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Sci Rep. 2017 Aug 23;7(1):9196. doi: 10.1038/s41598-017-09632-0.

A prospective multicenter study on genome wide associations to ranibizumab treatment outcome for age-related macular degeneration.

Author information

1
Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Sakyo, Kyoto, 606-8507, Japan. yamashro@kuhp.kyoto-u.ac.jp.
2
Department of Ophthalmology, Otsu Red Cross Hospital, Otsu, Shiga, 520-8511, Japan. yamashro@kuhp.kyoto-u.ac.jp.
3
Department of Ophthalmology, Saitama Medical University, Iruma, Saitama, 350-0495, Japan.
4
Department of Ophthalmology, International University of Health and Welfare, Nasu-Shiobara, Tochigi, 329-2763, Japan.
5
Department of Surgery, Division of Ophthalmology, Kobe University Graduate School of Medicine, Chuo, Kobe, 650-0017, Japan.
6
Department of Ophthalmology, Fukushima Medical University School of Medicine, Fukushima, 960-1247, Japan.
7
Department of Ophthalmology, Tokyo Women's Medical University, Yachiyo Medical Center, Chiba, 276-0046, Japan.
8
Department of Ophthalmology, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo, Tokyo, 113-0033, Japan.
9
Ophthalmology and Visual Sciences Program, Duke-NUS Medical School, National University of Singapore, Singapore, 119077, Singapore.
10
Singapore National Eye Centre, Singapore Eye Research Institute, Singapore, 168751, Singapore.
11
Department of Ophthalmology, Seirei Hamamatsu General Hospital, Shizuoka, 430-8558, Japan.
12
Department of Ophthalmology, Faculty of Medicine, University of Yamanashi, Chuo, Yamanashi, 409-3898, Japan.
13
Department of Ophthalmology, Gunma University School of Medicine, Gunma, 371-0034, Japan.
14
Takasaki Sato Eye Clinic, Gunma, 370-0036, Japan.
15
Department of Ophthalmology, Kansai Medical University, Osaka, 573-1191, Japan.
16
Ohtsuka Eye Hospital, Sapporo, 001-0016, Japan.
17
Hikichi Eye Clinic, Sapporo, 060-0807, Japan.
18
Miyata Ophthalmic Hospital, Miyazaki, 885-0051, Japan.
19
Department of Ophthalmology, Osaka University Graduate School of Medicine, Osaka, 565-0871, Japan.
20
Department of Ophthalmology, Shimane University Faculty of Medicine, Shimane, 693-0021, Japan.
21
Department of Ophthalmology, Tokyo Women's Medical University, School of Medicine, Tokyo, 162-8666, Japan.
22
Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Sakyo, Kyoto, 606-8507, Japan.
23
Department of Ophthalmology, Otsu Red Cross Hospital, Otsu, Shiga, 520-8511, Japan.
24
Division of Gene Regulation and Signal Transduction, Research Center for Genomic Medicine, Saitama Medical University, Hidaka, Saitama, 350-1241, Japan.
25
Department of Ophthalmology and Visual Sciences, Akita University Graduate School of Medicine, Akita, 010-8543, Japan.
26
Department of Ophthalmology, Jichi Medical University, Tochigi, 329-0498, Japan.
27
Department of Ophthalmology, Hyogo College of Medicine, Hyogo, 663-8501, Japan.
28
Maebashi Central Eye Clinic, Gunma, 371-0031, Japan.
29
Department of Diabetes, Endocrinology and Metabolism, International University of Health and Welfare Hospital, 537-3 Iguchi, Nasu-Shiobara, Tochigi, 329-2763, Japan.
30
Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto, 606-8507, Japan.
31
Department of Ophthalmology, Kagawa University Faculty of Medicine, Miki, Kagawa, 761-0793, Japan.
32
Division of Molecular and Cellular Biology, National Institute of Sensory Organs, National Hospital Organization Tokyo Medical Center, Tokyo, 152-8902, Japan.

Abstract

We conducted a genome-wide association study (GWAS) on the outcome of anti-VEGF treatment for exudative age-related macular degeneration (AMD) in a prospective cohort. Four hundred and sixty-one treatment-naïve AMD patients were recruited at 13 clinical centers and all patients were treated with 3 monthly injections of ranibizumab followed by pro re nata regimen treatment for one year. Genomic DNA was collected from all patients for a 2-stage GWAS on achieving dry macula after the initial treatment, the requirement for an additional treatment, and visual acuity changes during the 12-month observation period. In addition, we evaluated 9 single-nucleotide polymorphisms (SNPs) in 8 previously reported AMD-related genes for their associations with treatment outcome. The discovery stage with 256 patients evaluated 8,480,849 SNPs, but no SNPs showed genome-wide level significance in association with treatment outcomes. Although SNPs with P-values of <5 × 10-6 were evaluated in replication samples of 205 patients, no SNP was significantly associated with treatment outcomes. Among AMD-susceptibility genes, rs10490924 in ARMS2/HTRA1 was significantly associated with additional treatment requirement in the discovery stage (P = 0.0023), and pooled analysis with the replication stage further confirmed this association (P = 0.0013). ARMS2/HTRA1 polymorphism might be able to predict the frequency of injection after initial ranibizumab treatment.

PMID:
28835685
PMCID:
PMC5569099
DOI:
10.1038/s41598-017-09632-0
[Indexed for MEDLINE]
Free PMC Article

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