Kozhevnikova Oyuna S, Fursova Anzhella Zh, Derbeneva Anna S, Nikulich Ida F, Tarasov Mikhail S, Devyatkin Vasiliy A, Rumyantseva Yulia V, Telegina Darya V, Kolosova Nataliya G
Federal Research Center Institute of Cytology and Genetics SB RAS, Pr. Lavrentiev, 10, 630090 Novosibirsk, Russia.
State Novosibirsk Regional Clinical Hospital, St. Nemirovich-Danchenko, 130, 630087 Novosibirsk, Russia.
Biomedicines. 2022 Jul 10;10(7):1658. doi: 10.3390/biomedicines10071658.
Neovascular age-related macular degeneration (nAMD) is the leading cause of vision loss in the elderly. The gold standard of nAMD treatment is intravitreal injections of vascular endothelial growth factor (VEGF) inhibitors. Genetic factors may influence the response to anti-VEGF therapy and result in a high degree of response variability. The aim of the study was to evaluate the association of the polymorphisms in genes related to the complement system (rs2285714-CFI, rs10490924-ARMS2, rs2230199-C3, rs800292-CFH, and rs6677604-CFH) with nAMD its clinical features and optical coherent tomography (OCT) biomarkers of treatment response to anti-VEGF therapy. Genotyping by allele-specific PCR was performed in 193 AMD patients and 147 age-matched controls. A prospective study of the dynamics of changes in OCT biomarkers during aflibercept treatment included 110 treatment-naive patients. Allele T rs10490924 was associated with the increased risk of nAMD. For both rs800292 and rs6677604, carriage of the A allele was protective and decreased the nAMD risk. Associations of rs2230199 with central retinal thickness (CRT) and intraretinal cysts were revealed. The height of pigment epithelium detachment and the height of neuroretinal detachment were significantly higher in carriers of the minor allele of rs2285714, both at baseline and during treatment. The reduction of CRT was associated with higher CRT at baseline and the presence of the T allele of rs2285714. By the end of one-year follow-up the patients homozygous for the minor allele rs2285714 had significantly higher odds of the presence of anastomoses and loops and active neovascular membrane. Furthermore, minor allele carriers had decreased levels of complement factor I level in aqueous humor but not in the plasma, which may be due to the influence of rs2285714 on tissue-specific splicing. Our results suggest that the severity of AMD macular lesions is associated with rs2285714 and rs2230199 polymorphisms, which could be explained by their high regulatory potential. Patients with the minor allele of rs2285714 respond worse to antiangiogenic therapy.
新生血管性年龄相关性黄斑变性（nAMD）是老年人视力丧失的主要原因。nAMD治疗的金标准是玻璃体内注射血管内皮生长因子（VEGF）抑制剂。遗传因素可能影响对抗VEGF治疗的反应，并导致高度的反应变异性。本研究的目的是评估补体系统相关基因（rs2285714 - CFI、rs10490924 - ARMS2、rs2230199 - C3、rs800292 - CFH和rs6677604 - CFH）的多态性与nAMD及其临床特征以及抗VEGF治疗反应的光学相干断层扫描（OCT）生物标志物之间的关联。通过等位基因特异性PCR对193例AMD患者和147例年龄匹配的对照进行基因分型。对110例初治患者进行了阿柏西普治疗期间OCT生物标志物变化动态的前瞻性研究。rs10490924的T等位基因与nAMD风险增加相关。对于rs800292和rs6677604，A等位基因的携带具有保护作用并降低了nAMD风险。揭示了rs2230199与中心视网膜厚度（CRT）和视网膜内囊肿的关联。rs2285714次要等位基因携带者在基线和治疗期间色素上皮脱离高度和神经视网膜脱离高度均显著更高。CRT的降低与基线时较高的CRT以及rs2285714的T等位基因的存在相关。到一年随访结束时，rs2285714次要等位基因纯合的患者出现吻合和环以及活跃新生血管膜的几率显著更高。此外，次要等位基因携带者房水中补体因子I水平降低，但血浆中未降低，这可能是由于rs2285714对组织特异性剪接的影响。我们的结果表明，AMD黄斑病变的严重程度与rs2285714和rs2230199多态性相关，这可以用它们的高调控潜力来解释。rs2285714次要等位基因的患者对抗血管生成治疗反应较差。
