A MULTI-CENTER STUDY TO MAP GENES FOR FUCHS 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，约占美国总人口的1%。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，称为角膜点滴，随后间质水肿，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极大的角膜失代偿风险，需要随后的角膜移植。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将为咨询、实施治疗干预的标准方法以及最终的基因调节和/或治疗提供非常有用的信息。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建立的网络作为纽带，使用联合体模型识别FECD家族以及无关的FECD病例和对照。我们已经完成了该项目的家庭招募阶段，目前正在完成病例对照招募工作。正在使用标准化工具收集家族史、临床和其他人口统计信息。已获得受严重影响的指示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。专门为该项目开发的基于Web的数据库方便了多站点数据收集。我们发现FECD在我们的家族样本中具有很强的遗传性，无论是定义为二元特征还是定义为严重程度评分。经年龄、性别、眼压和既往眼科手术等混杂因素调整后的中央角膜厚度也具有很高的遗传性。对先前确定的FECD候选基因的初步关联研究在有限数量的家系上运行，表明解释所观察到的遗传性的主要遗传决定因素是新的。我们正准备对家庭样本进行全基因组连锁扫描，包括322个家庭，包含至少572个兄弟姐妹对，包括333个受影响的兄弟姐妹对。使用S.A.G.E.中的SIBPAL程序进行的非模型连锁分析将结合FECD上的临床数据对来自DNA样本的遗传标记数据进行。此外，我们将进行全基因组关联分析，包括大约500个无关病例(包括家族先证者)和500个对照。我们即将完成无关案件和控制措施的征聘阶段。我们预计，这项研究是第一次包括大量患有严重疾病的家庭和无关个体的FECD研究，将导致对FECD的病因学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, epithelia edema and, in advanced stages, painful bullous keratopathy. FECD is 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 genes that may contribute to the dystrophy would provide very useful information 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 as the nexus to identify families with FECD, as well as unrelated FECD cases and controls, using the consortium model. We have completed the family recruitment phase of the project and are currently finishing up case-control recruitment. Family history, clinical and other demographic information is being collected using a standardized instrument. Histopathologic confirmation of severely affected index cases has been obtained. Blood samples are being collected for molecular genetic analyses. A Web-based database developed specifically for this project facilitates multi-site data collection. We found FECD to be strongly heritable in our family sample, whether defined as a binary trait or as a severity score. Central corneal thickness, adjusted for confounding factors including age, sex, ocular pressure and previous eye surgery, is also highly heritable. An initial association study on previously identified FECD candidate genes, run on a limited number of families, suggests that the major genetic determinants explaining the observed heritability are novel. We are preparing to conduct a genomewide linkage scan on the family sample, comprising 322 families containing at least 572 sibling pairs, including 333 affected sibling pairs. Model-free linkage analysis, using the SIBPAL program in S.A.G.E., will be conducted on genetic marker data derived from DNA samples in conjunction with the clinical data on FECD. In addition, we will perform a genomewide association analysis including approximately 500 unrelated cases (including probands of families) and 500 controls. We are nearing completion of the recruitment phase for unrelated cases and controls. We anticipate that this studythe first FECD study to include a large number of families with severe disease and unrelated individualswill lead to novel insights into the etiology of FECD and the biology of the corneal endothelium.