Lores-Motta, Laura ORCID: 0000-0002-2423-9126, Riaz, Moeen, Grunin, Michelle ORCID: 0000-0002-3155-2858, Corominas, Jordi, van Asten, Freekje, Pauper, Marc ORCID: 0000-0001-6274-9891, Leenders, Mathieu, Richardson, Andrea J., Muether, Philipp, Cree, Angela J., Griffiths, Helen L., Pham, Connie, Belanger, Marie-Claude, Meester-Smoor, Magda A., Ali, Manir, Heid, Iris M., Fritsche, Lars G., Chakravarthy, Usha, Gale, Richard, McKibbin, Martin, Inglehearn, Chris F., Schlingemann, Reinier O., Omar, Amer ORCID: 0000-0003-1520-392X, Chen, John, Koenekoop, Robert K., Fauser, Sascha, Guymer, Robyn H., Hoyng, Carel B., de Jong, Eiko K., Lotery, Andrew J., Mitchell, Paul, den Hollander, Anneke I., Baird, Paul N. and Chowers, Itay (2018). Association of Genetic Variants With Response to Anti-Vascular Endothelial Growth Factor Therapy in Age-Related Macular Degeneration. JAMA Ophthalmol., 136 (8). S. 875 - 885. CHICAGO: AMER MEDICAL ASSOC. ISSN 2168-6173

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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 underlyingthis 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 x 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; beta, 0.034; SE, 0.008; P = 1.38 x 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 x 10(-7)) and UNC9.381(P = 6.09 x 10(-7)) genes, in both cases leading to a worse treatment outcome. Patients carrying rare variants in the C10orf88 and UNC93B1genes 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 UNC93B1genes are associated with a worse response to anti VEGF therapy in patients with nAMD, but these results require further validation in other cohorts.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Lores-Motta, LauraUNSPECIFIEDorcid.org/0000-0002-2423-9126UNSPECIFIED
Riaz, MoeenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Grunin, MichelleUNSPECIFIEDorcid.org/0000-0002-3155-2858UNSPECIFIED
Corominas, JordiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
van Asten, FreekjeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pauper, MarcUNSPECIFIEDorcid.org/0000-0001-6274-9891UNSPECIFIED
Leenders, MathieuUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Richardson, Andrea J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Muether, PhilippUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Cree, Angela J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Griffiths, Helen L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pham, ConnieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Belanger, Marie-ClaudeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Meester-Smoor, Magda A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ali, ManirUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Heid, Iris M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fritsche, Lars G.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Chakravarthy, UshaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gale, RichardUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
McKibbin, MartinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Inglehearn, Chris F.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schlingemann, Reinier O.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Omar, AmerUNSPECIFIEDorcid.org/0000-0003-1520-392XUNSPECIFIED
Chen, JohnUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Koenekoop, Robert K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fauser, SaschaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Guymer, Robyn H.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hoyng, Carel B.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
de Jong, Eiko K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lotery, Andrew J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mitchell, PaulUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
den Hollander, Anneke I.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Baird, Paul N.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Chowers, ItayUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-178447
DOI: 10.1001/jamaophthalmol.2018.2019
Journal or Publication Title: JAMA Ophthalmol.
Volume: 136
Number: 8
Page Range: S. 875 - 885
Date: 2018
Publisher: AMER MEDICAL ASSOC
Place of Publication: CHICAGO
ISSN: 2168-6173
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
GENOME-WIDE ASSOCIATION; INTRAVITREAL RANIBIZUMAB TREATMENT; TOLL-LIKE RECEPTORS; SUBGROUP ANALYSIS; NEOVASCULAR AMD; POLYMORPHISMS; VEGF; BEVACIZUMAB; PREDICTORS; RAREMultiple languages
OphthalmologyMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/17844

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