Cole Eye Institute, Cleveland Clinic, Cleveland, Ohio; Department of Ophthalmology, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio.
Department of Ophthalmology, University of Pennsylvania, Philadelphia, Pennsylvania.
Ophthalmology. 2013 Mar;120(3):593-599. doi: 10.1016/j.ophtha.2012.11.037. Epub 2013 Jan 18.
To evaluate the pharmacogenetic relationship between genotypes of single nucleotide polymorphisms (SNPs) known to be associated with age-related macular degeneration (AMD) and response to treatment with ranibizumab (Lucentis; Genentech, South San Francisco, CA) or bevacizumab (Avastin; Genentech) for neovascular AMD.
Clinical trial.
Eight hundred thirty-four (73%) of 1149 patients participating in the Comparison of AMD Treatments Trials (CATT) were recruited through 43 CATT clinical centers.
Each patient was genotyped for SNPs rs1061170 (CFH), rs10490924 (ARMS2), rs11200638 (HTRA1), and rs2230199 (C3), using TaqMan SNP genotyping assays (Applied Biosystems, Foster City, CA).
Genotypic frequencies were compared with clinical measures of response to therapy at one year, including mean visual acuity (VA), mean change in VA, 15-letter or more increase in VA, retinal thickness, mean change in total foveal thickness, presence of fluid on OCT, presence of leakage on fluorescein angiography (FA), mean change in lesion size, and mean number of injections administered. Differences in response by genotype were evaluated with tests of linear trend calculated from logistic regression models for categorical outcomes and linear regression models for continuous outcomes. To adjust for multiple comparisons, P≤0.01 was considered statistically significant.
No statistically significant differences in response by genotype were identified for any of the clinical measures studied. Specifically, there were no high-risk alleles that predicted final VA or change in VA, the degree of anatomic response (fluid on OCT or FA, retinal thickness, change in total foveal thickness, change in lesion size), or the number of injections. Furthermore, a stepwise analysis failed to show a significant epistatic interaction among the variants analyzed; that is, response did not vary by the number of risk alleles present. The lack of association was similar whether patients were treated with ranibizumab or bevacizumab or whether they received monthly or pro re nata dosing.
Although specific alleles for CFH, ARMS2, HTRA1, and C3 may predict the development of AMD, they did not predict response to anti-vascular endothelial growth factor therapy.
评估与年龄相关性黄斑变性（AMD）相关的单核苷酸多态性（SNP）基因型与雷珠单抗（Lucentis；基因泰克，加利福尼亚州南旧金山）或贝伐单抗（Avastin；基因泰克）治疗新生血管性 AMD 反应之间的药物遗传学关系。
临床试验。
参加 AMD 治疗试验比较（CATT）的 1149 名患者中有 834 名（73%）通过 43 个 CATT 临床中心招募。
使用 TaqMan SNP 基因分型测定法（Applied Biosystems，加利福尼亚州福斯特市）对每位患者进行 rs1061170（CFH）、rs10490924（ARMS2）、rs11200638（HTRA1）和 rs2230199（C3）的 SNP 基因分型。
在一年时，通过治疗反应的临床测量指标比较基因型频率，包括平均视力（VA）、VA 变化平均值、VA 增加 15 个字母或更多、视网膜厚度、总中心凹厚度变化平均值、OCT 上的液体、荧光素血管造影（FA）上的渗漏、病变大小的变化平均值和注射的平均次数。通过逻辑回归模型的线性趋势检验评估基因型与反应之间的差异，对于连续结果使用线性回归模型。为了调整多重比较，统计学显著差异的 P≤0.01。
对于所研究的任何临床指标，基因型与反应之间均未发现统计学显著差异。具体来说，没有预测最终 VA 或 VA 变化、解剖学反应程度（OCT 或 FA 上的液体、视网膜厚度、总中心凹厚度变化、病变大小变化）或注射次数的高风险等位基因。此外，逐步分析未能显示分析的变体之间存在显著的上位性相互作用；也就是说，反应并不随存在的风险等位基因数量而变化。无论患者接受雷珠单抗或贝伐单抗治疗，还是接受每月或按需治疗，这种关联都没有差异。
尽管 CFH、ARMS2、HTRA1 和 C3 的特定等位基因可能预测 AMD 的发生，但它们并未预测抗血管内皮生长因子治疗的反应。
