Masahiro Miyake1, Kenji Yamashiro2, Hiroshi Tamura2, Kyoko Kumagai2, Masaaki Saito3, Masako Sugahara-Kuroda2, Munemitsu Yoshikawa1, Maho Oishi2, Yumiko Akagi-Kurashige1, Isao Nakata4, Hideo Nakanishi2, Norimoto Gotoh1, Akio Oishi5, Fumihiko Matsuda6, Ryo Yamada6, Chiea-Chuen Khor7, Yasuo Kurimoto8, Tetsuju Sekiryu3, Akitaka Tsujikawa9, Nagahisa Yoshimura2. 1. 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. 2. Department of Ophthalmology and Visual Science Kyoto University Graduate School of Medicine, Kyoto, Japan. 3. Department of Ophthalmology, Fukushima Medical University, Fukushima, Japan. 4. Massachusetts Eye and Ear Infirmary, Boston, Massachusetts, United States. 5. Department of Ophthalmology and Visual Science Kyoto University Graduate School of Medicine, Kyoto, Japan 5Kobe City Medical Center General Hospital, Kobe, Japan. 6. Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan. 7. Division of Human Genetics, Genome Institute of Singapore, Singapore. 8. Kobe City Medical Center General Hospital, Kobe, Japan. 9. Department of Ophthalmology, Kagawa University, Kagawa, Japan.
Abstract
PURPOSE: 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.
PURPOSE: 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 AMDpatients, 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 ARMS2rs10490924 recessive model (hazard ratio [HR]meta = 2.04; Pmeta = 3.4 × 10⁻³) and CFHrs800292 additive model (HRmeta = 1.77; Pmeta = 0.013) revealed significant associations with second-eye involvement. The dominant model of TNFRSF10Ars13278062, VEGFArs943080, and CFIrs4698775 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.
Authors: Thomas J Heesterbeek; Laura Lorés-Motta; Carel B Hoyng; Yara T E Lechanteur; Anneke I den Hollander Journal: Ophthalmic Physiol Opt Date: 2020-02-25 Impact factor: 3.117