MMP20 and ARMS2/HTRA1 Are Associated with Neovascular Lesion Size in Age-Related Macular Degeneration.
OBJECTIVE
Age-related macular degeneration (AMD) is the leading cause of severe visual impairment. Despite treatment, a central scotoma often remains. The size of the scotoma depends on the lesion size of the choroidal neovascular membrane and significantly affects the patient's quality of life, and the lesion size of neovascularization also affects response to treatments. The aim of this study was to identify genes associated with the neovascular lesion size in neovascular AMD.


METHODS
A genome-wide association study (GWAS).


METHODS
We included 1146 Japanese patients with neovascular AMD.


METHODS
We performed a 2-stage GWAS for the lesion size of AMD as a quantitative trait among 1146 (first stage: 727, second stage: 419) Japanese patients with neovascular AMD. Lesion size was determined by the greatest linear dimension measured with fluorescein angiography examination before treatment. We examined the association between the genotypic distribution of each single nucleotide polymorphism (SNP) and the trait using an additive model adjusted for age and sex. To evaluate the associations between AMD development and SNPs associated with lesion size, we also performed a case-control study by using the genotype data from these 1146 Japanese patients as case subjects and the fixed dataset from the Nagahama Study as control subjects.


METHODS
Genes associated with the lesion size in neovascular AMD.


RESULTS
In the discovery stage, rs10895322 in MMP20 showed a genome-wide significant P value of 6.95×10(-8), and rs2284665 in ARMS2/HTRA1 showed a P value of 1.55×10(-7). The associations of these 2 SNPs were successfully replicated in the replication stage, and a meta-analysis of both stages showed genome-wide significant P values (2.80×10(-9) and 4.41×10(-9), respectively). In a case-control study using 3248 Japanese subjects as controls, we could not find contribution of MMP20 rs10895322 for AMD development. Although MMP20 has been thought to be expressed only in dental tissues, we confirmed MMP20 expression in the human retina and retinal pigment epithelium/choroid with polymerase chain reaction.


CONCLUSIONS
The growth of choroidal neovascularization in AMD would be affected by 2 genes: MMP20, a newly confirmed gene expressed in the retina, and ARMS2/HTRA1, a well-known susceptibility gene for AMD.
Department of Ophthalmology, Kyoto University Graduate School of Medicine, Kyoto, Japan; Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Yumiko
Y
Akagi-Kurashige
Department of Ophthalmology, Kyoto University Graduate School of Medicine, Kyoto, Japan. Electronic address: yamashro@kuhp.kyoto-u.ac.jp.
Kenji
K
Yamashiro
Department of Ophthalmology, Kyoto University Graduate School of Medicine, Kyoto, Japan; Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Norimoto
N
Gotoh
Department of Ophthalmology, Kyoto University Graduate School of Medicine, Kyoto, Japan; Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Masahiro
M
Miyake
Department of Ophthalmology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Satoshi
S
Morooka
Department of Ophthalmology, Kyoto University Graduate School of Medicine, Kyoto, Japan; Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Munemitsu
M
Yoshikawa
Department of Ophthalmology, Kyoto University Graduate School of Medicine, Kyoto, Japan; Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Isao
I
Nakata
Department of Ophthalmology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Kyoko
K
Kumagai
Department of Ophthalmology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Akitaka
A
Tsujikawa
Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Ryo
R
Yamada
Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Fumihiko
F
Matsuda
Department of Ophthalmology, Fukushima Medical University School of Medicine, Fukushima, Japan.
Masaaki
M
Saito
Department of Ophthalmology, Tokyo Women's Medical University, Tokyo, Japan.
Tomohiro
T
Iida
Department of Ophthalmology, Kobe City Medical Center General Hospital, Kobe, Japan.
Masako
M
Sugahara
Department of Ophthalmology, Kobe City Medical Center General Hospital, Kobe, Japan.
Yasuo
Y
Kurimoto
Singapore Eye Research Institute, Singapore; Duke-National University of Singapore Graduate School of Medicine, Singapore; Department of Ophthalmology, National University of Singapore and National University Health System, Singapore; Singapore National Eye Center, Singapore.
Ching-Yu
CY
Cheng
Singapore Eye Research Institute, Singapore; Division of Human Genetics, Genome Institute of Singapore, Singapore; Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore.
Chiea-Chuen
CC
Khor
Singapore Eye Research Institute, Singapore; Duke-National University of Singapore Graduate School of Medicine, Singapore; Department of Ophthalmology, National University of Singapore and National University Health System, Singapore; Singapore National Eye Center, Singapore.
Tien-Yin
TY
Wong
Department of Ophthalmology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Nagahisa
N
Yoshimura
D000368:Aged; D000369:Aged, 80 and over; D044466:Asian People / Q000208:ethnology; D016022:Case-Control Studies; D005260:Female; D005451:Fluorescein Angiography; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D000074289:High-Temperature Requirement A Serine Peptidase 1; D006801:Humans; D007564:Japan / Q000453:epidemiology; D008297:Male; D053519:Matrix Metalloproteinase 20 / Q000235:genetics*; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D011506:Proteins / Q000235:genetics*; D012607:Scotoma / Q000235:genetics / Q000473:pathology; D012697:Serine Endopeptidases / Q000235:genetics*; D057135:Wet Macular Degeneration / Q000235:genetics* / Q000473:pathology
C514392:ARMS2 protein, human; D011506:Proteins; D000074289:High-Temperature Requirement A Serine Peptidase 1; C474012:HTRA1 protein, human; D012697:Serine Endopeptidases; C507111:MMP20 protein, human; D053519:Matrix Metalloproteinase 20