Genetic Epidemiology of 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，其公共卫生和经济影响相当大。美国人治疗屈光不正的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。目前对屈光不正的治疗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；青光眼的发病率在低近视的眼睛中为4.2%，在中度至高度近视的眼睛中为4.4%，而在非近视的眼睛中为1.5%。远视患者患高眼压的可能性比远视患者高40%。屈光不正患者视网膜脱离增加；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。目前的治疗不能预防屈光不正引起的眼部并发症，因为它们的目标不是阻止屈光不正的进展。以前尝试用光学和药物方法控制屈光不正的进展，但收效甚微。有广泛的证据表明远视和近视有显著的遗传因素。如果一个人能识别与这些疾病相关的基因，他就能识别未知的疾病机制，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，并在疾病过程的早期治疗人们以防止继发性并发症。生物医学研究目前面临的主要挑战之一是发现显示复杂遗传模式的遗传性疾病背后的特定疾病机制。这包括复杂的眼病，如屈光不正。一个有吸引力的假设是，序列变异在屈光不正中起重要作用，类似于其他复杂疾病。遗传技术和生物信息学的进步使人们能够进行实验，检查大量个体中的数十万种遗传变异，并确定它们在影响疾病方面的位置和重要性。我们和其他人进行了实验，利用微卫星标记和单核苷酸多态性进行精细定位，以确定家庭屈光不正的遗传位点。在本提案中，我们将扩展我们以前的工作，以促进发现其他基因参与屈光不正。这项工作将利用已经获得的数千名特征明确的患者的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修饰作用的序列元素类别。

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.