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

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 Fuchs内皮角膜营养不良(FECD；MIM136800)是一种常见的眼病，影响大约1%的美国总人口。最初无症状，患者最终出现视力下降、异物感和醒来时疼痛。裂隙灯(显微镜)检查最初显示Descemet膜局限性增厚，称为角膜滴眼液，随后出现基质水肿(肿胀)，上皮水肿，晚期出现疼痛的大泡性角膜病变。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的白内障手术患者有发生角膜失代偿的极大风险，需要随后进行角膜移植。关于角膜营养不良遗传基础的分子数据有限。由于有大量的人群处于危险之中，识别可能导致营养不良的基因(S)将对咨询、实施治疗干预的标准方法以及最终的基因调节和/或治疗非常有用。在这项研究中，我们使用积极的、多中心NEI资助的角膜捐赠者研究(CDS)建立的网络作为纽带，使用联合体模式识别FECD家族。我们已接近完成该项目的招募阶段。我们已经确定了晚期FECD的病例，并将使用临床严重程度测量作为半定量特征来表征家族聚集性的程度。家族病史、临床和其他人口统计信息正在使用标准化工具收集。正在获得晚期指征病例的组织病理学确认。目前正在采集血液样本进行分子遗传分析。已经建立了一个基于网络的数据库，以便利多站点数据收集。将利用从索引病例和家庭(432个家庭，包含658个兄弟姐妹对，包括367个受影响的兄弟姐妹对，加上69个无关病例)收集的DNA进行全基因组扫描。一项全基因组关联分析将利用大约500个无关病例--家族先驱和无关病例--和500个对照进行。到目前为止，我们已经收集了270个无关的控件。此外，使用S.A.G.E.中的SIBPAL程序进行的非模型连锁分析将使用DNA标记数据与FECD的临床数据相结合来识别连锁信号。我们即将开始一项关于候选基因的初步关联研究，这些候选基因是通过先前对有限数量的家系的调查而确定的。因此，我们将通过在更大的样本中表征它们的作用，在更全球的基础上调查这些基因的重要性。我们预计，这项研究将导致对FECD的病因和角膜内皮生物学的新见解。

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.