Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Sakyo, Kyoto, 606-8507, Japan.
Department of Ophthalmology, Otsu Red Cross Hospital, Otsu, Shiga, 520-8511, Japan.
Sci Rep. 2017 Aug 23;7(1):9196. doi: 10.1038/s41598-017-09632-0.
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 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.
我们在一项前瞻性队列中对新生血管性年龄相关性黄斑变性（AMD）抗 VEGF 治疗结果进行了全基因组关联研究（GWAS）。在 13 个临床中心招募了 461 名未经治疗的 AMD 患者，所有患者均接受了 3 次每月雷珠单抗注射，随后采用 pro re nata 方案治疗 1 年。收集了所有患者的基因组 DNA，用于对初始治疗后干性黄斑的获得、额外治疗的需求以及 12 个月观察期内视力变化进行 2 阶段 GWAS。此外，我们评估了 8 个先前报道的 AMD 相关基因中的 9 个单核苷酸多态性（SNP）与治疗结果的关系。在包含 256 名患者的发现阶段，评估了 8480849 个 SNP，但没有 SNP 与治疗结果具有全基因组水平的显著关联。尽管在包含 205 名患者的复制样本中评估了 P 值 < 5×10 的 SNP，但没有 SNP 与治疗结果显著相关。在 AMD 易感基因中，ARMS2/HTRA1 中的 rs10490924 在发现阶段与额外治疗需求显著相关（P=0.0023），并且与复制阶段的汇总分析进一步证实了这种关联（P=0.0013）。ARMS2/HTRA1 多态性可能能够预测初始雷珠单抗治疗后的注射频率。
