原发性闭角型青光眼内表型的评估

Glaucoma, the leading cause of irreversible blindness worldwide, is classified according to the configuration of the irido-corneal angle into open angle or angle-closure glaucoma. Primary angle closure glaucoma (PACG) is the major form of glaucoma in China and Asia compared to primary open angle glaucoma (POAG), which is more common in Caucasians and Africans. 40% -60% of glaucoma in China is PACG that the prevalence rate of over the age of 50 is 1.2% -2.1%, the blindness rate up to 35%. PACG is a serious hazard to the visual health in our country and is material ophthalmology science problem. The pathogenesis of PACG is thought to occur through the interplay of multiple anatomical and physiological factors, and thus shows many indications of being a complex disease, with both genetic and environmental etiological factors. In order to reduce the etiological complexity of PACG and simplify the search for causative genes, the disease can be dissected into its individual intermediate traits or endophenotypes. The highly heritable traits for angle closure include the anterior chamber depth (ACD), angle width, and anterior chamber width (ACW) - they can be referred to as PACG-related endophenotypes. We hypothesize that by identifying the genes that govern these PACG-related endophenotypes, we may be successful in unraveling the genetic determinants that confer individual susceptibility to PACG. In this study, we plan to test the association between PACG-related quantitative endophenotypes and genotypes using quantitative trait locus (QTL) analysis. This will be followed by evaluation of the association with PACG of the GWAS significant SNPs/ loci identified for each endophenotype. An ability to elucidate the spectrum of genetic loci associated with the disease would provide perspectives into the genetic mechanisms responsible for individual susceptibility to the condition. In the future, the information obtained is likely to enhance the efforts to develop a clinically useful genetic profile for early detection or risk stratification for this blinding disorder.

原发性闭角型青光眼（简称"闭青"）是我国主要不可逆致盲眼病，致盲率高，若早期发现给予预防性治疗可有效控制病情，早期筛查诊断是降低致盲率、避免过度治疗的关键。闭青的发病机理被认为是由解剖和生理因素相互作用所致，遗传和环境因素均起作用，因此闭青是复杂性疾病。前房深度是闭青房角关闭的高度可遗传性状，是闭青相关的内表型。在课题组前期闭青全基因组关联分析研究基础上，我们假说是：为降低遗传研究的复杂性，拟将内表型之一的前房深度作为研究对象。通过鉴定调控前房深度的致病基因，可有助于揭示闭青个体易感性的遗传机制。本研究拟使用数量表型位点(QTL)分析方法检测前房深度和基因型之间的相关性；评估与前房深度相关的具有统计学意义的SNPs与闭青的相关性。对前房深度的遗传机制初步研究将有助于后续对闭青内表型的研究，将来有望建立一个整合遗传学易感基因（客观稳定的生物指标）及解剖学危险因素的发病风险预测模型，提高闭青的早期诊断率。

原发性闭角型青光眼（简称"闭青"）是我国主要不可逆致盲眼病，致盲率高，若早期发现给予及时的预防性周边虹膜切除治疗可有效控制病情。闭青的早期筛查诊断是降低致盲率、避免过度治疗的关键。闭青的发病机理被认为是由解剖和生理因素相互作用所致，遗传和环境因素均起作用，因此闭青是复杂性疾病。前房深度是闭青房角关闭的高度可遗传性状，是闭青相关的内表型。为了降低闭青遗传研究的复杂性，本研究将内表型之一的前房深度作为研究对象。拟通过鉴定调控前房深度的致病基因，以有助于揭示闭青个体易感性的遗传机制。通过闭青遗传学研究，希望建立一个整合遗传学易感基因（客观稳定的生物指标）及解剖学危险因素的发病风险预测模型，提高闭青的早期诊断率。按照原定的研究计划，我们基本完成了研究目标，达到了预定研究成果。研究建立起了269例闭青及365例正常对照者的前房深度数据库（包括人口学信息、疾病诊疗史、视力、眼压、眼底视神经损害、视野等临床信息），以及血样、DNA样本库。使用Illumina 芯片获得基因型数据，从中选取了4个SNP进行单个SNP关联分析、单个位点的数量性状分析(QTL分析)、多因素回归分析及基因相互作用分析等。结果分析一致发现rs1401999是和前房深度相关的SNP。本次研究为后续的进一步研究奠定了基础，提供了有益的信息。通过研究，进一步锻炼磨合了研究团队，理顺了研究流程，培养了相关人员。项目负责人乔春艳医生在项目资助下于2014年在美国哈佛大学哈佛医学院、麻省眼耳鼻喉医院做访问学者，进一步学习交流青光眼遗传学研究技术。并参加了2014 年5 月在美国举行的视觉及眼科学研究委员会年会（ARVO），文章做展板交流。总之，按照原定的研究计划，我们基本完成了研究目标，达到了预定研究成果。研究建立起了闭青及正常对照前房深度数据库及血样、DNA样本库；发现rs1401999是和前房深度相关的SNP。作为预实验性研究，本次研究为后续的进一步研究奠定了基础，指明了研究方向，并进一步锻炼磨合了研究团队。