Universität zu Köln

Smailhodzic, Dzenita, Muether, Philipp S., Chen, John, Kwestro, Angela, Zhang, Alice Yang ORCID: 0000-0001-5194-5256, Omar, Amer ORCID: 0000-0003-1520-392X, Van de Ven, Johannes P. H., Keunen, Jan E. E., Kirchhof, Bernd, Hoyng, Carel B., Klevering, B. Jeroen, Koenekoop, Robert K., Fauser, Sascha and den Hollander, Anneke I. (2012). Cumulative Effect of Risk Alleles in CFH, ARMS2, and VEGFA on the Response to Ranibizumab Treatment in Age-related Macular Degeneration. Ophthalmology, 119 (11). S. 2304 - 2312. NEW YORK: ELSEVIER SCIENCE INC. ISSN 1549-4713

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Abstract

Purpose: Intravitreal ranibizumab injections currently are the standard treatment for neovascular age-related macular degeneration (AMD). However, a broad range of response rates have been observed, the reasons for which are poorly understood. This pharmacogenetic study evaluated the impact of high-risk alleles in CFH, ARMS2, VEGFA, vascular endothelial growth factor (VEGF) receptor KDR, and genes involved in angiogenesis (LRP5, FZD4) on the response to ranibizumab treatment and on the age of treatment onset. In contrast to previous studies, the data were stratified according to the number of high-risk alleles to enable the study of the combined effects of these genotypes on the treatment response. Design: Case series study. Participants: A cohort of 420 eyes of 397 neovascular AMD patients. Methods: The change in visual acuity (VA) between baseline and after 3 ranibizumab injections was calculated. Genotyping of single nucleotide polymorphisms in the CFH, ARMS2, VEGFA, KDR, LPR5, and FZD4 genes was performed. Associations were assessed using linear mixed models. Main Outcome Measures: The VA change after 3 ranibizumab injections and the age of neovascular disease onset. Results: After ranibizumab treatment, AMD patients without risk alleles in the CFH and ARMS2 genes (4.8%) demonstrated a mean VA improvement of 10 Early Treatment Diabetic Retinopathy Study (ETDRS) letters, whereas no VA improvement was observed in AMD patients with 4 CFH and ARMS2 risk alleles (6.9%; P = 0.014). Patients with 4 high-risk alleles in CFH and ARMS2 were 5.2 years younger than patients with 1 or 2 risk alleles, respectively (63.5%; P<0.0001). The mean age at which the first ranibizumab treatment was carried out among AMD patients with all 6 risk alleles in CFH, ARMS2, and VEGFA was 65.9 years (2%) versus 75.3 years in patients with 0 or 1 high-risk allele (8.8%; P = 0.001). After ranibizumab treatment, patients with 6 high-risk alleles demonstrated a mean VA loss of 10 ETDRS letters (P<0.0001). Conclusions: This study evaluated the largest pharmacogenetic AMD cohort reported to date. A cumulative effect of high-risk alleles in CFH, ARMS2, and VEGFA seems to be associated with a younger age of onset in combination with poor response rates to ranibizumab treatment. Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article. Ophthalmology 2012;119:2304-2311 (C) 2012 by the American Academy of Ophthalmology.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Smailhodzic, Dzenita UNSPECIFIED UNSPECIFIED UNSPECIFIED Muether, Philipp S. UNSPECIFIED UNSPECIFIED UNSPECIFIED Chen, John UNSPECIFIED UNSPECIFIED UNSPECIFIED Kwestro, Angela UNSPECIFIED UNSPECIFIED UNSPECIFIED Zhang, Alice Yang UNSPECIFIED orcid.org/0000-0001-5194-5256 UNSPECIFIED Omar, Amer UNSPECIFIED orcid.org/0000-0003-1520-392X UNSPECIFIED Van de Ven, Johannes P. H. UNSPECIFIED UNSPECIFIED UNSPECIFIED Keunen, Jan E. E. UNSPECIFIED UNSPECIFIED UNSPECIFIED Kirchhof, Bernd UNSPECIFIED UNSPECIFIED UNSPECIFIED Hoyng, Carel B. UNSPECIFIED UNSPECIFIED UNSPECIFIED Klevering, B. Jeroen UNSPECIFIED UNSPECIFIED UNSPECIFIED Koenekoop, Robert K. UNSPECIFIED UNSPECIFIED UNSPECIFIED Fauser, Sascha UNSPECIFIED UNSPECIFIED UNSPECIFIED den Hollander, Anneke I. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-480654
DOI:	10.1016/j.ophtha.2012.05.040
Journal or Publication Title:	Ophthalmology
Volume:	119
Number:	11
Page Range:	S. 2304 - 2312
Date:	2012
Publisher:	ELSEVIER SCIENCE INC
Place of Publication:	NEW YORK
ISSN:	1549-4713
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language ENDOTHELIAL GROWTH-FACTOR; COMPLEMENT FACTOR-H; CHOROIDAL NEOVASCULAR MEMBRANES; INTRAVITREAL RANIBIZUMAB; MACULOPATHY; ASSOCIATION; POLYMORPHISM; THERAPY; PHARMACOGENETICS; BEVACIZUMAB Multiple languages Ophthalmology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/48065