The Contribution of Genetic Architecture to the 10-Year Incidence of Age-Related Macular Degeneration in the Fellow Eye.
OBJECTIVE
To correlate a genetic risk score based on age-related macular degeneration (AMD) susceptibility genes with the risk of AMD in the second eye.


METHODS
This is a retrospective, open cohort study consisting of 891 unilateral AMD patients, who were followed for at least 12 months and recruited from three institutes. DNAs were genotyped using Illumina OmniExpress, HumanOmni2.5-8, and/or HumanExome. Survival analyses and Cox proportional hazard models were used to examine the association between 11 AMD susceptibility genes and the duration until second-eye involvement in 499 samples from Kyoto University, which were replicated in two other cohorts. Genetic risk score (GRS) was also evaluated.


RESULTS
The ARMS2 rs10490924 recessive model (hazard ratio [HR]meta = 2.04; Pmeta = 3.4 × 10⁻³) and CFH rs800292 additive model (HRmeta = 1.77; Pmeta = 0.013) revealed significant associations with second-eye involvement. The dominant model of TNFRSF10A rs13278062, VEGFA rs943080, and CFI rs4698775 showed consistent effects across three datasets (I² = 0%; HRmeta = 1.46, 1.30, 1.51, respectively). The GRS using these five single nucleotide polymorphisms (SNPs) was also significantly associated (HRmeta [per score] = 2.42; P = 2.2 × 10⁻⁵; I² = 0%). After 10 years from the first visit, the patients within the top 10% by GRS showed a 51% hazard rate, in contrast to 2.3% among patients within the lowest 10% by GRS.


CONCLUSIONS
We demonstrated that the GRS using ARMS2, CFH, TNFRSF10A, VEGFA, and CFI was significantly associated with second-eye involvement. Genetic risk has high predictive ability for second-eye involvement of AMD.
Department of Ophthalmology and Visual Science Kyoto University Graduate School of Medicine, Kyoto, Japan 2Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Masahiro
M
Miyake
Department of Ophthalmology and Visual Science Kyoto University Graduate School of Medicine, Kyoto, Japan.
Kenji
K
Yamashiro
Department of Ophthalmology and Visual Science Kyoto University Graduate School of Medicine, Kyoto, Japan.
Hiroshi
H
Tamura
Department of Ophthalmology and Visual Science Kyoto University Graduate School of Medicine, Kyoto, Japan.
Kyoko
K
Kumagai
Department of Ophthalmology, Fukushima Medical University, Fukushima, Japan.
Masaaki
M
Saito
Department of Ophthalmology and Visual Science Kyoto University Graduate School of Medicine, Kyoto, Japan.
Masako
M
Sugahara-Kuroda
Department of Ophthalmology and Visual Science Kyoto University Graduate School of Medicine, Kyoto, Japan 2Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Munemitsu
M
Yoshikawa
Department of Ophthalmology and Visual Science Kyoto University Graduate School of Medicine, Kyoto, Japan.
Maho
M
Oishi
Department of Ophthalmology and Visual Science Kyoto University Graduate School of Medicine, Kyoto, Japan 2Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Yumiko
Y
Akagi-Kurashige
Massachusetts Eye and Ear Infirmary, Boston, Massachusetts, United States.
Isao
I
Nakata
Department of Ophthalmology and Visual Science Kyoto University Graduate School of Medicine, Kyoto, Japan.
Hideo
H
Nakanishi
Department of Ophthalmology and Visual Science Kyoto University Graduate School of Medicine, Kyoto, Japan 2Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Norimoto
N
Gotoh
Department of Ophthalmology and Visual Science Kyoto University Graduate School of Medicine, Kyoto, Japan 5Kobe City Medical Center General Hospital, Kobe, Japan.
Akio
A
Oishi
Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Fumihiko
F
Matsuda
Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Ryo
R
Yamada
Division of Human Genetics, Genome Institute of Singapore, Singapore.
Chiea-Chuen
CC
Khor
Kobe City Medical Center General Hospital, Kobe, Japan.
Yasuo
Y
Kurimoto
Department of Ophthalmology, Fukushima Medical University, Fukushima, Japan.
Tetsuju
T
Sekiryu
Department of Ophthalmology, Kagawa University, Kagawa, Japan.
Akitaka
A
Tsujikawa
Department of Ophthalmology and Visual Science Kyoto University Graduate School of Medicine, Kyoto, Japan.
Nagahisa
N
Yoshimura
D000483:Alleles; D017242:Complement Factor H / Q000096:biosynthesis / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D005544:Forecasting; D005786:Gene Expression Regulation; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D060005:Genotyping Techniques; D006801:Humans; D015994:Incidence; D007564:Japan / Q000453:epidemiology; D008268:Macular Degeneration / Q000453:epidemiology / Q000235:genetics* / Q000378:metabolism; D008297:Male; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D012313:RNA / Q000235:genetics; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000096:biosynthesis / Q000235:genetics*; D012189:Retrospective Studies; D012307:Risk Factors; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis / Q000235:genetics*
C514392:ARMS2 protein, human; D011506:Proteins; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; C105190:TNFRSF10A protein, human; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D012313:RNA; D017242:Complement Factor H