A MULTI-CENTER STUDY TO MAP GENES FOR FUCH'S DYSTROPHY

这个子项目是许多利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 Fuchs角膜内皮营养不良（FECD; MIM 136800）是一种常见的眼部疾病，影响约1%的美国普通人群。 最初无症状，个体最终表现为视力下降，醒来时有异物感和疼痛。裂隙灯（显微镜）检查最初显示局部后弹力层增厚，称为角膜滴，随后出现基质水肿（肿胀）、上皮水肿，晚期出现疼痛性大泡性角膜病变。 FECD是美国最常见的导致角膜移植的遗传性疾病。 此外，患有FECD的白内障手术患者存在角膜失代偿的显著风险，需要随后进行角膜移植。角膜营养不良的遗传基础的分子数据是有限的。在大量人群处于风险中的情况下，鉴定可能导致营养不良的基因对于咨询、实施治疗干预的标准方法以及最终的基因调节和/或治疗将是非常有用的。在这项研究中，我们使用了积极的，多中心NEI资助的角膜供体研究（CDS）建立的网络作为纽带，以确定家庭与FECD使用财团模型。我们已接近完成该项目的招聘阶段。 我们已经确定了晚期FECD的病例，并将使用临床严重程度作为半定量特征来描述家族聚集的程度。 使用标准化工具收集家族史、临床和其他人口统计学信息。 正在获得晚期指示病例的组织学确认。 正在收集血液样本进行分子遗传分析。 已经建立了一个网上数据库，以便利多地点数据收集。将利用从索引病例和家族（432个家族，包含658对兄弟姐妹，包括367对受影响的兄弟姐妹，加上69个无关病例）收集的DNA进行全基因组扫描。 全基因组关联分析将利用大约500个无关病例-家族和无关病例的先证者-和500个对照进行。 到目前为止，我们已经收集了270个不相关的对照。 此外，无模型连锁分析，使用SIBPAL程序在S.A.G.E.，将使用DNA标记数据结合FECD的临床数据进行，以确定连锁信号。 我们即将开始对通过以前对有限数量的家庭的调查确定的候选基因进行初步的关联研究。 因此，我们将通过在更大的样本中表征这些基因的作用，在更全球的基础上研究它们的重要性。 我们预计，这项研究将导致新的见解FECD的病因和角膜内皮的生物学。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Fuchs endothelial corneal dystrophy (FECD; MIM136800) is a common eye disease, affecting approximately 1% of the general US population. Initially asymptomatic, individuals eventually present with decreased vision, foreign body sensation and pain upon waking. Slit lamp (microscopic) examination initially shows focal thickenings of Descemet's membrane known as corneal guttae, with subsequent stromal edema (swelling), epithelial edema and, in advanced stages, painful bullous keratopathy. FECD is a the most common inherited disease in the USA leading to corneal transplantation. In addition, individuals undergoing cataract surgery with FECD are at significant risk for corneal decompensation, requiring subsequent corneal transplantation. Molecular data on the genetic basis of corneal dystrophies is limited. With a significant population at risk, the identification of the gene(s) that may contribute to the dystrophy would be very useful for counseling, implementation of standard methods for therapeutic intervention, and ultimately gene modulation and/or therapy. In this study, we have used the network built by the active, multi-center NEI-funded Cornea Donor Study (CDS) as the nexus to identify families with FECD using the consortium model. We have nearly completed the recruitment phase of the project. We have identified cases with advanced FECD and will characterize the extent of familial clustering using a clinical measure of severity as a semi-quantitative trait. Family history, clinical, and other demographic information is being collected using a standardized instrument. Histopathologic confirmation of advanced index cases is being obtained. Blood samples are being collected for molecular genetic analyses. A web-based database has been constructed to facilitate multi-site data collection. A genome-wide scan will be conducted utilizing DNA collected from the index cases and families (432 families containing 658 sibling pairs, including 367 affected sib pairs, plus 69 unrelated cases). A genomewide association analysis will be performed utilizing approximately 500 unrelated cases--probands of families and unrelated cases--and 500 controls. We have so far collected 270 unrelated controls. In addition, model-free linkage analysis, using the SIBPAL program in S.A.G.E., will be conducted using the DNA marker data in conjunction with the clinical data on FECD to identify linkage signals. We are about to begin an initial association study on candidate genes identified through previous investigations of a limited number of families. Thus, we will investigate the importance of these genes on a more global basis by characterizing their role in a larger sample. We anticipate that this study will lead to novel insights into the etiology of FECD and the biology of the corneal endothelium.