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

绘制 Fuch 营养不良基因图谱的多中心研究

• 批准号: 7723442
• 负责人: SUDHA K IYENGAR
• 金额: $ 0.91万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7723442
• 关键词: Affect; 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; DNA Markers; Data; Data Collection; Databases; Descemet' s membrane; Disease; Edema; Epithelial; Esthesia; Etiology; Family; Family Study; Family history of; Foreign Bodies; Funding; Gap Junctions; Genes; Genetic; Grant; Individual; Institution; Investigation; Keratoplasty; Lead; Measures; Methods; Microscopic; Modeling; Molecular; Molecular Genetics; Mutation; Nexus (resin cement); Numbers; Online Systems; Pain; Population; Populations at Risk; Research; Research Personnel; Resources; Risk; Role; Sampling; Severities; Signal Transduction; Site; Source; Staging; Standards of Weights and Measures; Swelling; Therapeutic Intervention; United States National Institutes of Health; Vision; base; case control; genetic analysis; genetic linkage analysis; genome wide association study; indexing; insight; instrument; novel; proband; 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 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 the Descemet's membrane known as corneal guttae, with subsequent stromal edema (swelling), epithelial edema and, in advanced stages, painful bullous keratopathy. FECD is a common indication for corneal transplantation alone or in combination with cataract surgery. 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 propose to use the network built by the active, multi-center NEI-funded Cornea Donor Study (CDS) as the nexus to identify 500 families with FECD using the consortium model. We will identify cases with advanced FECD and characterize the extent of familial clustering using a clinical measure of severity as a semi-quantitative trait. Family history, clinical, and other demographic information will be collected using a standardized instrument. Histopathologic confirmation of advanced index cases will be obtained. Blood samples will be collected for molecular genetic analyses. A web-based database is being constructed to facilitate multi-site data collection. A genome-wide scan will be conducted utilizing DNA collected from the index cases and families (N = 500 families; estimated N = 500 sib pairs). A secondary case-control analysis will be performed utilizing the probands from the family study and matched controls (N=500 cases; N = 500 controls).Model-free linkage analysis will be conducted using the DNA marker data in conjunction with the clinical data on FECD to identify linkage signals. Candidate genes identified through previous investigations of a limited number of families (e.g. COL8A2) will be examined for mutations. 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.

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（肿胀）、上皮水肿，晚期出现疼痛性大疱性角膜病。 FECD 是单独角膜移植或与白内障手术联合的常见适应症。 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对于咨询、实施治疗干预标准方法以及最终的基因调节和/或治疗非常有用。在本研究中，我们建议使用由 NEI 资助的活跃的多中心角膜捐赠者研究 (CDS) 建立的网络作为纽带，使用联盟模型识别 500 个患有 FECD 的家庭。我们将识别患有晚期 FECD 的病例，并使用严重程度的临床测量作为半定量特征来描述家族聚集的程度。 将使用标准化仪器收集家族史、临床和其他人口统计信息。 将获得晚期指标病例的组织病理学确认。 将收集血液样本进行分子遗传分析。 正在构建一个基于网络的数据库，以促进多站点数据收集。将利用从指示病例和家庭（N = 500 个家庭；估计 N = 500 个同胞对）收集的 DNA 进行全基因组扫描。 将利用来自家族研究的先证者和匹配对照（N = 500 例；N = 500 对照）进行二次病例对照分析。将使用 DNA 标记数据结合 FECD 的临床数据进行无模型连锁分析，以识别连锁信号。 将检查通过先前对有限数量的家族的调查而确定的候选基因（例如 COL8A2）是否存在突变。 因此，我们将通过表征它们在更大样本中的作用，在更全球的基础上研究这些基因的重要性。 我们预计这项研究将对 FECD 的病因学和角膜内皮生物学产生新的见解。