The influence of genetics on response to treatment with ranibizumab (Lucentis) for age-related macular degeneration: the Lucentis Genotype Study (an American Ophthalmological Society thesis).
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Abstract
Purpose: 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.
Methods: 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.
Results: 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.
Conclusions: 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.
目的:老年性黄斑变性(AMD)病因复杂，受遗传和环境影响。在过去的十年里，已经发现了几种与这种疾病相关的基因。五种基因的变异已被证实发挥了主要作用。本研究的目的是评估基因是否影响雷尼单抗对新生血管性AMD的治疗反应。假设是个体的基因变异将决定治疗效果。方法:该研究是一项双中心前瞻性开放标签观察研究，新诊断为渗出性(新血管性)AMD的患者接受玻璃体内雷尼单抗治疗。Treatment-naïve患者在就诊时登记，每月接受“按需”治疗。每月收集临床资料并提取DNA。使用Illumina (San Diego, California) 660-Quad单核苷酸多态性(SNP)芯片进行基因分型。进行回归分析以确定与治疗反应终点相关的snp。结果:65例患者入组。无严重不良事件记录。主要结局指标是12个月时ETDRS视力的变化。CFH基因中的SNP被发现与接受雷尼单抗治疗时视力改善较少相关。在其他基因中，C3基因与减少增厚和改善视网膜结构有关。在12个月的研究中，VEGFA、FLT1和CFH与需要更少的雷尼单抗注射相关。结论:本研究是首批玻璃体内雷尼珠单抗的前瞻性药物遗传学研究之一。虽然是初步的，但结果确定了一些假定的遗传变异，将通过复制和功能研究进一步检查，以阐明AMD治疗的完整药理学结构。
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