A MULTI-CENTER STUDY TO MAP GENES FOR FUCHS DYSTROPHY

该子项目是利用 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来源获得主要资金， 因此可以在其他CRISP条目中表示。列出的机构是 中心，不一定是研究者的机构。 Fuchs角膜内皮营养不良（FECD：MIM 136800）是一种常见的眼科疾病，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、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。 由于大量人群处于风险中，可能导致营养不良的基因的鉴定将为咨询、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，我们使用了积极的，多中心NEI资助的角膜供体研究建立的网络作为纽带，以确定家庭与FECD，以及无关的FECD病例和对照，使用财团模型。 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。 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。 已获得严重受累的指示病例的组织学证实。 正在收集血液样本进行分子遗传分析。 专门为此项目开发的一个基于网络的数据库便利了多站点数据收集。 我们发现FECD在我们的家庭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。 中央角膜厚度，调整混杂因素，包括年龄，性别，眼压和以前的眼科手术，也是高度遗传。 对有限数量的家庭进行的先前确定的FECD候选基因的初步关联研究表明，解释所观察到的遗传力的主要遗传决定因素是新颖的。 我们正准备对该家庭样本进行全基因组连锁扫描，该样本包括322个家庭，其中至少有572对兄弟姐妹，包括333对受影响的兄弟姐妹。 无模型连锁分析，使用SIBPAL程序在S.A.G.E.，将根据DNA样本的遗传标记数据以及FECD的临床数据进行。 此外，我们将进行全基因组关联分析，包括约500例无关病例（包括家族先证者）和500例对照。 我们即将完成不相关病例和对照的招募阶段。 我们预计这项研究第一个FECD研究包括大量患有严重疾病的家庭和无关个体将导致对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.