Institute of Medical Molecular Genetics, University of Zurich, Schwerzenbach, Switzerland.
Invest Ophthalmol Vis Sci. 2011 Jul 1;52(7):4694-702. doi: 10.1167/iovs.10-6080.
Neovascular age-related macular degeneration (AMD) resulting in decreased central vision severely impairs affected individuals. Current standard treatment is an intravitreal anti-VEGF therapy (ranibizumab), but responses to treatment show large variability. Genetic factors that influence AMD and that affect the outcome of ranibizumab treatment were sought within a sample of Swiss patients.
Changes in visual acuity (VA) after initiation of anti-VEGF treatment were observed during 12 months, and percentiles of VA were calculated. Genotypes of polymorphisms in known AMD susceptibility loci (CFH, CFB, HTRA1, AMRS2, and VEGFA) as well as not yet reported AMD-associated genes (KDR, LRP5, and FZD4) were determined, and their frequencies were compared.
Of the 309 eyes included in the study, 243 completed VA assessment. On average, 3.9 ±2.6 ranibizumab injections were administered. Based on the change in visual acuity, two responder groups were established: 63 eyes were assigned to the poor responders (≤25th percentile) and 63 eyes to the good responders (≥75th percentile). Individuals with genotype CC of p.Y402H in CFH had a decreased chance of positive treatment outcome compared with those with the CT and TT genotypes (P = 0.005 and P = 0.006). In this study, the genotype combination of AG at CFH with CT at FZD4 (SNP rs10898563) promised an increased chance of positive treatment outcome (P = 0.004). Furthermore, the association with the known genetic susceptibility loci CFH, HTRA1, and AMRS2 were confirmed, and a risk-conferring polymorphism in one new locus, LRP5, was identified.
Genetic predisposition may account for the variability in response to anti-VEGF treatment.
与年龄相关的新生血管性黄斑变性（AMD）导致中心视力下降，严重影响受影响者。目前的标准治疗是玻璃体内抗 VEGF 治疗（雷珠单抗），但治疗反应显示出很大的可变性。在瑞士患者样本中寻找影响 AMD 并影响雷珠单抗治疗结果的遗传因素。
在 12 个月的时间内观察抗 VEGF 治疗开始后视力（VA）的变化，并计算 VA 的百分位数。确定已知 AMD 易感性基因座（CFH、CFB、HTRA1、AMRS2 和 VEGFA）和尚未报道的 AMD 相关基因（KDR、LRP5 和 FZD4）的多态性的基因型，并比较其频率。
在纳入研究的 309 只眼中，有 243 只完成了 VA 评估。平均给予 3.9±2.6 次雷珠单抗注射。根据视力变化，建立了两组反应者：63 只眼被分配到不良反应者（≤25 百分位），63 只眼被分配到良好反应者（≥75 百分位）。与 CT 和 TT 基因型相比，CFH 中的 p.Y402H 处的 CC 基因型个体的治疗结果阳性机会降低（P=0.005 和 P=0.006）。在这项研究中，CFH 处的 AG 基因型与 FZD4 处的 CT 基因型（SNP rs10898563）的组合预示着治疗结果阳性的机会增加（P=0.004）。此外，还证实了与已知遗传易感性基因座 CFH、HTRA1 和 AMRS2 的关联，并鉴定了一个新基因座 LRP5 中的一个风险赋予多态性。
遗传易感性可能是抗 VEGF 治疗反应可变性的原因。
