Jin Enzhong, Bai Yujing, Huang Lvzhen, Zhao Min, Zhang Chunfang, Zhao Mingwei, Li Xiaoxin
Department of Ophthalmology, Peking University People's Hospital; Key Laboratory of Vision Loss and Restoration, Ministry of Education; Beijing Key Laboratory of Diagnosis and Therapy of Retinal and Choroid Diseases Beijing 100044, P. R. China.
Clinical Epidemiology & Biostatistics, Peking University People's Hospital Beijing 100044, P. R. China.
Int J Clin Exp Pathol. 2015 Nov 1;8(11):13928-44. eCollection 2015.
Polypoidal choroidal vasculopathy (PCV) is an exudative maculopathy, with clinical features distinct from neovascular age-related macular degeneration (nAMD) which is the leading cause of irreversible blindness in the elderly. Our studies focused on the genetic background and function of a novel gene HERPUD1 in PCV. HERPUD1 has been reported to increase the level of amyloid β (Aβ), which is a component of drusen deposits underlying the retinal pigment epithelium (RPE) layer. To verify the genetic functional associations of HERPUD1 with PCV, exome sequencing of HERPUD1 was performed in unrelated Chinese individuals, including nAMD patients, PCV patients and control subjects. Immunohistochemistry assays for HERPUD1 were performed in the subretinal membranes of PCV patients. The relationship between HERPUD1 and amyloid beta precursor was determined using real-time PCR in HERPUD1-overexpressing RPE cells. The gene expression patterns of angiogenesis cytokines and chemokines in both Aβ-treated RPE cells and in Brown Norway rats that received Aβ subretinal injections were determined. We showed that HERPUD1 rs2217332 is significant associated with Chinese PCV, and HERPUD1 was expressed in PCV subretinal membranes. Besides, Plasma Aβ42 protein was significantly higher in PCV patients compared to nAMD and control subjects. Aβ could upregulate angiogenic factors, chemokines and matrix metalloproteinases both in RPE cells and in a rat model of subretinal Aβ injection. The imbalance of the cytokines may be one of the mechanisms for the formation and development of PCV. Our results strongly suggest that HERPUD1 is highly associated with PCV patients.
息肉样脉络膜血管病变（PCV）是一种渗出性黄斑病变，其临床特征与新生血管性年龄相关性黄斑变性（nAMD）不同，后者是老年人不可逆性失明的主要原因。我们的研究聚焦于PCV中一个新基因HERPUD1的遗传背景和功能。据报道，HERPUD1可增加淀粉样β蛋白（Aβ）水平，而Aβ是视网膜色素上皮（RPE）层下玻璃膜疣沉积物的一个成分。为验证HERPUD1与PCV的遗传功能关联，对包括nAMD患者、PCV患者和对照受试者在内的无血缘关系的中国个体进行了HERPUD1外显子组测序。在PCV患者的视网膜下膜中进行了HERPUD1的免疫组织化学检测。在过表达HERPUD1的RPE细胞中使用实时PCR确定HERPUD1与淀粉样β前体之间的关系。确定了Aβ处理的RPE细胞以及接受Aβ视网膜下注射的棕色挪威大鼠中血管生成细胞因子和趋化因子的基因表达模式。我们发现，HERPUD1 rs2217332与中国PCV显著相关，且HERPUD1在PCV视网膜下膜中表达。此外，与nAMD患者和对照受试者相比，PCV患者血浆Aβ42蛋白水平显著更高。Aβ可在RPE细胞以及视网膜下Aβ注射大鼠模型中上调血管生成因子、趋化因子和基质金属蛋白酶。细胞因子失衡可能是PCV形成和发展的机制之一。我们的结果强烈表明，HERPUD1与PCV患者高度相关。
