Laura Lorés-Motta1, Moeen Riaz2,3, Michelle Grunin4, Jordi Corominas1,5, Freekje van Asten6,7, Marc Pauper1,5, Mathieu Leenders1, Andrea J Richardson2, Philipp Muether8, Angela J Cree9, Helen L Griffiths9, Connie Pham10, Marie-Claude Belanger10, Magda A Meester-Smoor11, Manir Ali12, Iris M Heid13, Lars G Fritsche14, Usha Chakravarthy15, Richard Gale16, Martin McKibbin17, Chris F Inglehearn12,17, Reinier O Schlingemann18,19, Amer Omar20, John Chen21,22,23, Robert K Koenekoop21,22,23, Sascha Fauser8,24, Robyn H Guymer2, Carel B Hoyng1, Eiko K de Jong1, Andrew J Lotery9, Paul Mitchell25, Anneke I den Hollander1,5, Paul N Baird2, Itay Chowers4. 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.
Abstract
Importance: 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. Objective: To identify genetic factors associated with variability in the response to anti-VEGF therapy for patients with nAMD. Design, Setting, and Participants: 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. Main Outcomes and Measures: Change in VA after the loading dose of 3 monthly anti-VEGF injections compared with baseline. Results: 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 P value less than 10 × 10-5. After replication and meta-analysis of the lead variants, rs12138564 located in the CCT3 gene remained nominally associated with a better treatment outcome (ETDRS letter gain, 1.7; β, 0.034; SE, 0.008; P = 1.38 × 10-5). Genome-wide gene-based optimal unified sequence kernel association test of rare variants showed genome-wide significant associations for the C10orf88 (P = 4.22 × 10-7) and UNC93B1 (P = 6.09 × 10-7) genes, in both cases leading to a worse treatment outcome. Patients carrying rare variants in the C10orf88 and UNC93B1 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. Conclusions and Relevance: 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 C10orf88 and UNC93B1 genes are associated with a worse response to anti-VEGF therapy in patients with nAMD, but these results require further validation in other cohorts.
Importance: 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. Objective: To identify genetic factors associated with variability in the response to anti-VEGF therapy for patients with nAMD. Design, Setting, and Participants: 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. Main Outcomes and Measures: Change in VA after the loading dose of 3 monthly anti-VEGF injections compared with baseline. Results: 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 P value less than 10 × 10-5. After replication and meta-analysis of the lead variants, rs12138564 located in the CCT3 gene remained nominally associated with a better treatment outcome (ETDRS letter gain, 1.7; β, 0.034; SE, 0.008; P = 1.38 × 10-5). Genome-wide gene-based optimal unified sequence kernel association test of rare variants showed genome-wide significant associations for the C10orf88 (P = 4.22 × 10-7) and UNC93B1 (P = 6.09 × 10-7) genes, in both cases leading to a worse treatment outcome. Patients carrying rare variants in the C10orf88 and UNC93B1 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. Conclusions and Relevance: 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 C10orf88 and UNC93B1 genes are associated with a worse response to anti-VEGF therapy in patients with nAMD, but these results require further validation in other cohorts.
Authors: Frank G Holz; Ramin Tadayoni; Stephen Beatty; Alan R Berger; Matteo G Cereda; Philip Hykin; Carel B Hoyng; Kim Wittrup-Jensen; Andreas Altemark; Jonas Nilsson; Kun Kim; Sobha Sivaprasad Journal: Ophthalmic Res Date: 2016-11-11 Impact factor: 2.892
Authors: Stephanie A Hagstrom; Gui-Shuang Ying; Gayle J T Pauer; Jiayan Huang; Maureen G Maguire; Daniel F Martin Journal: Ophthalmology Date: 2014-05-09 Impact factor: 12.079
Authors: Stephanie A Hagstrom; Gui-Shuang Ying; Gayle J T Pauer; Gwen M Sturgill-Short; Jiayan Huang; David G Callanan; Ivana K Kim; Michael L Klein; Maureen G Maguire; Daniel F Martin Journal: Ophthalmology Date: 2013-01-18 Impact factor: 12.079
Authors: Anjali R Shah; Steven Williams; Caroline R Baumal; Bernard Rosner; Jay S Duker; Johanna M Seddon Journal: Am J Ophthalmol Date: 2015-12-15 Impact factor: 5.258
Authors: Usha Chakravarthy; Simon P Harding; Chris A Rogers; Susan M Downes; Andrew J Lotery; Sarah Wordsworth; Barnaby C Reeves Journal: Ophthalmology Date: 2012-05-11 Impact factor: 12.079
Authors: Tobias Strunz; Michael Pöllmann; Maria-Andreea Gamulescu; Svenja Tamm; Bernhard H F Weber Journal: Int J Mol Sci Date: 2022-05-29 Impact factor: 6.208
Authors: Jussi J Paterno; Ali Koskela; Juha M T Hyttinen; Elina Vattulainen; Ewelina Synowiec; Raimo Tuuminen; Cezary Watala; Janusz Blasiak; Kai Kaarniranta Journal: Genes (Basel) Date: 2020-11-06 Impact factor: 4.096