Francis Peter James
Divisions of Retina and Ophthalmic Genetics, Casey Eye Institute, Oregon Health and Science University, Portland, OR, USA.
Trans Am Ophthalmol Soc. 2011 Dec;109:115-56.
Age-related macular degeneration (AMD) has a complex etiology arising from genetic and environmental influences. This past decade have seen several genes associated with the disease. Variants in five genes have been confirmed to play a major role. The objective of this study was to evaluate whether genes influence treatment response to ranibizumab for neovascular AMD. The hypothesis was that an individual's genetic variation will determine treatment response.
The study was a two-site prospective open-label observational study of patients newly diagnosed with exudative (neovascular) AMD receiving intravitreal ranibizumab therapy. Treatment-naïve patients were enrolled at presentation and received monthly "as needed" therapy. Clinical data was collected monthly and DNA extracted. Genotyping was performed using the Illumina (San Diego, California) 660-Quad single-nucleotide polymorphism (SNP) chip. Regression analyses were performed to identify SNPs associated with treatment-response end points.
Sixty-five patients were enrolled. No serious adverse events were recorded. The primary outcome measure was change in ETDRS visual acuity at 12 months. A SNP in the CFH gene was found to be associated with less improvement in visual acuity while receiving ranibizumab therapy. The C3 gene, among others, was associated with reduced thickening and improved retinal architecture. VEGFA, FLT1, and CFH were associated with requiring fewer ranibizumab injections over the 12-month study.
This study is one of the first prospective pharmacogenetic study of intravitreal ranibizumab. Although preliminary, the results identify a number of putative genetic variants, which will be further examined by replication and functional studies to elucidate the complete pharmacogenetic architecture of therapy for AMD.
年龄相关性黄斑变性（AMD）病因复杂，由遗传和环境因素共同影响。在过去十年中发现了多个与该疾病相关的基因。已证实五个基因中的变异发挥主要作用。本研究的目的是评估基因是否会影响雷珠单抗治疗新生血管性AMD的疗效。假设是个体的基因变异将决定治疗反应。
本研究是一项在两个地点开展的前瞻性开放标签观察性研究，纳入新诊断为渗出性（新生血管性）AMD并接受玻璃体内注射雷珠单抗治疗的患者。初治患者在就诊时入组，并接受每月一次的“按需”治疗。每月收集临床数据并提取DNA。使用Illumina（加利福尼亚州圣地亚哥）660-Quad单核苷酸多态性（SNP）芯片进行基因分型。进行回归分析以识别与治疗反应终点相关的SNP。
共纳入65例患者。未记录到严重不良事件。主要结局指标是12个月时ETDRS视力的变化。发现CFH基因中的一个SNP与接受雷珠单抗治疗时视力改善较少有关。C3基因等与视网膜增厚减轻和视网膜结构改善有关。VEGFA、FLT1和CFH与在12个月的研究期间需要较少的雷珠单抗注射有关。
本研究是首批关于玻璃体内注射雷珠单抗的前瞻性药物遗传学研究之一。尽管结果初步，但已识别出一些假定的基因变异，后续将通过重复研究和功能研究进一步检验，以阐明AMD治疗完整的药物遗传学结构。
