Klaassen Ingeborg, Vader Maartje J C, Aissa Khadija, Tanck Michael W T, Schlingemann Reinier O
Ocular Angiogenesis Group, Department of Ophthalmology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.
Microcirculation, Amsterdam Cardiovascular Sciences, Amsterdam, The Netherlands.
Invest Ophthalmol Vis Sci. 2025 Jun 2;66(6):2. doi: 10.1167/iovs.66.6.2.
This study aimed to identify genetic factors that may influence the effectiveness of anti-vascular endothelial growth factor (VEGF) treatment for macular edema (ME).
We performed a genome-wide association study (GWAS) on 606 patients with macular edema that were treated with bevacizumab or ranibizumab from three randomized clinical trials, using a Infinium Global Screening Array. Well-characterized patient groups included diabetic macular edema (DME), retinal vein occlusion (RVO), and neovascular age-related macular degeneration (nAMD), with changes in best-corrected visual acuity (BCVA) and anatomical changes in central subfield thickness (CST) as outcomes. We conducted a meta-analysis on the combined patient groups, a targeted analysis on 28 previously reported genetic variants related to anti-VEGF response, and on variants of six genes involved in ME pathophysiology.
GWAS meta-analysis identified 12 SNPs (P < 1 × 10-6), of which three SNPs reached genome-wide significance (P < 5 × 10-8) and were linked to changes in CST after 6 months of anti-VEGF treatment. In addition, a genomic locus in the SGCZ gene was linked to changes in BCVA. Targeted GWAS revealed significant associations between changes in BCVA and variants in KDR, IL6, NRP1, and SPNS2, all known for their roles in VEGF signaling and retinal vascular permeability. Furthermore, changes in CST were associated with PLVAP, an important gene in vascular hyperpermeability in ME.
This GWAS meta-analysis uncovered genetic variants potentially linked to responses to anti-VEGF treatment in patients with retinal conditions featuring vascular leakage and/or ME. These findings could aid in identifying genetic markers for treatment response prediction or uncover new pathways relevant to retinal vascular leakage and ME.
本研究旨在确定可能影响抗血管内皮生长因子（VEGF）治疗黄斑水肿（ME）疗效的遗传因素。
我们使用Infinium全球筛选阵列，对来自三项随机临床试验的606例接受贝伐单抗或雷珠单抗治疗的黄斑水肿患者进行了全基因组关联研究（GWAS）。特征明确的患者组包括糖尿病性黄斑水肿（DME）、视网膜静脉阻塞（RVO）和新生血管性年龄相关性黄斑变性（nAMD），以最佳矫正视力（BCVA）的变化和中心子野厚度（CST）的解剖学变化作为结果。我们对合并的患者组进行了荟萃分析，对28个先前报道的与抗VEGF反应相关的基因变异以及参与ME病理生理学的六个基因的变异进行了靶向分析。
GWAS荟萃分析确定了12个单核苷酸多态性（SNP）（P < 1×10-6），其中三个SNP达到全基因组显著性水平（P < 5×10-8），并与抗VEGF治疗6个月后CST的变化相关。此外，SGCZ基因中的一个基因组位点与BCVA的变化相关。靶向GWAS显示BCVA的变化与KDR、IL6、NRP1和SPNS2基因的变异之间存在显著关联，这些基因均因其在VEGF信号传导和视网膜血管通透性中的作用而闻名。此外，CST的变化与PLVAP相关，PLVAP是ME血管高通透性中的一个重要基因。
这项GWAS荟萃分析发现了可能与以血管渗漏和/或ME为特征的视网膜疾病患者对抗VEGF治疗的反应相关的基因变异。这些发现有助于识别用于预测治疗反应的遗传标记或揭示与视网膜血管渗漏和ME相关的新途径。
