Genetic Epidemiology of Refractive Error

屈光不正的遗传流行病学

基本信息

批准号：
7865949
负责人：
Dwight Edward Stambolian
金额：
$ 40万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-08-01 至 2015-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7865949
关键词：
Achievement Alleles Anatomy Animal Model Bioinformatics Biological Biology Biomedical Research Canada Categories Caucasians Caucasoid Race Choroidal Neovascularization Chromosomes, Human, Pair 22 Complex Complication DNA Data Diabetic Retinopathy Disease Elements Environment Environmental Risk Factor Epidemiologic Studies Europe Eye Eye diseases Family Follow-Up Studies Frequencies Gender Genes Genetic Genetic Determinism Genome Genotype Glaucoma Health system Human Human Identifications Hyperopia Individual Inherited Lead Location Macular degeneration Maps Meta-Analysis Microsatellite Repeats Modeling Myopia Ocular Hypertension Optics Pathway interactions Patients Pharmaceutical Preparations Play Population Prevalence Process Public Health Refractive Errors Regulatory Pathway Research Research Personnel Resources Retinal Detachment Risk Role Sampling Scanning Secondary to Signal Transduction Single Nucleotide Polymorphism Staging Testing Variant Vision Work age effect cohort cost economic impact gene interaction genetic epidemiology genetic technology genetic variant genome wide association study genome-wide health economics high risk insight instrument meetings new therapeutic target next generation novel prevent public health relevance research study success trait

项目摘要

DESCRIPTION (provided by applicant): Refractive error is the most common eye disorder in the world, and its public health and economic impact are considerable. Treatment of the U.S population for refractive error costs twice as much as glaucoma and 10x the amount for AMD or diabetic retinopathy and is a major burden to the U.S. public health system. Current treatments for refractive error are not directed at the secondary complications. Such complications include choroidal neovascularization, retinal detachment and glaucoma. Glaucoma is a complication of myopia; prevalence of glaucoma is 4.2% in eyes with low myopia and 4.4% of eyes with moderate to high myopia compared to 1.5% of eyes without myopia. Individuals with hyperopia are 40% more likely to develop ocular hypertension than those who are emmetropic. Retinal detachment is increased in eyes with refractive error; risk of retinal detachment is increased 4-10 fold in myopic eyes. Finally, the risk for choroidal neovascularization is increased from 2-fold for mild myopia to 9-fold for severe myopia. Current treatments do not prevent the ocular complications secondary to refractive error because they are not targeted at stopping progression of refractive error. Previous attempts to control progression of refractive error with optical and drug approaches have met with limited success. There is extensive evidence for significant heritable components for hyperopia and myopia. If one can identify the genes involved in these disorders, one can identify unsuspected disease mechanisms, develop animal models of these mechanisms and use these models to develop and test new treatments, identify interactions of these genes with modifiable environmental risk factors, and treat people very early in the course of the disease to prevent secondary complications. One of the major challenges now facing biomedical research is the discovery of specific disease mechanisms that underlie heritable disorders that display a complex mode of inheritance. This includes complex eye diseases such as refractive error. An appealing hypothesis is that sequence variations play an important role in refractive error similar to other complex diseases. Advances in genetic technology and bioinformatics have made it possible to perform experiments that examine hundreds of thousands of genetic variants in large numbers of individuals and to determine their location and significance in influencing disease. We and others have conducted experiments to identify genetic loci for refractive error in families using microsatellite markers followed by single nucleotide polymorphisms for fine mapping. In this proposal, we will extend our previous work to facilitate the discovery of additional genes involved in refractive error. This work will take advantage of already acquired DNA samples from thousands of well-characterized patients. Our work has the potential of discovering novel sequences and genes that interact with environmental risk factors, as well as categories of sequence elements that play a primary or modifying role in refractive error. PUBLIC HEALTH RELEVANCE (provided by applicant): Project Narrative We hypothesize that naturally occurring sequence variations can be used to develop an understanding of the anatomy of regulatory pathways that will prove important in developing new therapeutic targets to prevent the progression of refractive errors and lead to a decrease in secondary complications. The achievement of the aims of this project will lead to the identification of human sequence variation that regulate genes that contribute to refractive error.

描述（由申请人提供）：屈光不正是世界上最常见的眼部疾病，其对公共健康和经济的影响相当大。美国人口屈光不正的治疗费用是青光眼的两倍，是 AMD 或糖尿病视网膜病变的 10 倍，是美国公共卫生系统的主要负担。目前屈光不正的治疗方法并不针对继发性并发症。这些并发症包括脉络膜新生血管、视网膜脱离和青光眼。青光眼是近视的并发症；低度近视眼的青光眼患病率为 4.2%，中度至高度近视眼的青光眼患病率为 4.4%，而无近视眼的青光眼患病率为 1.5%。远视眼患者患高眼压症的可能性比正视眼患者高 40%。患有屈光不正的眼睛，视网膜脱离会增加；近视眼视网膜脱离的风险增加4-10倍。最后，脉络膜新生血管形成的风险从轻度近视的 2 倍增加到重度近视的 9 倍。目前的治疗方法不能预防屈光不正继发的眼部并发症，因为它们的目标不是阻止屈光不正的进展。之前通过光学和药物方法控制屈光不正进展的尝试取得了有限的成功。有大量证据表明远视和近视具有显着的遗传因素。如果人们能够识别出与这些疾病有关的基因，就可以识别出未被怀疑的疾病机制，开发这些机制的动物模型，并使用这些模型来开发和测试新的治疗方法，识别这些基因与可改变的环境风险因素的相互作用，并以非常好的方式治疗人们。在病程早期预防继发并发症。生物医学研究目前面临的主要挑战之一是发现表现出复杂遗传模式的遗传性疾病背后的特定疾病机制。这包括复杂的眼部疾病，例如屈光不正。一个有吸引力的假设是，与其他复杂疾病类似，序列变异在屈光不正中发挥着重要作用。遗传技术和生物信息学的进步使得进行实验来检查大量个体中的数十万个遗传变异并确定它们在影响疾病中的位置和重要性成为可能。我们和其他人进行了实验，使用微卫星标记和单核苷酸多态性进行精细定位来识别家庭中屈光不正的遗传位点。在这项提案中，我们将扩展我们之前的工作，以促进发现与屈光不正有关的其他基因。这项工作将利用已经从数千名特征明确的患者身上获取的 DNA 样本。我们的工作有可能发现与环境风险因素相互作用的新序列和基因，以及在屈光不正中起主要或改变作用的序列元素类别。公共卫生相关性（由申请人提供）：项目叙述我们假设自然发生的序列变异可用于加深对调节途径解剖学的理解，这对于开发新的治疗靶点以防止屈光不正的进展并导致继发性并发症减少。该项目目标的实现将导致识别调节导致屈光不正的基因的人类序列变异。