related macular degeneration (AMD). In addition, bevacizumab is used off-label to treat AMD, despite the absence of similar supporting data. In a multicenter, single-blind, noninferiority trial, we randomly assigned 1208 patients with neovascular AMD to receive intravitreal injections of ranibizumab or bevacizumab on either a monthly schedule or as needed with monthly evaluation. The primary outcome was the mean change in visual acuity at 1 year, with a noninferiority limit of 5 letters on the eye chart. Bevacizumab administered monthly was equivalent to ranibizumab administered monthly, with 8.0 and 8.5 letters gained, respectively. Bevacizumab administered as needed was equivalent to ranibizumab as needed, with 5.9 and 6.8 letters gained, respectively. Ranibizumab as needed was equivalent to monthly ranibizumab, although the comparison between bevacizumab as needed and monthly bevacizumab was inconclusive. The mean decrease in central retinal thickness was greater in the ranibizumab-monthly group (196 μm) than in the other groups (152 to 168 μm, P=0.03 by analysis of variance). Rates of death, myocardial infarction, and stroke were similar for patients receiving either bevacizumab or ranibizumab (P>0.20). The proportion of patients with serious systemic adverse events (primarily hospitalizations) was higher with bevacizumab than with ranibizumab (24.1% vs. 19.0%; risk ratio, 1.29; 95% confidence interval, 1.01 to 1.66), with excess events broadly distributed in disease categories not identified in previous studies as areas of concern. At 1 year, bevacizumab and ranibizumab had equivalent effects on visual acuity when administered according to the same schedule. Ranibizumab given as needed with monthly evaluation had effects on vision that were equivalent to those of ranibizumab administered monthly. Differences in rates of serious adverse events require further study. (Funded by the National Eye Institute; ClinicalTrials.gov number, NCT00593450.).
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            Ranibizumab versus bevacizumab to treat neovascular age-related macular degeneration: one-year findings from the IVAN randomized trial.

            To compare the efficacy and safety of ranibizumab and bevacizumab intravitreal injections to treat neovascular age-related macular degeneration (nAMD). Multicenter, noninferiority factorial trial with equal allocation to groups. The noninferiority limit was 3.5 letters. This trial is registered (ISRCTN92166560). People >50 years of age with untreated nAMD in the study eye who read ≥ 25 letters on the Early Treatment Diabetic Retinopathy Study chart. We randomized participants to 4 groups: ranibizumab or bevacizumab, given either every month (continuous) or as needed (discontinuous), with monthly review. The primary outcome is at 2 years; this paper reports a prespecified interim analysis at 1 year. The primary efficacy and safety outcome measures are distance visual acuity and arteriothrombotic events or heart failure. Other outcome measures are health-related quality of life, contrast sensitivity, near visual acuity, reading index, lesion morphology, serum vascular endothelial growth factor (VEGF) levels, and costs. Between March 27, 2008 and October 15, 2010, we randomized and treated 610 participants. One year after randomization, the comparison between bevacizumab and ranibizumab was inconclusive (bevacizumab minus ranibizumab -1.99 letters, 95% confidence interval [CI], -4.04 to 0.06). Discontinuous treatment was equivalent to continuous treatment (discontinuous minus continuous -0.35 letters; 95% CI, -2.40 to 1.70). Foveal total thickness did not differ by drug, but was 9% less with continuous treatment (geometric mean ratio [GMR], 0.91; 95% CI, 0.86 to 0.97; P = 0.005). Fewer participants receiving bevacizumab had an arteriothrombotic event or heart failure (odds ratio [OR], 0.23; 95% CI, 0.05 to 1.07; P = 0.03). There was no difference between drugs in the proportion experiencing a serious systemic adverse event (OR, 1.35; 95% CI, 0.80 to 2.27; P = 0.25). Serum VEGF was lower with bevacizumab (GMR, 0.47; 95% CI, 0.41 to 0.54; P<0.0001) and higher with discontinuous treatment (GMR, 1.23; 95% CI, 1.07 to 1.42; P = 0.004). Continuous and discontinuous treatment costs were £9656 and £6398 per patient per year for ranibizumab and £1654 and £1509 for bevacizumab; bevacizumab was less costly for both treatment regimens (P<0.0001). The comparison of visual acuity at 1 year between bevacizumab and ranibizumab was inconclusive. Visual acuities with continuous and discontinuous treatment were equivalent. Other outcomes are consistent with the drugs and treatment regimens having similar efficacy and safety. Proprietary or commercial disclosures may be found after the references. Copyright © 2012 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.
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              UNC93B1 delivers nucleotide-sensing toll-like receptors to endolysosomes.

