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Genetic biomarkers in the VEGF pathway predicting response to anti-VEGF therapy in age-related macular degeneration
  1. Irina Balikova1,2,
  2. Laurence Postelmans2,
  3. Brigitte Pasteels2,
  4. Pascale Coquelet2,
  5. Janet Catherine2,
  6. Azra Efendic2,
  7. Yoshikatsu Hosoda3,
  8. Masahiro Miyake3,
  9. Kenji Yamashiro3,4,
  10. ANGEL study group members,
  11. Bernard Thienpont5,6,
  12. Diether Lambrechts5,7
    1. 1Department of Ophthalmology, Ghent University Hospital, Ghent University, Ghent, Belgium
    2. 2Ophthalmology, University Hospital Brugmann, Université Libre de Bruxelles, Brussels, Belgium
    3. 3Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Kyoto, Japan
    4. 4Department of Ophthalmology, Otsu Red Cross Hospital, Otsu, Japan
    5. 5Laboratory of Translational Genetics, Department of Human Genetics, KU Leuven, Leuven, Belgium
    6. 6Laboratory of Functional Epigenetics, Department of Human Genetics, KU Leuven, Leuven, Belgium
    7. 7VIB Center for Cancer Biology, Leuven, Belgium
    1. Correspondence to Dr Irina Balikova; Irina.Balikova{at}uzleuven.be

    Abstract

    Objective Age-related macular degeneration (ARMD) is a leading cause of visual impairment. Intravitreal injections of anti-vascular endothelial growth factor (VEGF) are the standard treatment for wet ARMD. There is however, variability in patient responses, suggesting patient-specific factors influencing drug efficacy. We tested whether single nucleotide polymorphisms (SNPs) in genes encoding VEGF pathway members contribute to therapy response.

    Methods and analysis A retrospective cohort of 281 European wet ARMD patients treated with anti-VEGF was genotyped for 138 tagging SNPs in the VEGF pathway. Per patient, we collected best corrected visual acuity at baseline, after three loading injections and at 12 months. We also registered the injection number and changes in retinal morphology after three loading injections (central foveal thickness (CFT), intraretinal cysts and serous neuroepithelium detachment). Changes in CFT after 3 months were our primary outcome measure. Association of SNPs to response was assessed by binomial logistic regression. Replication was attempted by associating visual acuity changes to genotypes in an independent Japanese cohort.

    Results Association with treatment response was detected for seven SNPs, including in FLT4 (rs55667289: OR=0.746, 95% CI 0.63 to 0.88, p=0.0005) and KDR (rs7691507: OR=1.056, 95% CI 1.02 to 1.10, p=0.005; and rs2305945: OR=0.963, 95% CI 0.93 to 1.00, p=0.0472). Only association with rs55667289 in FLT4 survived multiple testing correction. This SNP was unavailable for testing in the replication cohort. Of six SNPs tested for replication, one was significant although not after multiple testing correction.

    Conclusion Identifying genetic variants that define treatment response can help to develop individualised therapeutic approaches for wet ARMD patients and may point towards new targets in non-responders.

    • degeneration
    • genetics
    • macula
    • retina
    • treatment medical

    This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

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    Footnotes

    • Collaborators Kenji Yamashiro; Keisuke Mori; Shigeru Honda; Mariko Kano; Yasuo Yanagi; Akira Obana; Yoichi Sakurada; Taku Sato; Yoshimi Nagai; Taiichi Hikichi; Yasushi Kataoka; Chikako Hara; Yasurou Koyama; Hideki Koizumi; Munemitsu Yoshikawa; Masahiro Miyake; Isao Nakata; Takashi Tsuchihashi; Kuniko Horie-Inoue; Wataru Matsumiya; Masashi Ogasawara; Ryo Obata; Seigo Yoneyama; Hidetaka Matsumoto; Masayuki Ohnaka; Hirokuni Kitamei; Kaori Sayanagi; Sotaro Ooto; Hiroshi Tamura; Akio Oishi; Sho Kabasawa; Kazuhiro Ueyama; Akiko Miki; Naoshi Kondo; Hiroaki Bessho; Masaaki, Saito; Hidenori Takahashi; Xue Tan; Keiko Azuma; Wataru Kikushima; Ryo Mukai; Akihiro Ohira; Fumi Gomi; Kazunori Miyata; Kanji Takahashi; Shoji Kishi; Hiroyuki Iijima; Tetsuju Sekiryu; Tomohiro Iida; Takuya Awata; Satoshi Inoue; Ryo Yamada; Fumihiko Matsuda; Akitaka Tsujikawa; Akira Negi; Shin Yoneya; Takeshi Iwata; Nagahisa Yoshimura.

    • Contributors IB: design of the study, conducted the study, writing manuscript, submission, overall content of the study; LP: clinical work, design of the study, writing of the manuscript; JC and PC: clinical work; AE: collected data; YH, MM, KY and Angel group: Japanese cohort; BT: conducted the study, analysis, writing manuscript, DL: design of the study, funding, writing manuscript.

    • Funding The study was funded by Brugmann Foundation grant.

    • Competing interests None declared.

    • Patient consent for publication Obtained.

    • Ethics approval This study was approved by the local ethics Committee (Le Comité d'Ethique du CHU Brugmann), under approval number CE2013/53.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Data availability statement Data are available upon request

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