Genetic biomarkers in the VEGF pathway predicting response to anti-VEGF therapy in age-related macular degeneration.
degeneration
genetics
macula
retina
treatment medical
Journal
BMJ open ophthalmology
ISSN: 2397-3269
Titre abrégé: BMJ Open Ophthalmol
Pays: England
ID NLM: 101714806
Informations de publication
Date de publication:
2019
2019
Historique:
received:
14
01
2019
revised:
18
10
2019
accepted:
11
11
2019
entrez:
8
1
2020
pubmed:
8
1
2020
medline:
8
1
2020
Statut:
epublish
Résumé
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. 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. 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. 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.
Identifiants
pubmed: 31909188
doi: 10.1136/bmjophth-2019-000273
pii: bmjophth-2019-000273
pmc: PMC6936450
doi:
Types de publication
Journal Article
Langues
eng
Pagination
e000273Investigateurs
Kenji Yamashiro
(K)
Keisuke Mori
(K)
Shigeru Honda
(S)
Mariko Kano
(M)
Yasuo Yanagi
(Y)
Akira Obana
(A)
Yoichi Sakurada
(Y)
Taku Sato
(T)
Yoshimi Nagai
(Y)
Taiichi Hikichi
(T)
Yasushi Kataoka
(Y)
Chikako Hara
(C)
Yasurou Koyama
(Y)
Hideki Koizumi
(H)
Munemitsu Yoshikawa
(M)
Masahiro Miyake
(M)
Isao Nakata
(I)
Takashi Tsuchihashi
(T)
Kuniko Horie-Inoue
(K)
Wataru Matsumiya
(W)
Masashi Ogasawara
(M)
Ryo Obata
(R)
Seigo Yoneyama
(S)
Hidetaka Matsumoto
(H)
Masayuki Ohnaka
(M)
Hirokuni Kitamei
(H)
Kaori Sayanagi
(K)
Sotaro Ooto
(S)
Hiroshi Tamura
(H)
Akio Oishi
(A)
Sho Kabasawa
(S)
Kazuhiro Ueyama
(K)
Akiko Miki
(A)
Naoshi Kondo
(N)
Hiroaki Bessho
(H)
Saito Masaaki
(S)
Hidenori Takahashi
(H)
Xue Tan
(X)
Keiko Azuma
(K)
Wataru Kikushima
(W)
Ryo Mukai
(R)
Akihiro Ohira
(A)
Fumi Gomi
(F)
Kazunori Miyata
(K)
Kanji Takahashi
(K)
Shoji Kishi
(S)
Hiroyuki Iijima
(H)
Tetsuju Sekiryu
(T)
Tomohiro Iida
(T)
Takuya Awata
(T)
Satoshi Inoue
(S)
Ryo Yamada
(R)
Fumihiko Matsuda
(F)
Akitaka Tsujikawa
(A)
Akira Negi
(A)
Shin Yoneya
(S)
Takeshi Iwata
(T)
Nagahisa Yoshimura
(N)
Informations de copyright
© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.
Déclaration de conflit d'intérêts
Competing interests: None declared.
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