              Signalling by means of toll-like receptors (TLRs) is essential for the development of innate and adaptive immune responses. UNC93B1, essential for signalling of TLR3, TLR7 and TLR9 in both humans and mice, physically interacts with these TLRs in the endoplasmic reticulum (ER). Here we show that the function of the polytopic membrane protein UNC93B1 is to deliver the nucleotide-sensing receptors TLR7 and TLR9 from the ER to endolysosomes. In dendritic cells of 3d mice, which express an UNC93B1 missense mutant (H412R) incapable of TLR binding, neither TLR7 nor TLR9 exits the ER. Furthermore, the trafficking and signalling defects of the nucleotide-sensing TLRs in 3d dendritic cells are corrected by expression of wild-type UNC93B1. However, UNC93B1 is dispensable for ligand recognition and signal initiation by TLRs. To our knowledge, UNC93B1 is the first protein to be identified as a molecule specifically involved in trafficking of nucleotide-sensing TLRs. By inhibiting the interaction between UNC93B1 and TLRs it should be possible to achieve specific regulation of the nucleotide-sensing TLRs without compromising signalling via the cell-surface-disposed TLRs.

                Author and article information

                JAMA Ophthalmology
                JAMA Ophthalmol
                American Medical Association (AMA)
                August 01 2018
                August 01 2018
                : 136
                : 8
                : 875
                [1 ]Department of Ophthalmology, Donders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands
                [2 ]Centre for Eye Research Australia, Department of Surgery in Ophthalmology, University of Melbourne, Royal Victorian Eye and Ear Hospital, East Melbourne, Victoria, Australia
                [3 ]Public Health Genomics, School of Public Health and Preventive Medicine, Monash University, Melbourne, Victoria, Australia
                [4 ]Department of Ophthalmology, Hebrew University Hadassah Medical School, Hadassah Medical Center–Hebrew University, Jerusalem, Israel
                [5 ]Department of Human Genetics, Donders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands
                [6 ]Division of Epidemiology and Clinical Application, National Eye Institute, National Institutes of Health, Bethesda, Maryland
                [7 ]Neurobiology, Neurodegeneration, and Repair Laboratory, National Eye Institute, National Institutes of Health, Bethesda, Maryland
                [8 ]Department of Ophthalmology, University Hospital of Cologne, Cologne, Germany
                [9 ]Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, England
                [10 ]Department Ophthalmology, McGill University Health Centre, Montreal, Québec, Canada
                [11 ]Department of Ophthalmology, Erasmus Medical Center, Rotterdam, the Netherlands
                [12 ]Section of Ophthalmology and Neuroscience, Leeds Institute of Molecular Medicine, University of Leeds, Leeds, England
                [13 ]Department of Genetic Epidemiology, University of Regensburg, Regensburg, Germany
                [14 ]Norwegian University of Science and Technology, Trondheim, Norway
                [15 ]Queen’s University Belfast, Belfast, Northern Ireland
                [16 ]The York Hospital, York, England
                [17 ]Eye Clinic, St James’s University Hospital, Leeds, England
                [18 ]Department of Ophthalmology, Ocular Angiogenesis Group, Academic Medical Center, Amsterdam, the Netherlands
                [19 ]Netherlands Institute for Neuroscience, Amsterdam, the Netherlands
                [20 ]Montreal Retina Institute, Westmount, Québec, Canada
                [21 ]Department of Pediatric Surgery, McGill University Health Centre, Montreal, Québec, Canada
                [22 ]Department of Human Genetics, McGill University Health Centre, Montreal, Québec, Canada
                [23 ]Department of Ophthalmology, McGill University Health Centre, Montreal, Québec, Canada
                [24 ]Roche Pharma Research and Early Development, Hoffmann–La Roche, Basel, Switzerland
                [25 ]Centre for Vision Research, Department of Ophthalmology and Westmead Millennium Institute for Medical Research, University of Sydney, Sydney, New South Wales, Australia
                © 2018


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