A MULTI-CENTER STUDY TO MAP GENES FOR FUCHS DYSTROPHY

绘制福克斯营养不良基因图谱的多中心研究

• 批准号: 8171716
• 负责人: SUDHA K IYENGAR
• 金额: $ 0.99万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8171716
• 关键词: Affect; Age; Biology; Blood specimen; Bullous Keratopathy; Candidate Disease Gene; Cataract Extraction; Chromosome Mapping; Clinical; Clinical Data; Computer Retrieval of Information on Scientific Projects Database; Cornea; Corneal Endothelium; Corneal dystrophy; Counseling; DNA; Data; Data Collection; Databases; Descemet' s membrane; Disease; Edema; Epithelium; Esthesia; Etiology; Eye diseases; Family; Family history of; Foreign Bodies; Fuchs' Endothelial Dystrophy; Funding; Gap Junctions; Genes; Genetic; Genetic Determinism; Genetic Markers; Grant; Heritability; Individual; Inherited; Institution; Keratoplasty; Lead; Methods; Microscopic; Modeling; Molecular; Molecular Genetics; Online Systems; Ophthalmologic Surgical Procedures; Pain; Phase; Population; Populations at Risk; Research; Research Personnel; Resources; Risk; Running; Sampling; Scanning; Severities; Siblings; Site; Source; Staging; Therapeutic Intervention; Thick; United States National Institutes of Health; Vision; base; case control; genetic analysis; genetic linkage analysis; genome-wide; genome-wide linkage; indexing; insight; instrument; novel; pressure; proband; programs; sex; trait

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.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目和 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 福克斯内皮性角膜营养不良（FECD：MIM136800）是一种常见的眼部疾病，影响约 1% 的美国普通人口。 最初无症状，患者最终会在醒来时出现视力下降、异物感和疼痛。 裂隙灯（显微镜）检查最初显示后弹力层（称为角膜内胶）局部增厚，随后出现基质水肿、上皮水肿，晚期出现疼痛性大疱性角膜病。 FECD 是美国最常见的导致角膜移植的遗传性疾病。 此外，接受 FECD 白内障手术的个体存在角膜失代偿的显着风险，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。 由于大量人群处于危险之中，识别可能导致营养不良的基因将为咨询、治疗干预标准方法的实施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，我们使用由 NEI 资助的活跃的多中心角膜捐赠者研究建立的网络作为纽带，使用联盟模型来识别 FECD 家庭以及不相关的 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。 使用标准化仪器收集家族史、临床和其他人口统计信息。 已获得严重受影响的指标病例的组织病理学证实。 正在收集血液样本用于分子遗传分析。 专门为此项目开发的基于网络的数据库有助于多站点数据收集。 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严重程度评分。 根据年龄、性别、眼压和既往眼科手术等混杂因素进行调整后，中央角膜厚度也具有高度遗传性。 对先前确定的 FECD 候选基因进行的初步关联研究（在有限数量的家系中进行）表明，解释观察到的遗传力的主要遗传决定因素是新颖的。 我们正准备对家庭样本进行全基因组连锁扫描，该样本包括 322 个家庭，包含至少 572 对兄弟姐妹，其中包括 333 对受影响的兄弟姐妹。 将使用 S.A.G.E. 中的 SIBPAL 程序，对源自 DNA 样本的遗传标记数据以及 FECD 的临床数据进行无模型连锁分析。 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（包括家庭先证者）和 500 个对照。 我们即将完成无关病例和对照的招募阶段。 我们预计，这项研究是第一个纳入大量患有严重疾病的家庭和无关个体的 FECD 研究，将为 FECD 的病因学和角膜内皮生物学提供新的见解。