The Genetic Architecture of Diabetic Retinopathy

糖尿病视网膜病变的遗传结构

• 批准号: 10605816
• 负责人: Joseph H Breeyear
• 金额: $ 3.29万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10605816
• 关键词: Address; Adult; Blindness; Blood-Retinal Barrier; Chronic Disease; Clinical Management; Cohort Studies; Complications of Diabetes Mellitus; Data; Development; Diabetes Mellitus; Diabetic Retinopathy; Diagnosis; Disease; Dyslipidemias; Electronic Medical Records and Genomics Network; Environment; Etiology; Eye; Gene Expression; Genes; Genetic; Genome; Genotype; Heart; Homeostasis; Hypertension; Individual; Insulin; Insulin Resistance; Kidney; Knowledge; Linkage Disequilibrium; Literature; Logistic Regressions; Meta-Analysis; Methods; Microvascular Dysfunction; Modeling; Monitor; National Eye Institute; Organ; Outcome; Participant; Patients; Performance; Phenotype; Predisposition; Prevalence; Public Health; Regression Analysis; Reporting; Resources; Retina; Risk; Risk Factors; Sample Size; Severities; Structure; System; Testing; Tissues; Training; Type 2 diabetic; Veterans; Work; clinical decision-making; clinical risk; diabetic; genetic architecture; genetic risk factor; genetic variant; genome wide association study; glucose metabolism; glycemic control; high body mass index; high risk; improved; multi-ethnic; neovascularization; polygenic risk score; predictive modeling; prevent; programs; racial population; screening; statistics; trait; transcriptome

The Genetic Architecture of Diabetic Retinopathy Project Summary/Abstract Diabetic retinopathy (DR) is the leading cause of vision loss and preventable blindness in adults, afflicting an estimated 93 million individuals worldwide. As the global prevalence of diabetes mellitus (DM) rises, the global prevalence of diabetic retinopathy will also rise. The eye is highly susceptible to damage from DM due to the delicate structures and intricate control of homeostasis in the ocular environment. DR has long been recognized as a microvascular disease triggered by the breakdown of the blood-retinal barrier and neovascularization in the retina. The course of diabetic disease and severity of sequelae vary substantially between cases, and the cause for this variability is not explained well by known risk factors. Several genome- wide association studies (GWAS) of DR have been completed, and while a modest number of significant loci have been reported only a single locus has been significantly associated with DR after a replication. These studies were conducted in collaborative consortia of cohort studies and the largest study to date included 22,279 cases and 23,977 diabetic controls. We will leverage the previous studies in combination with resources from the Million Veteran Program (MVP), BioVU, and the eMERGE Network (an estimated 77,518 cases, 133,295 type II diabetic controls) to test the hypothesis that common genetic variants are associated with DR in the largest multi-ethnic GWAS to date. AIM 1. We will combine evidence for association from logistic regression analysis of DR-SNP relationships across the resources described above using inverse variance-weighted fixed effects meta-analyses, both within and across racial groups. The majority of previous studies focused on detecting SNP-phenotype associations and did not evaluate regulatory genetic effects or polygenic and causal effects for DR. AIM 2. We will use the summary statistics from the meta-analysis and the Gene-Tissue Expression Project in an analysis using S-PrediXcan to evaluate associations between DR and genetically predicted gene expression. Additionally, we will identify genetically predicted gene effects that are not due to linkage disequilibrium contamination through the use of a colocalization analysis. Colocalization methods are under constant development, and we will monitor the literature for best practices. AIM 3. We will develop a genome-informed predictive model, combining a diabetic retinopathy polygenic risk score (PRS), DR PheWAS results, and current clinical risk factors for DR. We will develop a DR PRS utilizing the summary statistics of the MVP GWAS and Pollack et al., followed by training in BioVU. A PheWAS analysis incorporating the DR PRS can elucidate previously unknown association between DR associated loci and other disease traits. We will combine the PRS, PheWAS results, and current clinical risk factors into the genome informed predictive model that will be validated in the eMERGE Network. The outlined study will significantly increase the sample size of previous studies of DR, evaluate regulatory effects on DR, and develop predictive models that may have utility in clinical decision making of DR patients.

糖尿病性视网膜病的遗传结构 项目摘要/摘要 糖尿病性视网膜病（DR）是成年人视力丧失和可预防失明的主要原因，折磨于 估计全球有9300万个人。随着糖尿病的全球流行率（DM）的上升，全球 糖尿病性视网膜病的患病率也会升高。眼睛非常容易受到DM损害的影响 在眼部环境中，精致的结构和对体内平衡的复杂控制。 DR长期以来一直是 被公认为是由血液 - 视视屏障的崩溃和 视网膜中的新血管化。后遗症的糖尿病疾病和严重程度的进程差异很大 在案例之间以及这种可变性的原因没有通过已知的危险因素来很好地解释。几个基因组 - DR的广泛关联研究（GWAS）已经完成，而大量的重要基因座 据报道，复制后仅一个基因座与DR显着相关。这些 研究是在队列研究的协作联盟中进行的，迄今为止最大的研究包括 22,279例和23,977例糖尿病控制。我们将利用先前的研究与 来自百万退伍军人计划（MVP），BIOVU和Emerge Network的资源（估计77,518 病例，133,295型II型糖尿病控制），以检验常见遗传变异的假设 迄今为止，DR是最大的多种族GWA。目标1。我们将结合证据的证据 logistic回归分析DR-SNP关系在上述资源上使用逆向 跨种族群体内部和跨种族群体的方差加权固定效应荟萃分析。以前的大多数 研究重点是检测SNP - 表型关联，并且没有评估调节性遗传效应或 DR的多基因和因果关系。 AIM 2。我们将使用荟萃分析的摘要统计数据和 Gene-Tissue表达项目在分析中使用S-Predixcan评估DR与 遗传预测的基因表达。此外，我们将确定遗传预测的基因效应 并非由于使用共定位分析而进行连锁不平衡污染。共定位 方法正在不断发展，我们将监视文献以进行最佳实践。目标3。我们将 建立一个基因组信息的预测模型，结合了糖尿病性视网膜病多基因风险评分（PRS），DR PHEWAS的结果以及DR的当前临床风险因素。我们将利用摘要开发PRS博士 MVP GWAS和Pollack等人的统计数据，然后在Biovu进行培训。 PHEWAS分析合并 PRS博士可以阐明博士相关基因座与其他疾病之间以前未知的关联 特质。我们将将PRS，Phewas结果和当前的临床风险因素结合在一起。 预测模型将在Emerge网络中进行验证。概述的研究将大大增加 先前DR研究的样本量，评估对DR的调节作用，并开发预测模型 这可能在DR患者的临床决策中有用。